Study Identifies Critical Drug Interaction in Ischemic Stroke Treatment

Research led by The University of Manchester has revealed a negative interaction between a common clot-busting drug, tissue plasminogen activator (tPA), and the anti-inflammatory treatment anakinra, used for ischemic stroke. The study, published in the American Heart Association Stroke journal, emphasizes the importance of testing new stroke therapies alongside existing standard care.

The findings suggest that the timing of anakinra administration requires adjustment to maintain the benefits of tPA in ischemic stroke treatment.

Background on Stroke and Treatments

Stroke is a significant global health concern, ranking as the second leading cause of death and disability worldwide. Projections indicate an over 80% increase in affected individuals over the next 25 years.

Despite extensive research, tPA remains one of the few approved medications for ischemic stroke, which is the most common type. While tPA can be life-saving, it carries a risk of potentially fatal brain bleeding in 2-6% of patients and must be administered within 4.5 hours of symptom onset.

Inflammation is recognized as a key factor in exacerbating brain injury after a stroke, primarily driven by the molecule interleukin-1 (IL-1). Anakinra, an interleukin-1 receptor antagonist (IL-1Ra), blocks IL-1 and has shown potential in reducing inflammation in both laboratory and early clinical studies. However, the Phase II SCIL-STROKE clinical trial did not demonstrate overall improved patient recovery with IL-1Ra.

Discovery of the Interaction

The SCIL-STROKE trial findings prompted an investigation into whether IL-1Ra might negatively interact with tPA, given that nearly three-quarters of its patients received tPA before IL-1Ra.

Researchers re-examined SCIL-STROKE data and observed that patients who received tPA before IL-1Ra had significantly reduced levels of IL-1Ra in their blood, indicating drug degradation.

Laboratory research further confirmed that plasmin, an enzyme generated during tPA treatment, can break down IL-1Ra, potentially preventing the anti-inflammatory drug from being effective.

Mouse Model Findings

The interaction was further tested in a mouse model of stroke, using dosing schedules that mirrored those of the clinical trial.

• When IL-1Ra was administered after tPA, no harmful interaction was observed, and tPA's protective effects were maintained.
• However, when IL-1Ra was given simultaneously with tPA (during the clot-busting process), tPA's benefits were significantly diminished. Brain damage reduction was only 15% compared to 68% when tPA was given alone.
• Mice receiving both drugs concurrently also exhibited reduced brain blood flow, increased inflammatory immune cell infiltration, and higher levels of neutrophil extracellular traps, indicating a detrimental effect on IL-1Ra's anti-inflammatory action.

Implications and Future Research

Dr. Ioana-Emilia Mosneag, lead author, stated that IL-1Ra can interfere with tPA's ability to dissolve clots when both are present simultaneously in the bloodstream. The findings also explain the lower IL-1Ra levels in patients who received tPA first, due to plasmin breaking down IL-1Ra.

While the effect of tPA on IL-1Ra given in the opposite order (IL-1Ra after tPA) still requires evaluation, IL-1Ra remained active in reducing IL-6 in the SCIL-STROKE study in that context.

Professor Stuart Allan highlighted that timing is likely a critical factor for IL-1Ra's efficacy, suggesting benefits when administered after tPA rather than concurrently.

Professor Craig Smith emphasized the study's implications for the development of IL-1Ra as an ischemic stroke treatment, stressing the need for future studies to investigate the optimal timing and effectiveness of IL-1Ra treatment post-tPA. Further research is also needed to determine if similar interactions occur with other clot-busting drugs, such as tenecteplase, which may have a lower propensity to degrade IL-1Ra due to its higher specificity.