Abstract WMP61: Vulnerable And Stabilized States After Cerebral Ischemic Events: Implications Of Kinetic Modeling In The POINT, SOCRATES, And THALES Trials

Background: Trials of acute secondary prevention following initial minor stroke or TIA, such as POINT, SOCRATES, and THALES, demonstrate a high rate of initial recurrence of ischemic stroke, quickly dropping to a sustained lower rate. For the POINT trial, this was shown to support a two-state kinetic model, in which after the index event subjects are initially in a vulnerable state, with a high rate of stroke recurrence, and then transition to a stabilized state at lower risk for stroke recurrence. This allows for estimation of the distinct kinetic rates characterizing these events. We aimed to extend such a kinetic analysis to the SOCRATES and THALES trials, and to compare estimates of kinetic rates across these trials. Methods: Kaplan-Meier estimates of survival curves in POINT, THALES, and SOCRATES trials were constructed and fitted by a non-linear two-state model, producing estimates of kinetic parameters, using nonparametric bootstrap with repetitive resampling to estimate standard errors. Results: The two-state model closely fit survival curves in all the trials, with similar kinetic parameters across trials. Estimated kinetic rates for stroke recurrence in the vulnerable state were about 100-fold higher than rates in the stabilized state for subjects in the control groups. The transition rates from the vulnerable to stabilized state were still more rapid. Active treatment groups showed similar kinetics, with reduced rates of stroke in the vulnerable state. Conclusion: Across multiple trials of acute secondary stroke prevention following minor stroke or TIA, in both control and active treatment groups, recurrence of stroke is well-described by a two-state kinetic model postulating separate vulnerable and stabilized states. The distinct kinetic states may be revealing distinct pathobiologies with implications about differential impact of therapies delivered immediately or in a delayed fashion.