Background and Objective: Circadian rhythms in neuroinflammation may affect ischemic stroke outcomes and neuroprotective therapy efficacy. We aimed to explore whether the circadian pattern of stroke onset influences minocycline’s effect on functional recovery in moderate to severe acute ischemic stroke (AIS). Methods: This was a post-hoc subgroup analysis of the Efficacy and Safety of Minocycline in Patients with Moderate to Severe Acute Ischemic Stroke (EMPHASIS) trial——a randomized, placebo-controlled study in 58 Chinese hospitals. We enrolled patients with AIS within 72 hours of onset, a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 25, and an item Ia score ≤1. Stroke onset time was defined as the exact time when focal neurological deficits were first present, or the last-seen-well time for those with wake-up stroke. The onset time was dichotomized as daytime (06:00-17:59) or nighttime (18:00-05:59), and further into four 6-hour intervals: early morning (00:00-05:59), morning (06:00-11:59), afternoon (12:00-17:59), and evening (18:00-23:59). The primary endpoint was an excellent functional outcome (modified Rankin Scale mRS score 0-1) at 90 days. Odds ratios (ORs) were estimated using generalized linear models based on the intention-to-treat set. Results: Among 1,701 eligible participants, 1,093 (64.2%) and 609 (35.8%) had daytime- and nighttime-onset AIS, respectively. In detail, 151 patients (8.8%) had AIS at early morning, 605 (35.6%) at morning, 488 (28.7%) at afternoon, and 457 (26.9%) at evening. Compared with placebos, minocycline treatment was associated with a significantly higher rate of mRS 0-1 at 90 days in patients with nighttime onset (49.2% vs 40.8%; OR=1.40 1.02, 1.93; P=0.039), but not in those with daytime onset (54.4% vs 51.1%; OR=1.14 0.90, 1.45; P=0.272). Specifically, in patients with afternoon (55.6% vs 46.6%; OR=1.44 1.01, 2.05; P=0.046) and evening onset AIS (50.2% vs 39.7%; OR=1.53 1.06, 2.22; P=0.025), minocycline significantly improved 90-day functional outcomes. However, the treatment-by-onset interactions above did not reach statistical significance (P for interaction=0.317 and 0.185, respectively). Conclusions: The efficacy of minocycline for functional recovery varied across circadian patterns of stroke onsets, with the greatest benefits in nighttime-onset AIS. Our findings suggest the potential role of circadian rhythms in personalizing neuroprotective therapies for AIS.
Gao et al. (Thu,) studied this question.