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`Current Pharmaceutical Design, 2018, 24, 668-674
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`
`
`The Role of Colchicine in the Prevention of Cerebrovascular Ischemia
`
`ISSN: 1381-6128
`eISSN: 1873-4286
`
`no.
`
`Impact
`Factor:
`2.611
`
`BENTHAM
`S C I E N C E
`
`Georgios Tsivgoulis1,2,*, Aristeidis H. Katsanos1,3, Georgios Giannopoulos4, Vasiliki Panagopoulou4,
`Dalius Jatuzis5, Robin Lemmens6-8, Spyridon Deftereos4 and Peter J. Kelly9
`
`1Second Department of Neurology, “Attikon University Hospital”, School of Medicine, National and Kapodistrian University of Ath-
`ens, Athens, Greece; 2Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA; 3Department of
`Neurology, University of Ioannina School of Medicine, Ioannina, Greece; 4Second Department of Cardiology, Attikon University
`Hospital, National and Kapodistrian University of Athens, Athens, Greece; 5Department of Neurology and Neurosurgery, Center for
`Neurology, Vilnius University, Vilnius, Lithuania; 6Department of Neurosciences, Experimental Neurology and Leuven Research
`Institute for Neuroscience and Disease (LIND), KU Leuven - University of Leuven, B-3000 Leuven, Belgium; 7Center for Brain &
`Disease Research, Laboratory of Neurobiology, VIB, B-3000, Leuven, Belgium; 8Department of Neurology, University Hospitals
`Leuven, B-3000 Leuven, Belgium; 9Health Research Board Irish Stroke Clinical Trials Network and Mater University Hospi-
`tal/University College Dublin, Ireland
`
`A R T I C L E H I S T O R Y
`
`Received: December 21, 2017
`Accepted: January 12, 2018
`
`DOI:
`10.2174/1381612824666180116100310
`
`Abstract: Introduction: Despite the proven efficacy of anti-thrombotic, lipid-lowering, anti-hypertensive thera-
`pies and lifestyle modification changes for secondary ischemic stroke prevention, the risk of recurrent stroke,
`coronary events and vascular death remains substantial even for patients treated with high rates of established
`secondary preventive medications.
`Methods: In the present review, we summarize available literature data on the association between systemic in-
`flammation and symptomatic atherosclerosis including recurrent cerebral ischemia. We also highlight the poten-
`tial role of colchicine in the suppression of atherosclerosis-induced inflammation, plaque stabilization and throm-
`boembolism prevention.
`Results: Accumulating evidence suggests that inflammation is of key importance in the pathophysiology of athe-
`rosclerotic plaque de-stabilization and thromboembolism, with inflammatory cells being involved in all stages of
`atherosclerosis development. Therefore, anti-inflammatory therapies targeting the atherosclerotic plaque inflam-
`mation may be important contributors in plaque stabilization and in the prevention of thromboembolic events.
`Colchicine is known to have multiple anti-inflammatory properties including inhibition of microtubule polymeri-
`zation, leading to reduced secretion in monocyte-macrophages. Currently the randomized controlled CONVINCE
`trial is enrolling stroke patients to evaluate the effect of a daily low-dose of colchicine in reducing the rate of
`recurrent stroke and major vascular events.
`Conclusion: Inflammatory pathways seem to be key mediators in the development of atherosclerotic process,
`atheromatous plaque destabilization and thromboembolism. Colchicine as a novel therapeutic agent could be a
`safe and effective inhibitor of the inflammation cascade in patients with extra- or intracranial atherosclerosis or
`arteriolosclerosis, resulting in reduced vascular events.
`
`Keywords: Colchicine, inflammation, stroke, cerebral ischemia, transient ischemic attack, macrophages, prevention.
