Time of Stroke Onset and the Efficacy of Remote Ischemic Conditioning

Background and Objectives Remote ischemic conditioning (RIC) initiated in the prehospital setting did not improve 90-day functional outcomes in the RESIST randomized controlled trial. Emerging preclinical evidence suggests that the cerebroprotective effects of RIC are greatest during the circadian inactive phase in rodents (daytime). We tested whether time of stroke onset, a clinical proxy for circadian phase, modified RIC efficacy in RESIST. Methods Post hoc analysis of prehospitally randomized acute ischemic stroke (AIS) patients in the RESIST trial. Patients with a putative stroke and onset or last known well within 4 hours were randomized in the ambulance. Patients were dichotomized by stroke onset time using prespecified strata: (1) 19:00-06:59 vs 07:00–18:59 and (2) 23:00–06:59 vs 07:00 to 22.59. Outcomes were 90-day ordinal modified Rankin Scale shift (primary) and ≥4-point National Institutes of Health Stroke Scale improvement at 24 hours. Treatment-by-time-of-onset interactions were tested using multiplicative terms in unadjusted and adjusted logistic regression models. Functional outcome and 24-hour infarct growth were also examined when the day was divided in 4-hour strata. Results In 737 patients with AIS of 1,500 prehospitally randomized patients with suspected stroke, 120 (16.3%) had onset in the 19:00-06:59 period and 43 of 737 (5.8%) had onset during 23:00–06:59. Patients with stroke during the clock time–defined inactive phase were modestly younger (median 70 vs 74 years; p = 0.035), but baseline characteristics were otherwise balanced. There was no significant treatment-by-time-of-onset interaction observed for functional outcome or infarct growth under different periods in unadjusted or adjusted analyses. Discussion Time of stroke onset did not significantly modify the effect of RIC on early neurologic improvement, functional outcome, or 24-hour infarct growth in prehospitally randomized AIS patients. However, owing to the low number of patients enrolled during nocturnal windows, this exploratory analysis was underpowered to detect small-to-moderate treatment effects. Trial Registration Information The trial was registered at ClinicalTrials.gov (NCT03481777).