The Carotid Artery Multi-modality Imaging Prognostic (CAMP) Study
Study Details
Study Description
Brief Summary
Carotid artery disease is a main cause of ischemic stroke and vascular dementia, and a highly prevalent disease. There is uncertainty about the optimal management of patients with serendipitously or systematically detected asymptomatic carotid artery disease, due to the paucity of information on the predictive features of serious vascular events. While percent diameter stenosis is currently the accepted standard to decide about local interventions (carotid artery stenting or endarterectomy), international guidelines also recommend the evaluation of qualitative features of carotid artery disease as a guide to treatment. There is, however, no agreement on which qualitative features are best predictors of events. Furthermore, a role for metabolic plaque profile, local mechanical and hemorheologic factors in triggering microembolization and silent ischemic events has been proposed from experimental studies. This inadequate knowledge leads to a poor ability to identify patients at higher risk and to an unwarranted dispersion of medical resources, lack of standardization in diagnostic methods, and the use of expensive and resource-consuming techniques.
Against this background, the investigators aim at:
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Prospectively identifying the best predictors of (silent and overt) ischemic stroke and vascular dementia in patients with asymptomatic subcritical carotid artery disease, by identifying the non-invasive diagnostic features of the "vulnerable carotid plaque" as a possible guide for optimal - local and systemic - treatment.
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Transferring new ultrasound techniques possibly improving risk prediction to the clinical field
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Assess whether "smart", low-cost diagnostic methods, such as ultrasound-based evaluations integrating established and advanced techniques, may yield at least the same level of prospective information as more expensive and less cost-effective techniques.
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Detailed Description
BACKGROUND AND RATIONALE
State of the art and preliminary data Stroke is a most relevant health burden, the second most common cause of death and the third cause of disability worldwide. Stroke is a heterogeneous disorder with several disease mechanisms implicated in its pathogenesis. Ischemic stroke accounts for 87% of all stroke cases. The TOAST (Trial of Org 10172 in Acute Stroke Treatment) and the more recent SSS-TOAST (Stop Stroke Study TOAST) classifications currently provide the most widely used schemes of stroke classification for clinicians. Accordingly, pathomechanisms comprise: (a) large artery atherothrombosis (i.e., a major brain artery or branch cortical artery); (b) cardioembolism; (c) small vessel occlusion (lacunar infarcts); (d) other determined etiology (i.e., hypercoagulable states, hematologic disorders); (e) undetermined etiology (cryptogenic embolism; incomplete patient evaluation).
Silent stroke, usually defined as focal T2 hyperintensities >3 mm with correlative T1 hypointensities at magnetic resonance imaging (MRI), has a reported incidence of 10-15% and a relevant significance in terms of cognitive impairment and correlations with clinically overt stroke. Silent stroke is a cerebrovascular ischemic (less frequently haemorrhagic) lesion detected by neuroimaging such as magnetic resonance imaging (MRI) that does not determine acute focal neurological deficits but causes cerebral damage in an unaware way. Typically, silent stroke (SS) affects regions associated with various mental processes, mood regulation and cognitive functions, and therefore is a leading cause of vascular cognitive impairment that impacts about one-third of individuals over the age of 70. Cerebral small vessel disease related to aging (and possibly to age-related arterial stiffness) leading to leucoaraiosis and lacunar infarctions is a main cause of SS, but also microembolic lesions due to atrial fibrillation and carotid stenosis may be involved.
The diagnosis of SS stroke may be challenging. In many cases, subjects are not diagnosed until long after a stroke occurs or in case of progressive cognitive impairment. Occasionally, strategic lesions in cerebral areas related to cognitive function, the hippocampus or the thalamus, and, more frequently, incremental lesion load over time lead to vascular dementia (VD). VD is is the second most common form of dementia after Alzheimer's disease. The prevalence of the illness is about 5% in Western countries. Current epidemiologic research suggests that AF contributes to cognitive decline and dementia independent of a history of stroke. Further work is warranted to elucidate the potential mechanisms underlying this association, and better designed studies are needed to explore the possible cognitive benefits of different therapeutic options in patients with carotid disease. Potential pathophysiological pathways linking carotid disease with cognitive decline are microembolism, systemic inflammation, and cerebral hypoperfusion.