`
`1. INTRODUCTION
`
`Cerebrovascular disease is the most common cause of disability
`in older adults with rapidly increasing incidence rates in low-
`income and middle-income countries [1]. Despite the proven effi-
`cacy of anti-thrombotic, lipid-lowering, anti-hypertensive therapies
`and lifestyle modification changes for secondary ischemic stroke
`prevention, sub-optimal secondary prevention is common among
`patients with history of ischemic stroke (IS) or transient ischemic
`attack (TIA) [2, 3]. Moreover, the risk of recurrent stroke, coronary
`events and vascular death remains substantial even for those pa-
`tients treated with high rates of established secondary preventive
`therapies. Data from recent clinical trials and stroke registries indi-
`cate an annual recurrent stroke risk of 2.5%-4% in patients treated
`with high rates of statin and antiplatelet therapies after IS or TIA
`[4-6]. A recent meta-analysis reported that one in five patients with
`IS/TIA have antiplatelet resistance to either aspirin or clopidogrel
`and these patients are at a significantly higher risk of IS/TIA
`
`*Address correspondence to this author at the Second Department of Neu-
`rology, National and Kapodistrian University of Athens, School of Medi-
`cine, Athens, Greece, Iras 39, Gerakas Attikis, Athens, Greece 15344; Tel:
`+30 6937178635; Fax: +30 2105832471; E-mail: tsivgoulisgiorg@yahoo.gr
`
`recurrence [7]. A systematic review estimated that the cumulative
`pooled risk of recurrent stroke risk is 11.1% in the first 1 year and
`26.4% in the first 5 years after a cerebrovascular event [8]. Addi-
`tionally, the annual incidence rate of vascular death not attributed to
`stroke and non-fatal myocardial infarction in stroke survivors has
`been estimated to 2.1% and 0.9% respectively [9].
`
`2. ARTERY ATHEROTHROMBOSIS AND ARTERIOLO-
`SCLEROSIS: A TARGET FOR INTERVENTION
`
`Early stroke recurrence risk is higher in patients with large-
`artery atherosclerosis compared with other stroke etiologies [10-
`13]. Population-based and hospital registry studies have reported
`the presence of symptomatic ipsilateral carotid stenosis of more
`than 50% of arterial lumen in 12%-20% of IS patients [14-19], and
`intracranial atherosclerosis
`in 8%-10% of North Ameri-
`can/European and 30%-50% of Asian patients [20-22]. Addition-
`ally, in the North Dublin Population Stroke Study, 73% of cere-
`brovascular ischemic events classified as cryptogenic according to
`TOAST criteria [23] had evidence of aortic or cranio-cervical athe-
`rosclerosis [24]. The presence of thick plaques (>4mm) in the aortic
`arch and descending aorta is also frequent in patients with crypto-
`genic stroke [25-28]. In one prospective study protocol, patients
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`Current Pharmaceutical Design, 2018, Vol. 24, No. 6 669
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`with cryptogenic IS/TIA were found to have 5 times higher odds of
`aortic arch plaques >4mm compared to patients with stroke of iden-
`tified cause [29], supporting the hypothesis that aortogenic plaque
`embolism might have contributed to the cerebral ischemic event.
`
`4. INFLAMMATORY BIOMARKERS: INDICATORS OF
`PLAQUE DE-STABILIZATION AND PREDICTORS OF
`THROMBOEMBOLISM IN PATIENTS WITH ATHERO-
`SCLEROSIS
`
`Formation of micro-atheroma is an important contributor to
`
`small vessel cerebrovascular ischemia, accounting for up to 20% of
`total IS. Although the pathophysiology of cerebral ischemic events
`in small vessel disease is heterogeneous and not completely under-
`stood, existing data suggest that micro-atheroma of larger penetrat-
`ing arterioles causes distinct symptomatic acute lacunar infarcts,
`while lipohyalinosis (‘arteriolosclerosis’) is responsible for the
`diffuse white matter hyperintensities on neuroimaging and neuropa-
`thological evidence of cerebral demyelination [30].
`
`3. SYMPTOMATIC ATHEROMATOUS PLAQUES: A
`TRIGGER OF SYSTEMIC INFLAMMATION CASCADE
`
`Recent experimental and clinical-pathological studies have
`
`shown that microscopic cholesterol crystals form in the early stages
`of atherosclerotic plaque development, and may be a potent in-
`flammatory stimulus for neutrophils and macrophages [31]. Studies
`in apolipoprotein E (ApoE)-deficient mice have demonstrated that
`cholesterol crystals activate monocytes and macrophages via the
`intracellular nucleotide-binding leucine-rich repeat-containing pyrin
`receptor (NLRP) inflammasome protein complex [32]. This causes
`increased interleukin-1β (IL-1β) expression, which in turn is con-
`sidered as a key event in the initiation of local and systemic in-
`flammatory cascades, evidenced by increased systemic levels of
`interleukin-6 (IL-6) and C-Reactive Protein (CRP) [33].
