Early Versus Late Assessment of Stroke Outcome.

The purpose of a clinical trial is usually to assess whether and to what extent a treatment improves outcome and to identify the type and frequency of any associated risks. The question that is posed here refers only to acute trials, in which enrollment occurs within hours after stroke onset and treatment is exhibited and probably completed within at most a few days. We can reasonably assume that the treatment exerts its beneficial effect only while it is being administered and that any adverse effects are similarly acute in onset. Patients with acute stroke, and especially patients with severe stroke, are typically elderly and have elevated risk of cardiovascular disease; indeed, stroke survivors are more likely to die from cardiovascular disease than recurrent stroke. Long-term follow-up will dilute effects of treatment with other events that are part of the natural history of the condition. Any benefit may be revealed reasonably quickly, but with extended follow-up, there is an inevitable convergence of outcomes between treatment groups as complications of age, and associated risk factors come into play. We must, therefore, look at the natural history of outcomes after stroke, especially among patients with initially severe stroke, to see when recovery typically reaches its plateau at the group level. Data from the Virtual International Stroke Trials Archive, 2015 (Dr Rachael MacIsaac, personal communication) on the distribution of outcomes across 1 year assessed by modified Rankin Scale (mRS) among 159 ischemic stroke patients with admission National Institutes of Health Stroke Scale score of ≥20 indicate that the proportions of patients with good outcomes—mRS scores of 0, 1, 2, 3, or 4—each rises between 1 week and 3 months after stroke but falls progressively through 6 months to 1 year. The proportion of patients who are bedbound falls abruptly between 1 week and 3 months but drops by only 2% to 3% during the next 9 months. Twenty percent of severely affected patients die between 1 week and 3 months after stroke, and thereafter, ≈1.5% die each month. Thus, the recovery that we can expect to detect on a population basis has been completed by 3 months. Although some individual patients may continue to improve thereafter, their numbers are more than offset by deaths and deteriorations among others. Clinical trials are analyzed on the basis of group effects. For a clinical trial that uses mRS distribution or any usual dichotomization or variant of mRS as its primary outcome, there is no value in extending following up beyond 3 months. Where the value arises from an extension of follow-up is in demonstrating durability of effect and in assessing health economics. If a treatment limits the proportion of patients who have severe disability and if we assume that late deaths after stroke are mainly concentrated among the most disabled survivors, then it may allow a greater survival benefit to be detected through extended follow-up. This has limited value, when there is already general acceptance that bedbound survival should be considered an equally unattractive outcome to death: we already know the effect of our treatment by 3 months. It may be preferable to increase the sample size to improve trial power than to rely on extended follow-up to rescue an underpowered trial. Long-term effects can readily be collected as a secondary, descriptive measure. Taking 2 examples where patients with severe stroke have been selectively enrolled, the hemicraniectomy trials and the thrombectomy trials, neither needed extended followup to demonstrate its benefit. Although the final distribution of functional outcomes changes slightly between 6 months Early Versus Late Assessment of Stroke Outcome