STUDY DESIGN This is a monocenter, prospective, longitudinal, observational study. This is a no-profit study, granted by Regione Toscana - Bando Salute 2018.
Setting Eligible participants (see inclusion and exclusion criteria below) will be selected and recruited in the outpatient setting of the UO Cardiologia 1 - AOUP. Exclusion and inclusion criteria will be evaluated according the previous medical history and imaging tests of the participant. All participants identified as eligible will receive all the necessary information about the study and will sign the informed consent under the supervision of the Principal Investigator. In case of enrollment, a detailed plan will be prepared for each participant to schedule the study evaluations to be integrated with the routine examinations.
STUDY OUTCOMES Variables
Different variables will be assessed and analyzed, in particular:
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Baseline neurological, psychological and neurocognitive evaluation
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Baseline brain MRI evaluation
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Angio-MRI for carotid stenosis assessment and plaque tissue characterization
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Angio-CT evaluation for carotid stenosis assessment and plaque characterization
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Multigate Doppler (MGD) Investigation of Carotid Artery Stenosis
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Carotid stenosis assessment
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Wall shear rate and flow separation analysis
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Advanced ultrasound techniques for plaque vulnerability and local mechanical properties assessment a. Ultrasonographic markers of plaque composition b. Validation of 3D US for carotid plaque stenosis severity and morphology assessment c. Radiofrequency data for assessment of fibrous cap thickness, plaque deformation, and local arterial waveform and stiffness
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Follow-up (2-years) brain MRI evaluation
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Follow-up (2 years) neurological, psychological and neurocognitive evaluation
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Baseline neurological, psychological and neurocognitive evaluation
Each participant will be evaluated at baseline and at the 2-year follow-up with a detailed medical history and physical examination. A detailed assessment of cognitive decline/dementia will be performed as below detailed:
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Montreal Cognitive Assessment (MoCA), a brief screening tool wide used and sensitive for mild cognitive impairment. Moreover, performing a subtests analysis of MoCA results will allow to analyse performance visuospatial and executive functions, attention, and recall.
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Adopting a more focus on specific cognitive functions, and following results of two recent studies (The Tromso study - Mathiesen et al., 2004; Cheng et al., 2012) in asymptomatic carotid stenosis, the investigators will also assess:
• Working memory: Backward Digit Span
• Attention and psychomotor speed: Trail Making Test (Parts A and B)
• Motor functioning: Grooved Pegboard Test
• Memory: Verbal and Visual Paired Association (immediate and delayed recall - subtest of the Wechsler Memory Scale)
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Complex visuospatial perception: Modified Complex Figure Test (copy and recall)
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Finally, it is also important to evaluate subjective dizziness and changes in cognitive status, proved sensitive to carotid stenosis, using two brief self-report questionnaires:
• The Dizziness Handicap Inventory
• The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)
- The total assessment time will be around 30 minutes. The Clinical Psychology Unit will be responsible for preliminary tutorship of Centers about questionnaires administration, and subsequent centralized analysis.
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Baseline brain MRI evaluation Silent brain infarction will be defined as focal T2 hyperintensity >3 mm with correlative T1 hypointensities at MRI. This evaluation will be matched with the similar 2-year follow-up examination, to assess the occurrence of silent strokes.
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Angio-MRI for carotid stenosis assessment and plaque tissue characterization Angio-MRI of carotid arteries will be performed at baseline and after a two-year follow-up for carotid plaque characterization.
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Angio-CT evaluation for carotid stenosis assessment and plaque characterization Estimation of lumen stenosis and vessel anatomy with contrast agents. Specific algorithms (quantitative evaluation of calcifications - lipid core - haemorrhage): the two main CT techniques for plaque characterization here used will be multi-detector-row CT and dual-source CT. Multi-detector-row CT will characterize plaque calcification, ulcerations, fibrous plaque thickness, intra- plaque haemorrhage and the presence of lipid-rich necrotic cores, based on voxel Hounsfield units density (HUs).