`
`The Oxford Plaque Study found that 66% of 526 patients with
`
`symptomatic carotid stenosis had evidence of marked inflammation
`in resected plaques from the ipsilateral internal carotid arteries,
`while 64% had other features of plaque instability (thin fibrous cap,
`large lipid core, cap rupture, or superficial thrombus) [34]. Infiltra-
`tion of many inflammatory cells, large lipid core, and thin fibrous
`cap are the main features of an unstable atheromatous plaque that is
`prone to rupture and thrombosis [35]. Extensive macrophage infil-
`tration, cap thickness <200µm, intraplaque hemorrhage, and large
`lipid core were independently associated with plaque rupture. In a
`similar study of 44 consecutive patients with ipsilateral carotid
`stenosis who underwent endarterectomy within 10 days following
`the IS/TIA index event, stroke recurrence in the days between index
`event and surgery was independently associated with extensive
`macrophage and lymphocyte infiltration [36]. These important ob-
`servations provide direct evidence linking plaque lipid metabolism
`and inflammation.
`
`Indirect in-vivo support for the aforementioned findings have
`
`been provided by a positron emission tomography (PET) study in
`patients with symptomatic carotid stenosis, where 18-fluorodeoxy-
`glucose (18-FDG) uptake in symptomatic plaque was associated
`with total and LDL cholesterol, and inversely associated with HDL
`cholesterol, after adjustment for confounding variables [37]. FDG-
`PET is a validated technique for imaging plaque metabolic activity,
`mainly related to inflammatory monocyte-macrophage activity.
`Symptomatic carotid plaques had high FDG uptake that correlated
`strongly with plaque macrophage density [38]. Moreover, cross-
`sectional studies have reported that plaque FDG uptake is associ-
`ated with other markers of plaque instability, including micro-
`embolic signals on transcranial Doppler ultrasound, unstable plaque
`morphology, and expression of inflammatory cytokines and prote-
`ases [39-41]. Carotid plaque FDG uptake was identified as an inde-
`pendent predictor of early pre-endarterectomy stroke recurrence in
`patients with IS/TIA and ipsilateral carotid stenosis [42-44].
`
`
`
`
`
`
`
`
`
` Accumulating evidence supports the view that inflammation is
`of key importance in the pathophysiology of atherosclerotic plaque
`de-stabilization and thromboembolism, with inflammatory cells
`being involved in all stages of atherosclerosis development [45, 46].
`Retention of LDL lipids in the extracellular matrix of the arterial
`wall is accompanied by differentiation of monocytes and lipid up-
`take to lipid-laden ‘foamy’ macrophages. Trans-endothelial migra-
`tion of circulating monocytes is a key event in the initiation of athe-
`rosclerotic plaque induced inflammatory process, resulting in local
`expression of pro-inflammatory cytokines, particularly IL-1β and
`tumor necrosis factor-alpha (TNF-α) [45]. Other produced cytoki-
`nes, such as platelet-derived growth factor (PDGF), promote re-
`cruitment and proliferation of smooth muscle cells into the endothe-
`lial cell layer, which in turn promote the expression of matrix pro-
`teins such as collagen and elastin. Expression of cytokines and col-
`lagenolytic enzymes, such as metalloproteinases from macrophages
`and other cells, contributes to erosion and rupture of the fibrous
`cap, which results in exposure of circulating platelets and coagula-
`tion factors to the pro-thrombotic core, and subsequent thromboem-
`bolism [46].
`
`Increased inflammatory cells, including macrophages and acti-
`
`vated microglia, expressing matrix metalloproteinases (MMPs) are
`present around affected arterioles and areas of ischemic demyelina-
`tion in patients with small artery disease [47, 48]. Numerous studies
`have associated CRP levels and leucocyte count not only with
`pathological features of plaque instability (rupture, inflammation),
`but also with higher risk of recurrent stroke in patients with IS or
`TIA due to extracranial or intracranial atherosclerosis [49-55]. In
`1,244 patients with lacunar stroke in the SPS3 trial, baseline CRP
`was associated with a 2.32-fold increase in the adjusted risk of re-
`current stroke and vascular events [56]. In the Chinese CHANCE
`trial, which included 3,044 patients with non-severe stroke of non-
`cardioembolic origin, high CRP levels at baseline were associated
`with a 1.46-fold increase in the adjusted risk of early recurrent
`stroke at 90 days [57]. Likewise, in 1,232 patients with recent
`IS/TIA in the Oxford Vascular Study, CRP measured in the acute
`phase was an independent predictor of 90-day stroke recurrence
`[58]. Similar findings have been observed with other inflammatory
`biomarkers, including fibrinogen and IL-6 [59]. Epidemiological
`studies have consistently described dose-dependent associations
`between circulating blood cytokines IL-1, IL-6, TNF-α and vascular
`disease, including stroke [60].
