Is inflammation the next therapeutic target in intracerebral hemorrhage?

Intracerebral hemorrhage (ICH) is a devastating disease with an estimated incidence of 24.6 cases per 100,000 person-years. While just under a third of strokes are ICH, they account for 49% of the global burden of death from stroke. Despite the advances in primary and secondary ischemic stroke prevention, neither the incidence nor the case fatality rates of ICH have substantially decreased since 1980, in contrast to the case of ischemic stroke. As both ICH incidence and case fatality increase with age, the burden of ICH-related morbidity and mortality and ensuing healthcare expenditures are expected to increase substantially with our aging demographics over the coming decades.

Experimental, epidemiological and clinical trial data have highlighted that inflammation is a key mediator in the development of vascular events, including stroke. Evidence from large-scale randomized controlled clinical trials, summarized in a previous post , suggest that inhibition of inflammatory pathways in patients with coronary artery disease can ameliorate the risk of future cardiovascular events, including stroke prevention. In addition to the association with ischemic events, inflammatory processes also seem to be implicated in the resulting brain injury following an ICH. ICH seems to trigger an immunological reaction and systemic inflammatory response that contributes to secondary brain injury, following the initial mechanical forces of an expanding hematoma (primary injury). Hematoma-related blood components, such as iron, induce oxidative stress and the aggregation of immunocytes, both resident in the central nervous system and recruited from the peripheral circulation, with evidence from experimental and observational clinical studies suggesting an increased expression of inflammatory cytokines in brain microglia and the peripheral blood of patients with acute ICH. Inflammatory markers in the early acute phase of ICH have been associated with both hematoma enlargement and worsened patient outcomes. ICH-induced inflammatory response results in cytokines release, which promote neutrophil infiltration, and augment further the ongoing neuroinflammation, brain injury and cerebral edema.

Anakinra in Cerebral Haemorrhage to Target Secondary Injury Resulting From Neuroinflammation (ACTION) is a phase 2, multicentre, prospective, randomized, three-armed (1:1:1) trial assessing the effect of high-dose and low-dose anakinra compared to standard medical management on cerebral edema, serum inflammatory markers and functional outcomes of patients suffering from a spontaneous ICH. Colchicine for the prevention of vascular events after an acute intracerebral hemorrhage (CoVasc-ICH) is another vanguard-phase, randomized, placebo-controlled, multicenter clinical trial with the overarching goal to investigate the safety and efficacy of low-dose colchicine for the prevention of major cardiovascular events and brain injury after an acute spontaneous ICH.

Although current evidence is still insufficient to support the implementation of anti-inflammatory treatment strategies after an acute intracerebral hemorrhage, there are two ongoing randomized control clinical trials which are targeting the inflammatory cascade to ameliorate the cardiovascular risk and improve the functional outcomes of this fragile patient population.