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Multigate Doppler (MGD) Investigation of Carotid Artery Stenosis The University of Pisa has a long-standing collaboration with the Microeletronic System Design Lab (MSD-Lab) at the Department of Informational Engineering (DINFO) of Florence University, based upon an ultrasound advanced open platform (UlAOP) providing a detailed representation and quantification of flow velocity profile and wall shear rate by means of multiple spectral Doppler sample volumes (128) aligned perpendicularly through the longitudinal arterial axis.
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Carotid stenosis assessment A customized configuration developed in Florence will be used to provide in real time a simplified flow velocity profile in common and internal carotid artery, using 7 Doppler vectors aligned through the vessel transverse axis, before, within and after the plaque. This approach allows to overcome the assumption of a fully parabolic flow velocity profile through the vessel, which is instead variably skewed in the presence of curvatures and stenosis. The correlation of central flow velocity, peak flow velocity and flow velocity distribution with severity and shape of carotid stenosis as assessed by angio-TC will be investigated. The association of flow velocity values and skewness with MES and silent brain ischemic lesions will be also assessed.
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Wall shear rate and flow separation analysis By post-processing of MGD datasets, wall shear rate, oscillatory flow velocity patterns and retrograde flows will be estimated using a computational fluid dynamics (CFD) approach. The association of these parameters with MES and baseline and incident silent brain ischemic lesions will be assessed. This evaluation will be performed in a subset of 100 participants recruited in Pisa, no more than 2 months after the angio-TC evaluation
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Advanced ultrasound techniques for plaque vulnerability and local mechanical properties assessment After the baseline investigation, in a subset of participants, the ultrasound investigation of carotid arteries and plaques will be repeated by US system providing radiofrequency raw data for post-processing analysis. Conventional 2D US scan as well as acquisition of the RF-data sets will be performed. Two-dimensional images will be exploited for tissue characterization analysis; RF- datasets will be used to determine fibrous cap thickness, local plaque deformation, arterial contour- wave analysis with central pulsatile pressure and excess pressure estimate. This evaluation will be performed at baseline no more than 2 months after the angio-TC evaluation, and then repeated at the two-year follow-up.
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Ultrasonographic markers of plaque composition Carotid plaque characterization will be performed on 2D images at Lund University, by means of a customized software recently validated against immunohistochemistry by Nilsson J and Goncalves I within the context of a FP7 collaborative study on diabetes (IMI-SUMMIT project), with the participation of the University of Pisa (Palombo C et al).
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Validation of 3D US for carotid plaque stenosis severity and morphology assessment Plaque volume and shape assessment (concentric/eccentric, regular, irregular) will be assessed with a dedicated 3D probe implemented on a Philips cardiovascular US platform in 50 participants. After acquisition of a 3D dataset (Fully Automated Mechanical Transducer), including total plaque volume and maximum area reduction. Total ulcer volume and size will be integrated. Off-line texture analysis will be performed on a dedicated subset of images. Beside conventional 2D ultrasonographic assessment of stenosis severity (including Doppler findings and 2D findings), advanced ultrasonographic examinations will be performed with the aim of quantitative data acquisition on tissue characterization, detection of neovascularity, detection of total plaque burden (volume 3D), plaque deformation and flow profiling. This subproject will be performed only at baseline.
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Radiofrequency data for assessment of fibrous cap thickness, plaque deformation, and local arterial waveform and stiffness The RF-dataset provided by the Esaote systems will allow estimate of common carotid distensibility and plaque fibrous cap thickness and deformation thanks to an array of 16 parallel lines crossing the vessel longitudinal axis through 14 mm, with high spatial (10 μm) and temporal (660 Hz) resolution. A pressure- calibrated local arterial distension waveform is also obtained, from which indices of local stiffness, pulsatile pressure, including the so-called "excess pressure", and wave reflection can be assessed.