`
`5. ASSOCIATION OF STATIN-INDUCED SUPPRES-
`SION OF INFLAMMATION WITH ATHEROSCLEROTIC
`PLAQUE STABILIZATION
`
`Even though the exact mechanisms explaining the higher risk of
`
`cerebrovascular ischemia in patients with arterial atherosclerosis yet
`remain unclear, it has been hypothesized that inflammation-related
`plaque instability may be an important contributing factor [61],
`with recent data indicating that anti-inflammatory therapies target-
`ing the atherosclerotic plaque inflammation may be important con-
`tributors to plaque stabilization and in the prevention of throm-
`boembolic events [62].
`
`Randomized-controlled clinical trials in patients with non-
`
`cardioembolic IS or TIA have demonstrated benefit of targeting
`plaque-related lipid accumulation with high-dose atorvastatin and
`platelet activation to prevent recurrent stroke and coronary events
`
`
`
`
`
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`670 Current Pharmaceutical Design, 2018, Vol. 24, No. 6
`
`Tsivgoulis et al.
`
`[63-65]. In addition to their lipid-lowering effect, statins are known
`to influence other biological pathways including the upregulation of
`endothelium nitric oxide synthase (eNOS) and other anti-
`inflammatory effects [66]. Our study group has recently shown that
`statin pretreatment in patients with ischemic stroke due to large
`artery atherosclerosis is dose-dependently associated with several
`improved outcomes: neurologic improvement, disability, survival,
`and stroke recurrence. [67]. We also documented that statin pre-
`treatment was associated with reduced presence of microembolic
`signals (MES) on transcranial Doppler monitoring and lower MES
`burden with an apparently dose-dependent association in patients
`with extra- or intra-cranial atherosclerosis [68]. Likewise, other
`study protocols have demonstrated reduction in blood biomarkers
`and plaque FDG uptake in a dose-dependent manner by statins [69,
`70].
`
`These real-time in-vivo observations provide additional data on
`
`the positive role of statins on atherosclerotic plaque stabilization
`and cerebrovascular vasculature, and thus further support the bene-
`ficial effect of statins on recurrent ischemic events [66]. Interest-
`ingly, in the JUPITER trial, treatment with rosuvastatin reduced
`LDL by 50%, CRP levels by 37% and major vascular events by
`46% [71]. Likewise, in the IMPROVE-IT trial addition of ezetimibe
`to simvastatin was associated with significantly lower values of
`both LDL and high sensitivity CRP (hsCRP), and with lower inci-
`dence rates of primary endpoints (cardiovascular deaths, major
`coronary events, or strokes) compared to simvastatin alone after
`multivariable adjustment [72].
`
`6. ASSOCIATION OF CANAKINUMAB-INDUCED INHIBI-
`TION OF INFLAMMATION WITH CARDIOVASCULAR
`EVENT REDUCTION
`
`It has been estimated that in approximately 25% of patients
`
`with ischemic heart disease the risk of future vascular events is
`directly associated with inflammatory atherosclerosis, measured
`using the hsCRP biomarker [73]. Thus, the immune system may
`represent a novel and promising target for the prevention and treat-
`ment of atherothrombosis [74].
`
` ACZ885 (canakinumab) is a selective, high-affinity, fully hu-
`man monoclonal antibody inhibiting IL-1ß, a key cytokine in the
`pathway of inflammatory atherosclerosis [75-78]. The efficacy,
`safety and tolerability of quarterly subcutaneous injections of ca-
`nakinumab in combination with standard of care for the prevention
`of recurrent cardiovascular events in patients with a prior myocar-
`dial infarction and hsCRP levels ≥2mg/L has been evaluated in the
`the Canakinumab Anti-inflammatory Thrombosis Outcomes Study
`(CANTOS) trial [79]. According to a recently published media
`report CANTOS met the primary composite endpoint of heart at-
`tack, stroke and cardiovascular death after recruiting a total of
`10,061 participants with a median follow-up of 3.8 years [80]. The
`positive results of the CANTOS trial not only show that canakinu-
`mab reduces cardiovascular risk in people with a prior heart attack
`and inflammatory atherosclerosis [80], but also provide invaluable
`support to the inflammatory hypothesis of atherothrombosis and
`expand even further on the contribution of innate immunity to
`cardiovascular health [81].
