Neuroprotection with Glyceryl Trinitrate Post-Endovascular Therapy in Acute Ischemic Stroke: A Pilot Randomized Controlled Trial

Overview of Nitroglycerin-Based Neuroprotection in Acute Ischemic Stroke: A Pilot Randomized Controlled Trial Review

Background and Research Objectives

Acute ischemic stroke (AIS) is one of the leading global causes of disability and death. Despite the significant improvement in vascular recanalization rates and patient outcomes achieved with modern endovascular therapy (ET), a considerable proportion of patients fail to return to their pre-stroke functional baseline. The mortality rate of AIS associated with large vessel occlusion (LVO) remains as high as 15.3%, while the rate of functional independence post-recanalization is only 46%. This gap between the efficacy of recanalization and clinical outcomes has driven researchers to explore effective adjunctive neuroprotection strategies to further improve long-term patient outcomes.

Glyceryl trinitrate (GTN), as an exogenous donor of nitric oxide (NO), has shown potential neuroprotective effects in animal models. However, traditional methods of GTN administration, such as transdermal or sublingual delivery, have not demonstrated significant improvements in AIS clinical outcomes in trials. Recent studies have suggested that intra-arterial administration via middle cerebral artery models may provide a more rapid and effective approach. This study aims to assess the safety, feasibility, and potential efficacy of intra-arterial GTN administration in AIS patients following ET.

Source and Study Design

This paper, authored by Zhe Cheng, Jie Gao, Yuchuan Ding, et al., is a collaborative effort from institutions including Luhe Hospital of Capital Medical University (Beijing) and Wayne State University School of Medicine (USA). Published online in October 2023 in the journal Neurotherapeutics, the study is a single-center exploratory randomized controlled trial.

The trial (AGAIN study) was conducted from May 2021 to January 2022 and included AIS patients meeting specific criteria. The primary focus was to evaluate the safety and preliminary efficacy of intra-arterial GTN administration post-ET. The study was registered on the Chinese Clinical Trial Registry (ChiCTR2100045254) and approved by the Ethics Committee of Luhe Hospital, Capital Medical University.

Methods

1. Participants and Grouping

The trial included 40 AIS patients who met the following criteria: - Aged between 18 and 80 years; - Large vessel occlusion in anterior circulation treated with ET; - Stroke onset to puncture time less than 6 hours; - NIHSS (National Institutes of Health Stroke Scale) scores of 6–25, and ASPECTS (Alberta Stroke Program Early CT Score) of 6–10.

Patients were randomly assigned into experimental and control groups (20 patients each). The experimental group received an intra-arterial GTN infusion, while the control group received an equivalent volume of saline. Both groups followed standard stroke management guidelines.

2. Intervention

GTN was delivered through an arterial catheter, starting 3 minutes post-recanalization and administered over a 10-minute period. The control group received an identical infusion of saline under the same conditions.

3. Outcome Measures

• Primary Safety Endpoint: Incidence of symptomatic intracranial hemorrhage (SICH).
• Secondary Safety Endpoints: Mortality, hypotension, neurological deterioration, infections, and other complications.
• Secondary Efficacy Endpoints: Functional independence at 90 days (modified Rankin Scale score 0–2), infarct volume changes, NIHSS scores, and blood NOx (nitrate and nitrite) levels.

Results

1. Safety Outcomes

Both groups had the same incidence of SICH (5.0%), with no significant differences in mortality (5.0% vs. 5.0%) or other complications such as hypotension or infection. This indicates that intra-arterial GTN is safe for this patient population.

2. Efficacy Outcomes

The GTN group showed trends of improvement in: - 90-day functional independence rates: 75.0% vs. 65.0% in the control group; - Reduction in infarct volume: 33.2 ml vs. 38.9 ml.

While these differences were not statistically significant, NOx levels in the GTN group were significantly higher 2 hours post-administration compared to the control group (26.2 μmol/L vs. 18.0 μmol/L, p < 0.05), suggesting increased NO bioavailability.

Discussion

1. Neuroprotective Mechanisms of GTN

NO plays a critical role in reducing oxidative stress and inflammation during ischemia-reperfusion (I/R) injury. By inhibiting reactive oxygen species (ROS) and maintaining endothelial integrity, NO provides cytoprotective effects. GTN, as an NO donor, can potentially reduce infarct size and improve functional outcomes. However, the efficacy of NO donors is highly dependent on the dose, route, and timing of administration. This study highlights the potential advantages of intra-arterial delivery in optimizing the neuroprotective effects of GTN.

2. Study Limitations and Future Directions

As a single-center, small-sample trial, the primary aim was to establish safety. Future multi-center randomized controlled trials with larger sample sizes are needed to confirm efficacy and determine the optimal GTN dosage and timing. Additionally, the response of different stroke mechanisms (e.g., atherosclerotic vs. embolic) to NO donors warrants further investigation.

Conclusion

The AGAIN study demonstrated that intra-arterial GTN administration is safe and feasible as an adjunctive therapy for AIS patients post-ET. While efficacy outcomes were not conclusively established, the study provides a foundation for future large-scale trials and highlights the potential of GTN to improve functional outcomes by increasing NO levels. These findings represent an important step toward enhancing neuroprotection strategies for AIS, offering significant clinical and research implications.