Kinetic analysis of acute stroke secondary prevention trials: Insights from combined datasets guiding future trial design - Project Summary Recent clinical trials of platelet-inhibiting medications for preventing a second stroke following an initial minor stroke or transient ischemic attack (TIA) have shown that recurrences of strokes over time follow a distinct time course, with a high rate of recurrence over the first few days, slowing to a steady lower rate over subsequent months. We have shown that this temporal course can be predicted from a model of stroke recurrence risk based on kinetic analysis, in which rates of events are proportional to numbers of subjects in a given state multiplied by a fixed kinetic rate for that state. A kinetic model that postulates both a transient vulnerable state and a stabilized state following initial ischemic events predicts a specific mathematical form for the time course of the event-free survival curve (the proportion of subjects not yet having experienced a recurrence, over time). The predictions of this model closely match the data from the POINT, SOCRATES, and THALES trials, and allow for estimation of the kinetic rate constants that describe the rate of ischemic stroke recurrence in the vulnerable state (k1), the rate in the stabilized state (k2), and also the rate of transition from the vulnerable to stabilized state (k0).These different rates that determine risks of stroke recurrence are likely to relate to different underlying biological mechanisms, and to be distinct in their responses to different treatments. In fact, we have shown that the added anti-platelet medication strategies used in these trials only affected only k1, not the other rates. Understanding the condition of patients following stroke in these kinetic terms of distinct vulnerable and stabilized states, subject to different biologically-determined rates of stroke recurrence, allows for exploring what patient risk factors or treatments may selectively affect the different rates. These insights have implications for how clinical trials of treatments should be designed. For instance, if a certain type of treatment only affects k1, the rate of stroke recurrence in the transient vulnerable state, then it is only likely to make an impact when applied rapidly and for the short-term following the initial stroke. In contrast, interventions affecting the recurrence rate in the stabilized state will need to be applied for longer periods to impact overall stroke recurrence. Determining the distinct effects of risk factors or treatments on the individual rate constants requires data from large numbers of patients to quantify the effects. By combining the data from the large SOCRATES, POINT, and THALES trials into a unified and harmonized data set, these types of careful analyses can be performed, testing important questions as to which kinetic rates are specifically affected by patient risk characteristics, by treatments such as cholesterol-lowering medicines or anti-inflammatory medicines, or by the presence of significant plaque and stenosis in intracranial arteries. These important insights, with implications for the design of future clinical trials, are the goal of this project.