`
`7. COLCHICINE: A POTENTIAL DRUG TARGETING ON
`ATHEROSCLEROSIS INDUCED INFLAMMATION AND
`SECONDARY STROKE PREVENTION
`
`Colchicine has been the cornerstone treatment for gout,
`
`Bechet’s Disease and Familial Mediterranean Fever for decades
`[82]. Colchicine is readily-absorbed after oral administration in the
`jejunum and ileum, by a P-glycoprotein (ABCB1-transporter) de-
`pendent process. It undergoes significant 1st-pass hepatic metabo-
`lism, resulting in oral bioavailability averaging 45% (range 24-
`88%) in healthy volunteers. It is excreted primarily (80-90%) via
`biliary secretion (via the cytochrome P450 CYPA34 system), and
`
`also partly by the renal route (10-20%), and via intestinal epithe-
`lium [82].
`
`Its primary cellular action is binding to α - and β-tubulin pro-
`
`teins, which are highly-expressed in neutrophils and monocyte-
`macrophage inflammatory cells. It has multiple anti-inflammatory
`properties including inhibition of microtubule polymerization, with
`inhibition of E-selectin mediated leucocyte rolling and endothelial
`adhesion, and leucocyte motility, phagocytosis, and cytokine secre-
`tion. In vitro, colchicine inhibits crystal-induced activation of the
`NLRP inflammasome, possibly via inhibition of microtubule po-
`lymerisation, which is a pre-requisite for inflammasome assembly.
`This leads to inhibition of proteolytic cleavage of pro-IL1β by
`caspase-1, leading to reduced secretion in monocyte-macrophages
`(Fig. 1) [83]. On the other hand, evidence on the potential use of
`colchicines in chronic low-grade inflammatory conditions is still
`limited [84].
`
`
`
`
`
`Fig. (1). Potential pathophysiological mechanisms of colchicine on plaque
`
`stabilization and thromboembolic event prevention.
`
`
` Observational data have reported lower rates of coronary artery
`disease in patients with gout and Familiar Mediterranean Fever
`receiving colchicine therapy [85]. In the LoDoCo RCT of 532 pa-
`tients with chronic stable coronary artery disease, low dose of col-
`chicine (0.5mg/day) reduced the risk of major cardiovascular events
`by 67% over a median follow-up period of 36 months. In this trial
`colchicine had an excellent safety profile, with the more frequently
`reported adverse events being intestinal upset (2.5%), myalgia
`(0.9%) and myositis, rash, itch, alopecia, or peripheral neuropathy
`(<0.5%), and no excess of death observed [86]. Recent trials have
`also demonstrated benefit of low-dose colchicine (0.5-1mg/day) for
`prevention of recurrent pericarditis and reduced infarct size when
`used acutely in patients with ST-elevation myocardial infarction
`[87, 88]. A recent systematic review of 39 trials and 4,992 total
`patients focusing on the safety and efficacy of long term colchicine
`use on cardiovascular disease reported that colchicine was related
`
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`The Role of Colchicine in the Prevention of Cerebrovascular Ischemia
`
`Current Pharmaceutical Design, 2018, Vol. 24, No. 6 671
`
`Table 1. Outcomes of interest reported in the meta-analysis of available randomized clinical trials by Hemkens et al. [76] on the ef-
`fect of Colchicine on the prevention of cardiovascular events.
`
`Outcome
`
`No of Participants
`
`Relative Effect (95%CI)
`
`Heterogeneity
`
`Stroke
`
`Myocardial infarction
`
`Cardiovascular mortality
`
`All-cause mortality
`
`Total adverse events
`
`RR: risk ratio, OR: odds ratio
`
`(Studies)
`
`874
`
`(3 studies)
`
`652
`
`(2 studies)
`
`1132
`
`(7 studies)
`
`4174
`
`(30 studies)
`
`1313
`
`(11 studies)
`
`OR 0.38
`
`(0.09 to 1.70)
`
`RR 0.20
`
`(0.07 to 0.57)
`
`RR 0.34
`
`(0.09 to 1.21)
`
`RR 0.94
`
`(0.82 to 1.09)
`
`RR 1.52
`
`(0.93 to 2.46)
`
`I2=0%
`
`N/A
`
`I2=9%
`
`I2=27%
`
`I2=45%
`
`with an 80% decrease on the risk of myocardial infarction, with no
`increased risk of serious adverse events [89]. The main findings of
`this meta-analysis are summarized in Table 1.
