Safety and Efficacy of Angong Niuhuang Pills in Patients with Moderate-to-Severe Acute Ischemic Stroke (ANGONG TRIAL): A Randomized Double-Blind Placebo-Controlled Pilot Clinical Trial

Introduction

Acute ischemic stroke (AIS) remains a leading cause of disability and mortality worldwide. Despite advancements in reperfusion therapies like intravenous thrombolysis and endovascular thrombectomy (EVT), many patients experience poor outcomes due to infarct growth and cerebral edema. Final infarct volume strongly correlates with neurological outcomes, and interventions targeting infarct reduction or edema mitigation are critical. Angong Niuhuang Pills (ANP), a traditional Chinese medicine containing ingredients such as realgar, cinnabar, and Bovis Calculus, have shown neuroprotective effects in preclinical studies. However, robust clinical evidence supporting its use in acute stroke is lacking. The ANGONG TRIAL aimed to evaluate the safety and efficacy of ANP in reducing cerebral infarct and edema volumes in patients with moderate-to-severe AIS.

Methods

Study Design and Participants

This multicenter, randomized, double-blind, placebo-controlled pilot trial enrolled 120 patients from 17 centers in China between April 2021 and July 2022. Eligible participants were aged 40–80 years, diagnosed with AIS in the internal carotid artery territory, and had National Institutes of Health Stroke Scale (NIHSS) scores of 10–20 within 36 hours of symptom onset. Exclusion criteria included contraindications to ANP, hemorrhagic transformation, or planned EVT. Participants were stratified and randomized 1:1 to receive ANP (3 g/day) or placebo for five days.

Interventions and Outcomes

ANP and placebo pills were identical in appearance and packaging. The primary outcomes were changes in cerebral infarct and edema volumes measured via magnetic resonance imaging (MRI) at baseline and day 14. Secondary efficacy outcomes included changes in NIHSS scores, modified Rankin Scale (mRS) scores, and Glasgow Coma Scale (GCS) at days 14 and 90. Safety outcomes encompassed severe adverse events (SAEs), mortality, and changes in blood mercury/arsenic levels.

Imaging and Data Analysis

MRI scans (3.0T) were performed at baseline, day 14, and day 90. Infarct and edema volumes were quantified using AccuBrain2.0®, a validated software for automated segmentation. Statistical analyses compared median differences using Wilcoxon rank-sum tests and Hodges-Lehmann estimation. Subgroup analyses focused on patients with large artery atherosclerosis (LAA), a common etiology of severe stroke.

Results

Baseline Characteristics

Of 120 randomized participants, 117 (57 ANP, 60 placebo) were included in the modified intention-to-treat analysis. The median age was 66 years (IQR: 58–73), with 34% females. Baseline NIHSS scores (median: 12) and infarct volumes (ANP: 41.4 mL vs. placebo: 32.1 mL) were comparable between groups. Intravenous thrombolysis was administered to 25% of participants in both arms.

Primary Outcomes

At day 14, median changes in infarct volume were 0.3 mL (ANP) versus 0.4 mL (placebo), with no significant difference (median difference [MD]: −7.1 mL, P = 0.30). Cerebral edema volume increased by 11.4 mL (ANP) and 4.0 mL (placebo), but the difference was not statistically significant (MD: 3.0 mL, P = 0.15).

Subgroup Analysis in LAA Patients

In the LAA subgroup (76 patients), ANP significantly reduced infarct growth at day 14 (MD: −12.3 mL, P = 0.03). No significant differences in edema volume or secondary outcomes were observed.

Secondary Outcomes

By day 90, 38% of ANP-treated patients achieved functional independence (mRS 0–2) compared to 24% in the placebo group, though this did not reach statistical significance (OR: 1.9, P = 0.16). NIHSS scores improved similarly in both groups (median reduction: 6 points).

Safety Profile

SAEs occurred in 5% (3/57) of ANP recipients and 12% (7/60) of placebo recipients (P = 0.36). Mortality rates at 90 days were comparable (5% vs. 3%, P = 0.95). Mercury and arsenic levels remained stable in both groups, with no evidence of heavy metal toxicity.

Discussion

The ANGONG TRIAL represents the first randomized controlled trial evaluating ANP in moderate-to-severe AIS. While the primary outcomes did not demonstrate statistical significance, the study highlighted ANP’s potential to reduce infarct growth in the LAA subgroup. This finding aligns with preclinical evidence suggesting ANP’s anti-inflammatory and anti-apoptotic properties, which may attenuate secondary injury in atherosclerotic strokes.

The lack of significant edema reduction contrasts with prior animal studies, possibly due to differences in pathophysiology between experimental models and human stroke. The trend toward improved functional outcomes (mRS 0–2) at 90 days warrants further investigation in larger trials. Notably, ANP’s safety profile was comparable to placebo, addressing concerns about heavy metal toxicity from realgar (arsenic sulfide) and cinnabar (mercury sulfide).

Limitations

The pilot nature of the trial limited statistical power, and the high dropout rate (≈20%) may have influenced results. Additionally, infarct growth dynamics within the first 24 hours post-stroke were not assessed, potentially overlooking ANP’s early effects. The exclusion of EVT patients restricts generalizability to broader stroke populations.

Conclusion

The ANGONG TRIAL provides preliminary evidence that ANP is safe and may reduce infarct volume in LAA-related strokes. While the primary outcomes were neutral, the subgroup findings and favorable safety profile justify larger phase III trials to confirm efficacy and explore mechanisms. Future studies should incorporate advanced imaging biomarkers, broader inclusion criteria, and longer follow-up to elucidate ANP’s role in acute stroke management.

doi.org/10.1097/CM9.0000000000003133

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