Abstract Body: Background: We investigate whether the NIHSS at 24 hours could serve as an alternative primary outcome measure in acute ischemic stroke trials, and whether combining 90-day modified Rankin Score (mRS) and 24-hour NIHSS in a hierarchical outcome could enhance detection of treatment effect, using EVT as an exemplary study intervention.

Methods: Post-hoc analysis from the HERMES collaboration that pooled data from 7 randomized controlled EVT trials. Validity of 24-hour NIHSS as a surrogate outcome for 90-day mRS was assessed in a causal mediation model (Figure 1). A 7-point ordinal NIHSS score was generated by grouping 24-hour NIHSS, including death as a separate category (“ordinal” NIHSS). EVT effect sizes and sample sizes required for detecting EVT benefit with 80% power were compared when using granular 24-hour NIHSS, ordinal 24-hour NIHSS, 90-day mRS, and hierarchical outcome (win-ratio) that combines 90-day mRS and 24-hour NIHSS. Subgroup analyses were performed in patients with baseline NIHSS<10 and ≥25.

Results: A total of 1720 patients were included. Median 90-day mRS in the EVT/control arms was 3.0(IQR:1.0-4.0)/4.0(IQR:2.0-5.0) and median 24-hour NIHSS was 9.0(IQR:3.0-17.0)/14.0(IQR:7.5-19.0), see Figure 2. 24-hour NIHSS mediated the association between EVT and 90-day mRS and met the criteria for a surrogate outcome. Effect sizes were highest and sample sizes required to detect EVT benefit smallest for the win ratio approach (228), followed by 90-day mRS(240) and ordinal 24-hour NIHSS(242), see Table 1. In subgroup analyses of patients with baseline NIHSS<10 and≥25, ordinal 24-hour NIHSS resulted in the highest effect size/ smallest sample size.

Conclusion: 24-hour NIHSS may be a valid surrogate outcome for 90-day mRS in acute ischemic stroke patients undergoing EVT, with a similar EVT effect size compared to 90-day mRS. It could potentially enhance detection of EVT benefit in patient subgroups with very low or very high baseline NIHSS. Combining 90-day mRS and 24-hour NIHSS in an ordered hierarchical could improve detection of EVT treatment effect compared to 90-day mRS.