Dr. Daniel Hanley, co-principal investigator for the MISTIE clinical trial, was a featured speaker this week at the 2013 International Stroke conference (ISC) in Honolulu as he presented 365-day results from this phase-II clinical trial. MISTIE is an acronym for Minimally Invasive Surgery + rt-PA for Intracerebral Hemorrhage (ICH) Evacuation. ICH is a type of stroke caused by bleeding within the brain, often the result of uncontrolled hypertension. It is also referred to as cerebral stroke or hemorrhagic stroke.
This recently-completed proof-of-concept trial evaluated the use of tPA (a thrombolytic or clot-busting drug) delivered via a catheter placed under CT (a series of x-ray images) guidance. Data from the 123 patients enrolled across 26 medical centers provides ground-breaking evidence, which now needs to be verified in a larger phase-III trial, that this technique offers future promise for reducing the high rate of death and serious disability in ICH patients. Preliminary results were presented at last year's conference. Now that study participants have reached the one-year mark, the final results are even more encouraging. A summary of these results have been published on the American Stroke Society's ISC website -- scroll to the bottom to see Dr. Hanley's late-breaking presentation materials.
Additionally, in an interview conducted by the American Stroke Association, Dr. Hanley reviews these results and describes, in simple terms, why the MISTIE-II results are so startling to the medical community. To summarize, current practice standards call for placing ICH patients in intensive care units to manage blood pressure and stroke complications while the blood slowly dissipates over a period of weeks to months. (This is called "medical management" in this study and is used as the non-treated control group for the statistical comparison of outcomes.) In severe cases, craniotomy (cutting into the brain to remove the blood clot) is used as a last resort. Despite best efforts, most ICH patients who survive are left with permanent mental and/or physical disability, often requiring expensive long-term institutional care.
Alternatively, the MISTIE minimally-invasive surgical procedure (the "surgical" or "treated" patients in the study) involves inserting a small catheter into the brain using stereotactic CT guidance (akin to using GPS to map a route) and then dissolving the clot using small doses of tPA over a 1 to 3 day period.
Putting a clot-busting drug into the site of recent bleeding seems counter-intuitive, and early attempts by medical researchers did have a high rate of complications. During this seven-year multistage effort, the MISTIE researchers found a way to use lower doses and to optimize placement of the drug-delivery catheter precisely within the clot using stereotactic neuronavigation, a relatively inexpensive (compared to craniotomy), minimally-invasive technique pioneered in brain cancer that is now readily available at stroke care facilities.
The investigators (neurologists and neurosurgeons) in the trial were able to learn the catheter placement technique quickly. Unlike ischemic stroke where the patient must be emergently treated within the first few hours, with the MISTIE approach in hemorrhagic stroke, investigators have plenty of time to stabilize the patient and schedule the surgery (lasting only about 45-minutes after inducing anesthesia). In comparison to ischemic stroke, a greater percentage of patients are thereby eligible for treatment. Given this minimal learning curve, readily available equipment and permissive time window, the MISTIE approach is highly generalizable, meaning it could be easily adopted and widely used throughout the world.
Due to the fairly small number of patients and the exploratory design of this phase-II trial, a second, larger study of 500 patients across 75 to 100 hospitals is now needed to confirm the early results. Such a trial is planned to start later this year and is expected to take 5 years to complete. There is still much to do and more to learn, but the hope is that within a few years there may finally be a proven beneficial treatment for ICH. Meanwhile, MISTIE remains an investigational approach and should be used only within the context of an established clinical trial under the guidance of participating clinical trial investigators.
The MISTIE-II trial was funded by the National Institute of Neurological Disorders and Stroke (NINDS, part of NIH), with supplies donated by Genentech and Codman. The Brain Injury Outcomes clinical trial center (BIOS) at Johns Hopkins University served as the clinical coordinating center, led by Dr. Daniel Hanley. The surgical coordinating center was at the University of Cincinnati led by co-principal investigator Dr. Mario Zuccarello. Biostatistical support was provided by Johns Hopkins University. Independent monitoring and quality assurance services were provided by Emissary International. The eClinical trial software was provided by Prelude Dynamics. Over 26 sites participated across North America and Europe. The highest-enrolling sites were University of Cincinnati, Virginia Commonwealth University, NorthShore University, University of Maryland, Stanford University, and the University of Texas. Hundreds of researchers and study patients made significant contributions to advance the research of the MISTIE approach and we express our gratitude to each of them.