In stroke treatment, the saying “time is brain” has been a long-held belief stated as fact. But a new editorial in the March 2019 issue of Stroke questions that assumption. Rudiger von Kummer, Prof Dr Med, of University Hospital Carl Gustav Carus in Dresden, Germany, points out that the level of evidence for immediate treatment of stroke with IV alteplase is low. This, he asserts, is because there has not yet been a prospective study that evaluates how stroke-onset-to-treatment time (OTT) and clinical outcome after alteplase treatment interact. Other pathological conditions that may interact with both OTT and clinical outcomes have not been explored in randomized trials, and the results of the controlled randomized trials thus far are not clearly in support of the “time is brain” hypothesis.1
“It is time to question, which conditions affect the chances for favorable outcome while patients are waiting for treatment,” writes vom Kummer.1 The editorial was penned in response to a study in the same issue of Stroke reporting that faster treatment with IV alteplase is correlated with lower levels of disability at 3 months post-stroke in patients who had large vessel occlusion (LVO).2
This study aimed to improve understanding of alteplase treatment in patients with ischemic stroke due to LVO. The meta-analysis pooled the data from seven recent randomized controlled trials of patients with LVO who were treated with EVT and IV alteplase compared to alteplase alone, looking only at the control arm patients in the trials who were treated with IV alteplase alone. The authors analyzed interval times in the context of several prognostic clinical and imaging variables and correlated those times with outcomes that included functional recovery.2
They discovered that “slower initiation of alteplase therapy was associated with worse outcomes over the entire disability range and lower rates of excellent recovery and functional independence.” However, the rate at which the benefits of quicker treatment declined was modest. But patients with LVO showed a more dramatic decline in the benefit with time from hospital arrival, or door-to-needle time (DTN). The study authors conclude that since time is more critical to outcome for these patients, hospitals should set standards for their processes “much more aggressively than currently,” they write. 2
Von Kummer cites an ad-hoc analysis by the National Institute of Neurological Disorders and Stroke (NINDS) Study Group and several other studies and a meta-analysis which support that “ischemic stroke patients presenting early have more brain tissue to loose [sic] because of major artery occlusion than have late-presenting patients.” He states that patients who present late have “brain circulation pathology” that allows for greater spontaneous recovery. In trials that look at late-presenting patients, there is an “impressive” number of patients with good outcomes simply from placebo treatment, he says. But the specific condition or conditions that lead to good outcomes in these patients is not yet known. Von Kummer hypothesizes that less severe strokes may be associated with several conditions that facilitate better recovery of the brain, such as occlusion of more minor arteries or ischemia of less eloquent brain regions.1
Of the study, von Kummer notes that they were not able to determine whether the interaction between OTT and outcome was due to the failure of treatment with alteplase or other confounders. Major artery occlusion leads to a variable reduction in local cerebral blood flow and thus a variable level of neurological deficits. Drops in cranial perfusion pressure may impair the tolerance of tissue to reduced blood flow. The volume of brain tissue potentially affected by this reduced blood flow is much larger in proximal major artery occlusions compared to distal occlusions or small vessel disease. von Kummer argues that while “time is brain” is indeed fact for these LVO strokes, it may be more of fiction in strokes that occur in small distal arteries.1
1. Time is Brain: Fact or Fiction. Stroke. DOI: 10.1161/STROKEAHA.118.024214 Last accessed March 21, 2019.
2. Rapid Alteplase Administration Improves Functional Outcomes in Patients With Stroke due to Large Vessel Occlusions: Meta-Analysis of the Noninterventional Arm From the HERMES Collaboration. Stroke. DOI: 10.1161/STROKEAHA.118.021840 Last accessed March 21, 2019.