Hematoma Enlargement as a Target for Treating Intracerebral Hemorrhage: A More Granular View

The choice of outcome in therapeutic trials for any neurologic disease is crucial. The proper choice and calibration of that outcome should be based on a fundamental understanding of the expected biological effect of the treatment on the outcome being measured. Acute stroke treatment trials have been particularly challenging and informative in this regard. For instance, in the first positive stroke study, the National Institute of Neurological Disorders and Stroke tissue plasminogen activator (tPA) stroke study comparing tPA to placebo in patients with acute ischemic stroke,1 the primary analysis compared the proportion of patients achieving a modified Rankin Scale (mRS) score of 0 or 1 (near-complete or complete recovery back to baseline) vs 2 to 6 representing ascending levels of disability or death. This choice was made because half of the patients would be treated within 90 minutes of stroke onset, and preclinical and pilot clinical data suggested that removing the offending clot so soon after stroke onset might completely prevent infarction. Thus, measuring the proportion of patients who were “cured” (mRS score 0 or 1) was the biological sweet spot of treatment. On the other hand, another positive treatment, hemicraniectomy applied to patients herniating from massive infarction,2 could not be expected to “cure” patients but rather to salvage them from severe disability of death, so dichotomization of mRS score ≤3 vs 4 to 6 was the appropriate endpoint. A careful analysis of the outcomes of negative/neutral studies can also shed light on the possible biological effect of treatment and help determine the most sensitive outcome for a revised trial. Successful endovascular trials in delayed time windows used a dichotomization of mRS score of ≤2 vs 3 to 6 because earlier neutral studies showed that patients treated late had already suffered some irreversible ischemic brain damage and were often not completely cured.3 The study by Yogendrakumar et al.4 in this issue of Neurology® follows this line of thinking for patients with intracerebral hemorrhage (ICH) by analyzing outcomes from a neutral trial to understand the biology being targeted by the treatment.,5

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