Argatroban plus alteplase shows no daytime benefit but nighttime association with better stroke outcomes

BACKGROUND AND OBJECTIVES: The Argatroban Plus Recombinant Tissue-Type Plasminogen Activator for Acute Ischemic Stroke (ARAIS) trial did not show the benefit of argatroban as an adjunct in patients with acute ischemic stroke who received intravenous alteplase. This post hoc exploratory analysis aimed to determine whether the circadian rhythm can affect the efficacy of argatroban as an adjunct in this population. METHODS: From the per-protocol population of the ARAIS trial, patients were divided into 2 groups based on the beginning time of intravenous thrombolysis: daytime (06:00-17:59) and nighttime (18:00-05:59) groups. Each group was divided into argatroban plus alteplase and alteplase alone groups. The primary outcome was excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 1 at 90 days. The safety outcome was symptomatic intracerebral hemorrhage (sICH). RESULTS: Among 692 patients from the per-protocol analysis, 489 were in the daytime group, and 203 in the nighttime group. In the daytime group, the proportion of patients with an excellent functional outcome was 60.5% (144/238) in the argatroban plus alteplase group versus 66.9% (168/251) in the alteplase-alone group, respectively, without significant difference between two groups (adjusted odds ratio [aOR] = 1.19; 95% CI 0.80-1.78; p = 0.40). In the nighttime group, argatroban plus alteplase was significantly associated with higher proportion of excellent functional outcome compared with alteplase alone (75.9% vs 60.3%; aOR = 0.47; 95% CI 0.24-0.93; p = 0.03). An interaction effect was found between intervention (argatroban plus alteplase or alteplase only) by different treatment period on primary outcome (P for interaction = 0.02). For safety outcomes, no significant differences in sICH rates were observed between treatment groups within either time stratum. CONCLUSION: This is the first report that suggested a potential association between argatroban and a higher rate of excellent functional outcome in patients with acute ischemic stroke who received intravenous alteplase during the nighttime. This finding requires further validation in future studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03740958.