A clotbusting drug commonly used to treat ischemic stroke interacts negatively with a promising anti-inflammatory treatment (anakinra), underscoring the need to test new stroke therapies alongside existing standard care.
According to The University of Manchester led study on mice, published in the American Heart Association Stroke journal today (insert date) and funded by the Medical Research Council, the timing of anakinra must be adjusted to avoid reducing the benefits of the clot‑busting therapy known as tissue plasminogen activator(tPA).
Stroke is the second leading cause of death and disability worldwide; experts estimate the number of people affected could rise by more than 80% over the next 25 years.
But despite decades of research and thousands of experimental drugs, the only approved medicines for treating the most common type of stroke - ischemic stroke - are clot‑busting drugs known as plasminogen activators, like tPA.
Though tPA can be lifesaving for acute ischemic stroke, about 2-6% of treated patients develop potentially fatal brain bleeding, according to the ECASS III trial of the early 2000s.
Though it must be given within 4.5 hours of symptom onset, many patients arrive too late or don't know when symptoms started.
Scientists now know that inflammation plays a major role in worsening brain injury after a stroke, mostly driven by a molecule called interleukin‑1 (IL‑1).
Anakinra - an interleukin‑1 receptor antagonist (IL‑1Ra) - blocks IL‑1 and has shown promise in reducing inflammation in both laboratory and early clinical studies of stroke.
However, a phase II clinical trial known as SCIL‑STROKE based at The Northern care Alliance NHS foundation Trust found that IL‑1Ra did not improve patient recovery overall.
"The findings of SCIL‑STROKE raise questions about whether the drug might interact negatively with standard clot‑busting treatment, " said lead author Dr Ioana-Emilia Mosneag, based at the University of Manchester.
Because nearly three‑quarters of patients in the SCIL‑STROKE trial received the clot‑busting drug tPA before IL‑1Ra, the researchers set out to investigate whether the two treatments might negatively interact with each other.
They re‑examined data from the SCIL-STROKE trial and discovered that patients who received tPA before IL‑1Ra had significantly lower levels of IL‑1Ra in their blood, suggesting the drug was being broken down.
Laboratory research confirmed that IL‑1Ra can be cut apart by plasmin, an enzyme produced during tPA treatment, meaning the anti‑inflammatory drug may be degraded before it can work.
Researchers then tested the interaction in a mouse model of stroke, using dosing schedules that matched those used in the clinical trial.
When IL‑1Ra was given after tPA, no harmful interaction was seen, and the protective effects of tPA were preserved.
However, when IL‑1Ra was given at the same time as tPA - during the clot‑busting process - the benefits of tPA were dramatically reduced, with brain damage shrinking by only 15% compared to 68% with tPA alone.
The mice receiving both drugs together also showed poorer blood flow in the brain, more inflammatory immune cells entering damaged tissue, and higher levels of harmful structures called neutrophil extracellular traps. This indicates that the drug interaction is also detrimental to the anti-inflammatory effect of IL-1Ra.
Dr Mosneag added: "Our findings suggest that IL‑1Ra can interfere with tPA's ability to dissolve clots when the two drugs are present in the bloodstream at the same time.
"The results also help explain why IL‑1Ra levels were lower in patients who received tPA first, as plasmin generated during clot‑busting appears to break down IL‑1Ra.
"However, the effect of tPA on IL-RA - the opposite order - isn't necessarily a problem as IL-1RA was still active in reducing IL-6 in the SCIL-STROKE study, but this needs further evaluation."
Co-author Professor Stuart Allan from The University of Manchester said: "This study shows that timing is very likely to be a critical factor in the efficacy of IL‑1Ra, which will be beneficial if given after tPA rather than alongside it.
"We also need to test whether similar interactions occur with other clot‑busting drugs such as tenecteplase, which may be less likely to break down IL‑1Ra due to its greater specificity."
Co-author Professor Craig Smith from the University of Manchester said: "This study has important implications for further development of IL-1Ra as a treatment for ischaemic stroke, where there remains a focus on maximising delivery of thrombolysis drugs to eligible patients as quickly as possible in clinical care. Future studies will need to investigate the timing and effectiveness of IL-1Ra treatment after receiving tPA."
