title: Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  National Institute of Neurological Disorders and Stroke, Genentech, and Codman.
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA. Electronic address: dhanley@jhmi.edu.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hanley
authors.affiliation: Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Thompson
authors.affiliation: Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Muschelli
authors.affiliation: Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosenblum
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Nichol
authors.initials: N
authors.lastname: McBee
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Lane
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bistran-Hall
authors.affiliation: Emissary International, Austin, TX, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Mayo
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Penelope
authors.initials: P
authors.lastname: Keyl
authors.affiliation: Department of Neuroradiology, University of Maryland, Baltimore, MD, USA.
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Gandhi
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Tim C
authors.initials: TC
authors.lastname: Morgan
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Ullman
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: W Andrew
authors.initials: WA
authors.lastname: Mould
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: J Ricardo
authors.initials: JR
authors.lastname: Carhuapoma
authors.affiliation: Department of Neurology, Boston University, Boston, MA, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Kase
authors.affiliation: Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Ziai
authors.affiliation: Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Carol B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gayane
authors.initials: G
authors.lastname: Yenokyan
authors.affiliation: Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Huang
authors.affiliation: Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Broaddus
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Graham
authors.affiliation: Department of Neurosurgery, University of Maryland, Baltimore, MD, USA.
authors.forename: E Francois
authors.initials: EF
authors.lastname: Aldrich
authors.affiliation: Department of Neurosurgery, Stanford University, Palo Alto, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Dodd
authors.affiliation: Department of Neurology, Stanford University, Palo Alto, CA, USA.
authors.forename: Cristanne
authors.initials: C
authors.lastname: Wijman
authors.affiliation: Department of Neurosurgery, University of Texas, San Antonio, TX, USA.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Caron
authors.affiliation: Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, University of Kansas, Kansas City, KS, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Camarata
authors.affiliation: Neurosurgery, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A David
authors.initials: AD
authors.lastname: Mendelow
authors.affiliation: Neurosurgery, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gregson
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Janis
authors.affiliation: Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Vespa
authors.affiliation: Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Martin
authors.affiliation: Department of Neurosurgery, University of Chicago, Chicago, IL, USA.
authors.forename: Issam
authors.initials: I
authors.lastname: Awad
authors.affiliation: Department of Neurosurgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Zuccarello
mesh_terms: D000368:Aged; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D003131:Combined Modality Therapy; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D017063:Outcome Assessment, Health Care; D019106:Postoperative Hemorrhage / Q000209:etiology*; D025321:Surgery, Computer-Assisted; D017131:Thrombectomy / Q000009:adverse effects / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator