Clinical trial NCT05539781: Change of Hemodynamics and Cerebral Functions After Carotid Artery Revascularization
Official title: Change of Hemodynamics and Cerebral Functions After Carotid Artery Revascularization
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Carotid Artery Diseases
Carotid Artery Stenosis
Cerebrovascular; Disorder, Arteriosclerotic
Cardiovascular Diseases
Nervous System Diseases
Keywords: carotid endarterectomy
carotid stenting
computational fluid dynamic
cognitive function
medical therapy
Lead sponsor: Beijing Friendship Hospital
Sponsor class: OTHER
First posted: 2022-09-14
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Adult, Older Adult

Brief summary: The majority (\>80%) of strokes are of ischemic etiology, of which ≈15% to 20% are attributable to atherosclerosis of the extracranial carotid arteries. The primary goal in carotid artery revascularization is to prevent stroke in patients with carotid artery stenosis. Treatment options including carotid endarterectomy (CEA) and carotid artery stenting (CAS). Hence, the investigators aim to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in terms of long-term prognostic endpoints. Also, CEA and CAS result in different postoperative geometric features of carotid arteries that entail relevant modifications of rheological parameters, that may be associated with the risk of local complications and carotid artery restenosis. Finally, long-term and sustained cognitive benefits after carotid artery revascularization need further research and evidence.

Detailed description: Hypothesis and Significance: We hypothesize that hemodynamically changes after carotid artery revascularization influence the cerebral function or carotid artery patency. If cognitive improvement or impairment and carotid artery restenosis can be demonstrated relate to hemodynamic remodeling in these patients, then we will have established a new prognostic factor for carotid revascularization independent of the existing study.

Specific Aim: 1) To compare the impact of carotid artery revascularization on long-term post-operative baroreceptor function and on cognitive brain function, and analyze their influence on clinical outcome. The specific goal is to assess the potential correlation between post-operative autonomic and cognitive function.

2) To assess the solicitation on the carotid wall due to CAS as compared to CEA through structural analysis and mechanical modeling. The specific goal is to assess the potential correlation between stenting, wall damage, baroceptor impairment, and late neurological sequelae. 3) To assess the post-operative carotid hemodynamics combining medical image analysis, clinical data, and computer simulations. The specific goal aims at correlating both local (e.g., wall shear stress (WSS), oscillatory shear index (OSI), relative residence time (RRT)) and global phenomena (controlateral flow, arterial stiffening) with baroreflex function and post-operative neurological outcomes.

Cognitive Assessment. HALO will use existing cognitive assessment infrastructure. Cognitive assessments in our study must take place prior to revascularization or within two weeks after assignment to medical therapy alone. Testing is repeated at 44 days, and every year thereafter up to 4 years. At each test interval, a composite (mean) Z-score is derived from published normative samples for each test outcome. The primary outcome will be at 1 year in which the change in the composite Z-score from baseline will be calculated. Covariates will include age, education and depression. The test battery will be administered the same way for all enrolled patients. The cognitive domains being assessed in HALO are entirely consistent with those encompassed within the NINDS Common Data Elements (CDE).

Imaging protocol. Multimodal MRI, including routine parenchymal sequences and PWI utilizing dynamic susceptibility contrast technique, will be acquired at each participating HALO site. Imaging will take place within 14 days after HALO enrollment and prior to any intervention (carotid artery revascularization).

Standardized contrast agent injection protocol, appropriate preparation, and IV setup is used to ensure good scan quality. An antecubital vein IV catheter of 18-20 gauge is required. A test injection will be performed with approximately 10 ml of normal saline solution.

MRI image acquisition DWI/ADC (b=0, 1000 s/mm2 applied in each of three principal gradient directions), FLAIR, high-resolution T1, and GRE sequences will be acquired on 1.5-3.0 T scanners equipped with echo-planar imaging capability, using standard clinical protocols at participating HALO sites. Total scanning time will be approximately 40 minutes. PWI acquisition protocol will be standardized across all HALO sites, using sequential T2\*-weighted (gradient echo) EPI time sequence scanning. A modified 2-phase contrast injection scheme will be used to perform CEMRA and DSC perfusion imaging, without need for additional contrast.