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Follow-up (2-years) brain MRI evaluation This examination will be performed at the 2-year follow-up and matched with the baseline examination, to assess new incident events. Silent stroke will be similarly defined as focal T2 hyperintensity >3 mm with correlative T1 hypointensities at MRI. At this visit, MRI will be limited to the brain, without carotid reassessment
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Follow-up (2 years) neurological, psychological and neurocognitive evaluation This will be done with a complete physical examination and the use of dedicated scales to perform an evaluation of signs of silent stroke or cerebral involution, as per item 1.
Tools/equipment: questionnaires. Expected results: assessment of possible neuropsychologic and cognitive status changes after two years + correlations between changes in neuropsychologic and cognitive status after follow-up and MES, carotid plaque features, local arterial mechanics, and atherosclerotic risk profile at baseline (longitudinal study) + correlations between changes in neuropsychologic and cognitive status after follow-up and changes in silent brain ischemic lesions (MRI), and in carotid plaque features and local arterial mechanics by ultrasound, conventional and advanced (longitudinal study).
DATA MANAGEMENT Data collection All variables listed above will be safely reported on the case report form, collected and stored, including some self-reported questionnaires, i.e. the Dizziness Handicap Inventory and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE).
Data management All data will be managed in compliance with the General Data Protection Regulation (GDPR). A dedicated platform (Data Platform) in full compliance with the GDPR rules and the Italian Legislative Decree no. 196 dated 30/06/2003 will be developed. Digital and paper-based case report forms will be generated to collect participants' data. Data will be then uploaded on the Data Platform for safe storing by using cloud technologies and secured access credentials and protocols (TLS / HTTPS). All necessary measures to ensure full protection of data will be applied.
Pseudonymisation will be guaranteed by a secured alphanumeric code, whose key will be password-protected and available only to the study investigators.
Data storage The principal investigator (Prof. Raffaele De Caterina) will be responsible for data collection, management, storage and pseudonymisation.
Statistical analysis Correlation and regression analysis will be performed in uni- and multivariate manner, after correction for collinearity. Bland-Altman Analysis will assess the predictive power and concordance of each methods for specific plaque features. Logistic regression analysis, Cox regression analysis and survival analysis will be performed according to different predictors, after determination of cut-off values for single continuous variables. Incremental analysis (Chi-square; Net reclassification) will be performed in order to assess the integrated value of combined (multi-imaging; soluble biomarkers; clinical) methods. Finally, an inter- and intra-observer analysis will be performed. A mathematical models combining the features derived from all the techniques used to construct the best model predictive of stroke and the development of neurocognitive decline.
ADMINSITRATIVE ASPECTS Study financial support The study will be financially supported by Regione Toscana, Bando Salute 2018. There will be no interference from Regione Toscana on the scientific management of the study. Three financial tranches will be bestowed as for formal agreements (at the beginning of the study, at 18 months, at 36 months or termination of the study).
Ethical considerations The study will be conducted according to the norms of Good Clinical Practice (ICH/GCP) and to the ethical guidelines of the Declaration of Helsinki. Enrollment will start only after the protocol is approved by the local Ethical Committee. Written informed consent will be obtained from each participant before enrollment.
Informed consent acquisition Each participant will be carefully and thoroughly informed by the investigators involved in the study at the time of enrollment. Written informed consent will be requested only after a comprehensive discussion with the participant.
There are no financial conflict of interest for any of the investigators involved in the study.
Study Design
Outcome Measures
Primary Outcome Measures
- Number of participants developing TIA/stroke and/or subclinical ischemic lesions [2 years]
The incidence of TIA/stroke and, mainly, the development of subclinical ischemic lesions, as demonstrated by the comparative evaluation of two brain MRI, one at baseline - at the time of acquisition of the carotid plaque characteristics by the multiple techniques here used - and at a 2-year follow-up.
