Importance of stroke: The World Health Organisation (WHO) estimates that cardiovascular diseases are the leading cause of death globally, causing 17.3 million deaths in 2008. Of these, stroke was the second leading cause of global death and a major cause of healthcare costs. High risk of recurrent vascular events in stroke survivors: Despite high rates of optimal medical and surgical treatment, we and others have demonstrated high risk of recurrent stroke associated with atherosclerosis of the internal carotid and intracranial arteries. A recent systematic review reported a cumulative pooled recurrent stroke risk of 11.1% at one year and 26.4% at 5 years. The risk of myocardial infarction and vascular death is also substantial in long-term stroke/TIA survivors. In a systematic review (39 studies, 65,996 patients), Touze found a 2.1%/year rate of non-stroke vascular death and 0.9%/year risk of non-fatal Myocardial Infarction (MI) in stroke survivors.
Importance of inflammation: Accumulating evidence indicates that inflammation is of key importance in the pathophysiology of atherosclerotic plaque destabilisation and thrombo-embolism . The central inflammatory pathway is characterised by the key cytokines interleukin-1, interleukin-6 [IL-6], and tumour-necrosis factor α [TNF-α]. Epidemiological studies have consistently described dose-dependent associations between ‘downstream’ markers of this pathway (e.g. C-reactive protein [CRP]), ‘up-stream’ markers (e.g. IL 6, TNF-α]) and vascular disease, including stroke. Mendelian randomisation studies have shown that polymorphisms in the IL-6 receptor are associated with lower CRP and reduced vascular risk. In the JUPITER trial, rosuvastatin reduced the rate of vascular events in patients with low LDL but high CRP at entry, with benefit proportionate to the degree of CRP reduction. In large-artery atherosclerosis, plaque inflammatory cells (mainly monocyte- macrophages), are increasingly recognised as key mediators of lipid oxidation, plaque remodelling, smooth muscle cell apoptosis, loss of extracellular matrix integrity via release of collagenolytic matrix metalloproteinases and other proteolytic enzymes, leading to fibrous cap rupture and thrombo-embolism. Tawakol reported high FDG uptake on positron emission tomography (PET) in symptomatic carotid plaque, with high (r=0.89) correlation with plaque macrophage density. We have shown that carotid plaque inflammation related FDG uptake predicts stroke recurrence independently of stenosis. In cerebral small artery disease, available data indicate that inflammation may be an important mediator of lacunar stroke and arteriolar pathology. In patients with small artery disease, increased inflammatory cells (macrophages, activated microglia) expressing matrix metalloproteinases (MMPs) are present around affected arterioles and ischemic demyelination, and MMP-9 is increased in cerebrospinal fluid [11, 12]. In SPARCL, patients with lacunar stroke randomised to atorvastatin lipid-lowering therapy had similar reduction in stroke and coronary events as those with large-artery atherosclerosis. In lacunar stroke patients enrolled in the SPS3 trial, baseline CRP independently predicted recurrent stroke and vascular events. Recent laboratory and clinical-pathological studies have shown that cholesterol crystals form in atherosclerotic plaques, and may activate the nucleotide-binding leucine-rich repeat-containing pyrin receptor (NLRP) inflammasome, an intracellular protein complex which promotes IL-1β expression in response to crystal stimulation, leading to elevated IL-6 and CRP. These important observations provide direct evidence linking plaque lipid metabolism and inflammation.
Aim of Review: To systematically review the randomised clinical trials evaluating anti-inflammatory medications plus standard medical therapy for the prevention of recurrent vascular events after ischaemic stroke / transient ischaemic attack compared with standard medical therapy.
Why is this review needed now?
Few completed trials have directly tested the benefit of anti-inflammatory agents for vascular risk reduction and even fewer have investigated stoke or recurrent stroke as a primary outcome. Small studies have demonstrated reduction in inflammatory blood and imaging surrogate-markers such as plaque FDG uptake in a dose dependent manner by statins, possibly mediated by an anti-inflammatory effect. The LoDoCo1 trial demonstrated a 66% relative risk reduction in cardiovascular events (including stroke) in patients with stable coronary disease treated with low dose colchicine, plus anti-platelet agents and statins, compared with usual care. However, several trials are currently under way. In CANTOS, canukinumab (an interleukin-1β antagonist) is under evaluation in 10,000 patients with stable coronary disease. The National Institutes of Health (NIH) funded Cardiovascular Inflammation Reduction Trial (CIRT) is comparing low-dose weekly methotrexate with placebo plus recommended care in 7,000 patients with coronary disease and diabetes or metabolic syndrome. In Australia, the LoDoCo2 trial is testing low-dose colchicine for prevention of vascular events in 3,000 patients with stable coronary syndromes. Other trials have recently targeted inflammatory pathways (e.g. LpPLA2) unrelated to the IL1-IL6-TNFα pathway (STABILITY, VISTA, SOLID-TIMI52).
