Vulnerable and Stabilized States After Cerebral Ischemic Events: Implications of Kinetic Modeling in the SOCRATES, POINT, and THALES Trials

Abstract

Background and objectives: Trials of acute secondary prevention after minor stroke or transient ischemic attack (TIA), such as SOCRATES, POINT, and THALES, demonstrate a high initial rate of recurrence after ischemic events that drop quickly to a lower rate, suggesting a transient vulnerable clinical state, which may call for different treatments than the subsequent stabilized state. A kinetic model incorporating vulnerable and stabilized states provides estimates of the distinct kinetic rates reflecting the temporal features of underlying stroke mechanisms. We aimed to compare these kinetic rates between treatments and across trials, asking whether these features point to common pathophysiologic processes underlying stroke recurrence, and inform the targeting and timing of enhanced antiplatelet therapy in recurrent stroke prevention.

Methods: Kaplan-Meier recurrence-free survival curves in the SOCRATES, POINT, and THALES trials were estimated for each treatment group and fitted by nonlinear regression to the 2-state kinetic model, producing estimates of kinetic parameters, with standard errors estimated using the nonparametric bootstrap with repetitive resampling.

Results: For each trial, the 2-state kinetic model fit the survival curves better than did the null (single-state) kinetic model or the Weibull model (p < 0.05). Recurrence rates in the vulnerable state (k ₁ ) were 100-fold higher than in the stabilized state (k ₂ ). Transition rates from the vulnerable to stabilized state (k ₀ ) were still more rapid. Kinetic parameters were consistent across the trials, without significant differences between the trials. Enhanced antiplatelet regimens produced significant reductions in k ₁ (aspirin alone: 0.030 ± 0.004 d^-1; active treatment: 0.016 ± 0.003 d^-1; p < 0.01) but did not affect k ₀ or k ₂ , suggesting that active treatment only affected risk in the vulnerable state. Modeling based on these kinetic parameters suggests that most of the benefit of active treatment occurred within 3 days.

Discussion: Across multiple trials of acute secondary prevention after minor stroke or TIA, recurrence of stroke is well-described by a 2-state kinetic model postulating vulnerable and stabilized states, with similar kinetic parameters across trials. Enhanced antiplatelet regimens only affected the recurrence rates in the vulnerable state, over a brief period. This analysis suggests that 2 distinct states follow acute cerebral ischemic events, subject to differential impact of immediate or delayed therapies.