Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE)

a randomised, controlled, open-label, phase 2 trial

Daniel F Hanley, Richard Thompson, John Muschelli, Michael Aaron Rosenblum, Nichol McBee, Karen Lane, Amanda J. Bistran-Hall, Steven Mayo, Penelope Keyl, Dheeraj Gandhi, Tim C. Morgan, Natalie Ullman, W. Andrew Mould, Juan Carhuapoma, Carlos Kase, Wendy C Ziai, Carol Thompson, Gayane Yenokyan, Emily Huang, William C. Broaddus & 14 others R. Scott Graham, E. Francois Aldrich, Robert Dodd, Cristanne Wijman, Jean Louis Caron, Judy Huang, Paul Camarata, A. David Mendelow, Barbara Gregson, Scott Janis, Paul Vespa, Neil Martin, Issam Awad, Mario Zuccarello

Research output: Contribution to journalArticle

Abstract

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 clot 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 ClinicalTrials.gov, 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. Funding National Institute of Neurological Disorders and Stroke, Genentech, and Codman.

Original languageEnglish (US)
Pages (from-to)1228-1237
Number of pages10
JournalThe Lancet Neurology
Volume15
Issue number12
DOIs
StatePublished - Nov 1 2016

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Minimally Invasive Surgical Procedures
Cerebral Hemorrhage
Tissue Plasminogen Activator
Safety
Hemorrhage
Mortality
National Institute of Neurological Disorders and Stroke
Craniotomy
Brain
Bacterial Infections
Canada
Germany
Catheters
Infection

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE) : a randomised, controlled, open-label, phase 2 trial. / Hanley, Daniel F; Thompson, Richard; Muschelli, John; Rosenblum, Michael Aaron; McBee, Nichol; Lane, Karen; Bistran-Hall, Amanda J.; Mayo, Steven; Keyl, Penelope; Gandhi, Dheeraj; Morgan, Tim C.; Ullman, Natalie; Mould, W. Andrew; Carhuapoma, Juan; Kase, Carlos; Ziai, Wendy C; Thompson, Carol; Yenokyan, Gayane; Huang, Emily; Broaddus, William C.; Graham, R. Scott; Aldrich, E. Francois; Dodd, Robert; Wijman, Cristanne; Caron, Jean Louis; Huang, Judy; Camarata, Paul; Mendelow, A. David; Gregson, Barbara; Janis, Scott; Vespa, Paul; Martin, Neil; Awad, Issam; Zuccarello, Mario.

In: The Lancet Neurology, Vol. 15, No. 12, 01.11.2016, p. 1228-1237.

Research output: Contribution to journalArticle

Hanley, DF, Thompson, R, Muschelli, J, Rosenblum, MA, McBee, N, Lane, K, Bistran-Hall, AJ, Mayo, S, Keyl, P, Gandhi, D, Morgan, TC, Ullman, N, Mould, WA, Carhuapoma, J, Kase, C, Ziai, WC, Thompson, C, 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 2016, 'Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial', The Lancet Neurology, vol. 15, no. 12, pp. 1228-1237. https://doi.org/10.1016/S1474-4422(16)30234-4
Hanley, Daniel F ; Thompson, Richard ; Muschelli, John ; Rosenblum, Michael Aaron ; McBee, Nichol ; Lane, Karen ; Bistran-Hall, Amanda J. ; Mayo, Steven ; Keyl, Penelope ; Gandhi, Dheeraj ; Morgan, Tim C. ; Ullman, Natalie ; Mould, W. Andrew ; Carhuapoma, Juan ; Kase, Carlos ; Ziai, Wendy C ; Thompson, Carol ; Yenokyan, Gayane ; Huang, Emily ; Broaddus, William C. ; Graham, R. Scott ; Aldrich, E. Francois ; Dodd, Robert ; Wijman, Cristanne ; Caron, Jean Louis ; Huang, Judy ; Camarata, Paul ; Mendelow, A. David ; Gregson, Barbara ; Janis, Scott ; Vespa, Paul ; Martin, Neil ; Awad, Issam ; Zuccarello, Mario. / Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE) : a randomised, controlled, open-label, phase 2 trial. In: The Lancet Neurology. 2016 ; Vol. 15, No. 12. pp. 1228-1237.
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abstract = "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 clot 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 ClinicalTrials.gov, 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. Funding National Institute of Neurological Disorders and Stroke, Genentech, and Codman.",
author = "Hanley, {Daniel F} and Richard Thompson and John Muschelli and Rosenblum, {Michael Aaron} and Nichol McBee and Karen Lane and Bistran-Hall, {Amanda J.} and Steven Mayo and Penelope Keyl and Dheeraj Gandhi and Morgan, {Tim C.} and Natalie Ullman and Mould, {W. Andrew} and Juan Carhuapoma and Carlos Kase and Ziai, {Wendy C} and Carol Thompson and Gayane Yenokyan and Emily Huang and Broaddus, {William C.} and Graham, {R. Scott} and Aldrich, {E. Francois} and Robert Dodd and Cristanne Wijman and Caron, {Jean Louis} and Judy Huang and Paul Camarata and Mendelow, {A. David} and Barbara Gregson and Scott Janis and Paul Vespa and Neil Martin and Issam Awad and Mario Zuccarello",
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T1 - Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE)

T2 - a randomised, controlled, open-label, phase 2 trial

AU - Hanley, Daniel F

AU - Thompson, Richard

AU - Muschelli, John

AU - Rosenblum, Michael Aaron

AU - McBee, Nichol

AU - Lane, Karen

AU - Bistran-Hall, Amanda J.

AU - Mayo, Steven

AU - Keyl, Penelope

AU - Gandhi, Dheeraj

AU - Morgan, Tim C.

AU - Ullman, Natalie

AU - Mould, W. Andrew

AU - Carhuapoma, Juan

AU - Kase, Carlos

AU - Ziai, Wendy C

AU - Thompson, Carol

AU - Yenokyan, Gayane

AU - Huang, Emily

AU - Broaddus, William C.

AU - Graham, R. Scott

AU - Aldrich, E. Francois

AU - Dodd, Robert

AU - Wijman, Cristanne

AU - Caron, Jean Louis

AU - Huang, Judy

AU - Camarata, Paul

AU - Mendelow, A. David

AU - Gregson, Barbara

AU - Janis, Scott

AU - Vespa, Paul

AU - Martin, Neil

AU - Awad, Issam

AU - Zuccarello, Mario

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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 clot 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 ClinicalTrials.gov, 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. Funding National Institute of Neurological Disorders and Stroke, Genentech, and Codman.

AB - 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 clot 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 ClinicalTrials.gov, 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. Funding National Institute of Neurological Disorders and Stroke, Genentech, and Codman.

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