- Number of participants developing neurocognitive decline [2 years]
Neurocognitive decline, as assessed by comparative neurocognitive testing, at baseline, and at the 2-year follow-up
Secondary Outcome Measures
- The cost of the least expensive effective pathway [3 years]
A cost-effectiveness evaluation, to design the least expensive patient evaluation pathway to effectively predict the occurrence of the endpoints, in order to translate it into clinical routine
Eligibility Criteria
Criteria
Inclusion Criteria:
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Asymptomatic carotid artery lesions between 40 and 60%, at carotid artery ultrasound, for which lesions an interventional strategy - beside optimal medical therapy - is not clearly defined.
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Patients with asymptomatic carotid artery stenosis higher than 60% will be enrolled when revascularization by either carotid endarterectomy (CEA) or stenting will be considered not indicated or not feasible
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Both genders (with capping implemented in order to ensure a 50±5% balance of males to females),
Exclusion Criteria:
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Severe comorbidities a priori precluding the 2-year follow-up (cachexia; end-stage cancer; severe renal/respiratory insufficiency; advanced (class IV) heart failure; atrial fibrillation and other significant arrhythmias).
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Severe allergic diathesis; contraindications to contrast agents for angio-TC or MRI; claustrophobia; presence of prostheses/implanted electronic devices not suitable for MRI; lack of consent for any reason.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
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| 1 | Azienda Ospedaliero Universitaria Pisana | Pisa | Tuscany | Italy | 56124 |
Sponsors and Collaborators
- Azienda Ospedaliero, Universitaria Pisana
- University of Florence
- Azienda USL Toscana Nord Ovest
- Fondazione Toscana Gabriele Monasterio
- Lund University Hospital
- University Medical Center Groningen
Investigators
- Principal Investigator: Raffaele De Caterina, MD, Azienda Ospedaliero, Universitaria Pisana
Study Documents (Full-Text)
None provided.More Information
Publications
- Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993 Jan;24(1):35-41.
- Ay H, Furie KL, Singhal A, Smith WS, Sorensen AG, Koroshetz WJ. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol. 2005 Nov;58(5):688-97.
- Barrett KM, Brott TG. Stroke Caused by Extracranial Disease. Circ Res. 2017 Feb 3;120(3):496-501. doi: 10.1161/CIRCRESAHA.117.310138. Review.
- Fabiani I, Palombo C, Caramella D, Nilsson J, De Caterina R. Imaging of the vulnerable carotid plaque: Role of imaging techniques and a research agenda. Neurology. 2020 May 26;94(21):922-932. doi: 10.1212/WNL.0000000000009480. Epub 2020 May 11. Review. Erratum in: Neurology. 2021 Nov 16;97(20):968.
- Feigin VL, Norrving B, Mensah GA. Global Burden of Stroke. Circ Res. 2017 Feb 3;120(3):439-448. doi: 10.1161/CIRCRESAHA.116.308413. Review.
- Gupta A, Giambrone AE, Gialdini G, Finn C, Delgado D, Gutierrez J, Wright C, Beiser AS, Seshadri S, Pandya A, Kamel H. Silent Brain Infarction and Risk of Future Stroke: A Systematic Review and Meta-Analysis. Stroke. 2016 Mar;47(3):719-25. doi: 10.1161/STROKEAHA.115.011889. Review.
- Lim JS, Kwon HM. Risk of "silent stroke" in patients older than 60 years: risk assessment and clinical perspectives. Clin Interv Aging. 2010 Sep 7;5:239-51. Review.
- Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, Elkind MS, George MG, Hamdan AD, Higashida RT, Hoh BL, Janis LS, Kase CS, Kleindorfer DO, Lee JM, Moseley ME, Peterson ED, Turan TN, Valderrama AL, Vinters HV; American Heart Association Stroke Council, Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; Council on Peripheral Vascular Disease; Council on Nutrition, Physical Activity and Metabolism. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013 Jul;44(7):2064-89. doi: 10.1161/STR.0b013e318296aeca. Epub 2013 May 7. Erratum in: Stroke. 2019 Aug;50(8):e239.
- CAMP study