`
` Moreover, in another RCT a short perioperative course of col-
`chicine was effective in attenuating postoperative myocardial injury
`of patients undergoing coronary artery bypass grafting [90]. Simi-
`larly, diabetic patients with contraindication to a drug-eluting stent
`undergoing percutaneous coronary intervention randomized to re-
`ceive colchicine 0.5 mg twice daily for 6 months were found to
`have significantly lower rates of bare-metal stent restenosis com-
`pared to those receiving placebo [91]. Within the setting of other
`published RCTs colchicine was effective and safe treatment for the
`prevention of early atrial fibrillation recurrence after pulmonary
`vein isolation in the absence of antiarrhythmic drug treatment, with
`this effect being strongly associated with a significant decrease of
`the inflammatory mediators IL-6 and CRP [92], while several other
`RCTs that will evaluate the role of colchicine in the prevention of
`atrial fibrillation after cardio-thoracic surgery are still ongoing [93,
`94]. Treatment with colchicine was also associated with reduction
`in inflammation biomarker levels in patients with stable chronic
`heart failure [95].
`
`Colchicine for prevention of Vascular Inflammation in Non-
`
`CardioEmbolic stroke (CONVINCE) trial is an ongoing RCT that
`will test the hypothesis that daily low-dose colchicine (0.5mg/day)
`combined with usual care (lifestyle changes, antiplatelet, antihyper-
`tensive and lipid-lowering therapy) will have benefit in the preven-
`tion of recurrent stroke and major vascular events compared with
`usual care alone [96, 97]. Similar to other stroke secondary preven-
`tion trials of antiplatelet and lipid-lowering therapy, CONVINCE
`will include patients with non-severe (modified Rankin score 3 or
`less) stroke or TIA, randomized between 72 hours and 28 days of
`symptom onset and followed for a median of 36 months. Patients
`with cardioembolic stroke/TIA, those with other identified non-
`atherosclerotic stroke mechanisms (e.g. arterial dissection), or con-
`tra-indication to colchicine therapy will be excluded. The tolerabil-
`ity and safety of colchicine will be closely monitored, with a pre-
`specified review after completion of randomization of the initial
`10% of the trial sample [96, 97]. The study primary endpoint aims
`to investigate the efficacy of low dose colchicine (0.5mg/day) in
`this study population to prevent non-fatal recurrent ischemic stroke,
`myocardial infarction, cardiac arrest, and vascular death. Other
`secondary endpoints include the safety of colchicine, the effect of
`
`colchicine on each component of the composite primary outcome
`measure and the effect of treatment on the primary outcome across
`different patient categories [94]. Moreover, CONVINCE trial will
`investigate the effect of colchicine on direct health care costs, in-
`corporating quality-adjusted life years [96, 97].
`
`CONCLUSION
`
`Experimental, epidemiological and clinical data suggest that
`
`inflammatory pathways are key mediators in the development of
`atherosclerotic process, atheromatous plaque destabilization, throm-
`boembolism and arteriolosclerosis
`leading
`to cerebrovascular
`ischemia and other vascular events. Recent RCT data indicate that
`inhibition of inflammatory pathways in patients with coronary ar-
`tery disease and elevated CRP levels may result in additional pre-
`vention of cardiovascular and cerebrovascular events. Colchicine
`could be a safe and effective inhibitor of the inflammation cascade
`induced by extracranial or intracranial atherosclerosis, providing
`thus an additional
`therapeutic agent
`in
`secondary non-
`cardioembolic stroke prevention. CONVINCE trial will test the role
`of colchicine in the secondary prevention of non-cardioembolic
`stroke and hopefully improve our knowledge on the role of inflam-
`mation in stroke pathogenesis.
`
`DISCLOSURE
`
`“Part of this article has previously been published in Journal of
`
`Neurology Neurosurgery Psychiatry, 2017”.
`
`CONSENT FOR PUBLICATION
`
` Not applicable.
`
`CONFLICT OF INTEREST
`
`The authors declare no conflict of interest, financial or other-
`
`wise.
`
`ACKNOWLEDGEMENTS
`
`
`
`RL is a senior clinical investigator of FWO Flanders.
`
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