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

• Published in: The Lancet (British edition) 2019-03, Vol.393 (10175), p.1021-1032
• Main Authors: Thompson, Richard E, Lane, Karen, Mayo, Steven W, Bistran-Hall, Amanda J, Ullman, Natalie, Dawson, Jesse, Betz, Joshua F, Sugar, Elizabeth A, Hao, Yi, Caron, Jean-Louis, Harrigan, Mark R, Bulters, Diederik, Chicoine, Michael R, Patel, Hiren, Dodd, Robert, Wolfe, Stacey, Money, P Lynn, Mitchell, Patrick, Sarabia, Rosario, Zuccarello, Mario, Abdul-Rahim, Azmil, Ahmed, Azam, Altschul, David, Amin-Hanjani, Sepideh, Barrer, Steven J., Becker, Kyra J., Bergman, Thomas, Braun, Jamie, Brindley, Peter, Broaddus, William C., Cao, Ying, Chalela, Julio, Chang, Tiffany, Chorro, Indalecio Moran, Csiba, Laszlo, Diringer, Michael, Dlugash, Rachel, Economas, Tracey, Enriquez, Pedro, Ezer, Erzsebet, Feng, Hua, Franz, Douglas, Galicich, Walter, Gonzalez, Alejandro Carrasco, Grabarits, Christina, Greenberg, Steven, Gress, Daryl, Hall, Christiana, Hoesch, Robert, Hoh, Brian L., Houser, Jennifer, Hu, Rong, Hussain, Mohammed Akbar, James, Robert F., Jeon, Esther, Karlen, Nicki, Keric, Naureen, Kerz, Thomas, Knopman, Jared, Krishnamurthy, Satish, Kumar, Avinash, MacDonald, Joel, Major, Otto, Malhorta, Rishi, McCaul, Scott, Mohan, Krishna K., Muir, Keith, Muñoz, Lorenzo, Nakaji, Peter, Nee, Alex, Nekoovaght-Tak, Saman, O'Kane, Roddy, Okasha, Mohamed, O'Kelly, Cian, Ostapkovich, Noeleen, Pandey, Aditya, Quinn, Terry, Rajajee, Ventatakrishna, Rehman, Mohammed, Reimer, Ronald, Rybinnik, Igor, Sansing, Lauren, Schneck, Michael, Schuerer, Ludwig, Seder, David B., Sheth, Kevin, Tamayo, Gonzalo, Tanczos, Krisztian, Taussky, Philipp, Thomas, Kathrine, Tran, Huy, Tucker, Kristi, Ungar, Lior, Varelas, Panos, Wang, Ying, Whitworth, Louis Tony, Willis, Byron, Wright, Shawn E., Yi, Xuxia, Zomorodi, Ali
• Format: Article
• Language: English
• Subjects: Aged; Bacterial diseases; Bleeding; Brain; Cerebral Hemorrhage - surgery; Clinical trials; Coma; Drug dosages; Effectiveness; Evacuation; Evidence-based medicine; Female; Health care; Hematoma; Hemorrhage; Humans; Intensive care; Intention to Treat Analysis; Laparoscopy; Male; Medical instruments; Middle Aged; Minimally Invasive Surgical Procedures - adverse effects; Minimally Invasive Surgical Procedures - methods; Morbidity; Mortality; Neurological diseases; Patients; Randomization; Regression analysis; Regression models; Safety; Sensitivity analysis; Stability analysis; Statistical analysis; Stroke; Surgery; Thrombolysis; Thrombolytic Therapy - adverse effects; Thrombolytic Therapy - methods; Treatment Outcome
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(19)30195-3

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. 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. 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