Randomized controlled trials (RCT) are the basis for evidence-based acute stroke care. For an RCT to change practice, its results have to be statistically significant and clinically meaningful. While methods to assess statistical significance are standardized and widely agreed upon, there is no clear consensus on how to assess clinical significance. Researchers often refer to the minimal clinically important difference (MCID) when describing the smallest change in outcomes that is considered meaningful to patients and leads to a change in patient management. It is widely accepted that a treatment should only be adopted when its effect on outcome is equal to or larger than the MCID. There are however situations in which it is reasonable to decide against adopting a treatment, even when its beneficial effect matches or exceeds the MCID, for example when it is resource- intensive and associated with high costs. Furthermore, while the MCID represents an important concept in this regard, defining it for an individual trial is difficult as it is highly context specific. In the following, we use hypothetical stroke trial examples to review the challenges related to MCID, sample size and pragmatic considerations that researchers face in acute stroke trials, and propose a framework for designing meaningful stroke trials that have the potential to change clinical practice.

Background: and Purpose Infarcts in acute ischemic stroke (AIS) patients may continue to grow even after reperfusion, due to mechanisms such as microvascular obstruction and reperfusion injury. We investigated whether and how much infarcts grow in AIS patients after near-complete (expanded Thrombolysis in Cerebral Infarction [eTICI] 2c/3) reperfusion following endovascular treatment (EVT), and to assess the association of post-reperfusion infarct growth with clinical outcomes. Methods: Data are from a single-center retrospective observational cohort study that included AIS patients undergoing EVT with near-complete reperfusion who received diffusion-weighted magnetic resonance imaging (MRI) within 2 hours post-EVT and 24 hours after EVT. Association of infarct growth between 2 and 24 hours post-EVT and 24-hour National Institutes of Health Stroke Scale (NIHSS) as well as 90-day modified Rankin Scale score was assessed using multivariable logistic regression. Results: Ninety-four of 155 (60.6%) patients achieved eTICI 2c/3 and were included in the analysis. Eighty of these 94 (85.1%) patients showed infarct growth between 2 and 24 hours post-reperfusion. Infarct growth ≥5 mL was seen in 39/94 (41.5%) patients, and infarct growth ≥10 mL was seen in 20/94 (21.3%) patients. Median infarct growth between 2 and 24 hours post-reperfusion was 4.5 mL (interquartile range: 0.4–9.2 mL). Post-reperfusion infarct growth was associated with the 24-hour NIHSS in multivariable analysis (odds ratio: 1.16 [95% confidence interval 1.09–1.24], P<0.01). Conclusion Infarcts continue to grow after EVT, even if near-complete reperfusion is achieved. Investigating the underlying mechanisms may inform future therapeutic approaches for mitigating the process and help improve patient outcome.