Inflammation and Stroke, the story thus far…

Despite contemporary medical treatment of antiplatelets and statins, the risk of vascular recurrence (recurrent stroke, MI and vascular death) after ischaemic stroke remains high- estimated at 30% at 5 years¹. New therapies are required to reduce this risk after stroke. In coronary disease, randomised controlled trials of anti-inflammatory agents have shown benefit with reduced recurrent vascular events². As such, targeting inflammatory pathways is an attractive potential therapy to translate to stroke. ³

Atherosclerosis is recognised as a chronic inflammatory condition⁴: adhesion molecules, stimulated by proinflammatory cytokines, shear stress (hypertension) and reactive oxygen species (smoking), facilitate the adherence and rolling of monocytes along the endothelium. Leukocytes migrate to the arterial intima, facilitated by chemokines (IL-1, TNFa, MCP-1). This facilitates entry and accumulation of lipid particles within arterial intima, in turn  triggering macrophages, which engulf the lipid, to form foam cells, pathognomonic of early atherosclerosis. The NLRP3 inflammasome is activated, stimulating downstream cytokines IL-1, IL-18, IL-6 and CRP. This cycle of inflammation continues, driving both maturation and fibrosis but also ulceration and rupture of atherosclerotic plaques.

Support for the inflammatory hypothesis comes from observational studies, imaging studies, genetic epidemiology and randomised clinical trials:

¹⁸FDG-PET imaging  studies (¹⁸FDG uptake in carotid atherosclerotic plaques correlates with macrophage density at the site of the plaque) have demonstrated that patients with highly metabolically active carotid plaques are at highest risk of recurrent stroke in the same vascular territory, irrespective of the severity of stenosis in the carotid artery. ⁵ Mendelian randomisation studies, which use genetic proxies for inflammatory proteins randomly distributed in large population cohorts, found that genetically downregulated IL-6 activity is associated with a lower risk of ischaemic stroke and coronary artery disease. ⁶ In pooled individual participant data of over 8000 participants, people with the highest IL-6 and CRP levels measured after stroke, were at highest risk of recurrent MACE events. ⁷

These studies have set the scene for definitive randomised controlled trials of anti-inflammatory therapies in stroke patients:

The CHANCE3 trial, performed in China, randomised patients with mild ischaemic stroke or TIA to low-dose colchicine within 24 hours of their acute event. They followed patients for 90 days collecting recurrent stroke and MACE events. The results were presented at the World Stroke Congress in Toronto in 2023. The CHANCE3 trial was neutral: there was no difference in the recurrence rate (approximately 6%) between trial arms. However, with only 3 months of follow-up, this study was unable to investigate the effect of colchicine on later events. We know that the risk of recurrent cardiovascular events after stroke increases cumulatively with time after stroke event.

This year at ESOC, we heard the results of the CONVINCE trial: the first RCT of low-dose colchicine with long-term follow-up performed in an ischaemic stroke and TIA population. This study included patients with non-cardioembolic stroke (i.e. strokes were caused by large artery stenosis, small vessel disease and cryptogenic stroke, but cardioembolic strokes were excluded). While there was a 2% absolute difference in risk of recurrent MACE events between the treatment arm (9.8%) and control (11.8%), the difference was not statistically significant (HR 0.84, CI 0.68-1.05, p=0.12). Power was reduced as the trial was stopped due to lack of funding when 92% of the planned outcomes were collected- recruitment had slowed significantly during the pandemic. Interestingly, when the CONVINCE data were meta-analysed with the coronary colchicine trials, for the outcome of ischaemic stroke there was a significant risk reduction of 27% (RR 0.73, CI 0.58-0.90) with 80% of the power coming from CONVINCE. Reassuringly, colchicine was safe with no excess serious adverse effects reported and none of the harmful signals (such as increased sepsis or malignancies) that have been reported with other anti-inflammatory therapies.

In the future, perhaps colchicine, a simple and cheap anti-inflammatory drug used for centuries for gout, can be repurposed to be used in clinical practice to prevent recurrent stroke and cardiovascular events in patients who suffer a stroke. However at present, further large studies are needed to definitively confirm its efficacy.

Figure: Inflammatory cascades in Atherosclerosis ⁸

---

References:

1. Boulanger M, Béjot Y, Rothwell PM, Touzé E. Long-Term Risk of Myocardial Infarction Compared to Recurrent Stroke After Transient Ischemic Attack and Ischemic Stroke: Systematic Review and Meta-Analysis. J Am Heart Assoc 2018; 7(2).
2. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017; 377(12): 1119-31.
3. Kelly PJ, Lemmens R, Tsivgoulis G. Inflammation and Stroke Risk: A New Target for Prevention. Stroke 2021; 52(8): 2697-706.
4. Libby P, Rocha VZ. All roads lead to IL-6: A central hub of cardiometabolic signaling. Int J Cardiol 2018; 259: 213-5.
5. McCabe JJ, Camps-Renom P, Giannotti N, et al. Carotid Plaque Inflammation Imaged by PET and Prediction of Recurrent Stroke at 5 Years. Neurology 2021; 97(23): e2282-e91.
6. Georgakis MK, Malik R, Gill D, et al. Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes. Circulation: Genomic and Precision Medicine 2020; 13(3): e002872.
7. McCabe JJ, Walsh C, Gorey S, et al. C-Reactive Protein, Interleukin-6, and Vascular Recurrence After Stroke: An Individual Participant Data Meta-Analysis. Stroke 2023; 54(5): 1289-99.
8. Gorey S, McCabe JJ, Kelly PJ. Inflammation—The new treatment target for ischaemic stroke prevention. Frontiers in Stroke 2023; 2.