MRI structural analysis. silent infarct --- non-confluent hyperintense lesion \>1mm on FLAIR sequence on 1-year MRI not present on baseline FLAIR MRI.

Cerebral microbleed - hypointense 1-2mm non-confluent lesion on baseline GRE sequence.

WMH volume -- White matter hyperintensity volume refers to confluent periventricular high intensity lesions on FLAIR imaging, and will be derived using an automated T2 WMH quantification at the Huston lab.

. Analysis. Specific Aim 1. To determine whether cognition can be improved by revascularization among a subset of HALO patients with hemodynamic changes at baseline.

The primary hypothesis is to assess if the magnitude of the treatment differences (revascularization versus medical management alone) differs between those with flow failure compared to those without flow failure using the Z-scored cognitive outcomes (C0, C(1). That is, the primary hypothesis is an interaction hypothesis that will be assessed using linear regression, specifically: (C1 - C0) = β0 + β1T + β2F + β3TF + β4C0 + (other covariates), where C1 is the cognitive z-score at year 1, C0 the cognitive z-score at baseline, T the treatment indicator variable, F the flow failure indicator variable, and βi the regression parameters to be estimated. The parameter of interest for the primary hypothesis is then β3 that would assess if the magnitude of treatment difference in the change in cognitive score between baseline and 1-year is similar for those with versus without flow failure.

Secondary Aims: To determine if the number of silent infarcts and white matter hyperintensity volume at 1 year is different between the revascularization and the medical-only arms.

For the secondary aims we will calculate the number of new silent cerebral infarctions occurring over the first year, and the change in the WMH volume. The approach for analysis of the number of new silent infarcts will depend on the average number and distribution of the number of new infarcts. The analytic approach will be linear regression if the number of new infarcts is large (considered more likely the case), or Poisson Regression if the number is smaller (considered less likely the case). The analysis of the change in WMH will use a linear regression approach.

Eligibility criteria: Inclusion Criteria:

Informed consent signed Patients with \>=70% symptomatic or \>=80% asymptomatic internal carotid stenosis

Exclusion Criteria:

Incapability to give informed consent Previous disabling stroke Contralateral carotid occlusion or \>70% stenosis Systemic disease judged non compatible with the procedures or randomization Suspected or manifested pregnancy General contraindications to MRI or CT studies

Primary outcomes:
measure: Change in cognitive score
timeFrame: 1 year
measure: Change in carotid stenosis
timeFrame: 1 year
measure: Change in wall shear stress（WSS）
timeFrame: 1 year
measure: Change in oscillatory shear index （OSI）
timeFrame: 1 year
measure: Change in relative residence time（RRT）
timeFrame: 1 year
Secondary outcomes:
measure: Silent infarcts
timeFrame: 1 year
measure: White matter hyperintensity (WMH) volume
timeFrame: 1 year
measure: Major adverse cardiovascular events
timeFrame: 1 year
measure: The mortality rate
timeFrame: 1 year
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Friendship Hospital, Capital Medical University
state: Beijing
Study officials:
References:
citation: Cutlip DE, Pinto DS. Extracranial carotid disease revascularization. Circulation. 2012 Nov 27;126(22):2636-44. doi: 10.1161/CIRCULATIONAHA.112.110411. No abstract available.
citation: Auricchio F, Conti M, De Beule M, De Santis G, Verhegghe B. Carotid artery stenting simulation: from patient-specific images to finite element analysis. Med Eng Phys. 2011 Apr;33(3):281-9. doi: 10.1016/j.medengphy.2010.10.011. Epub 2010 Nov 9.
citation: Conti M, Van Loo D, Auricchio F, De Beule M, De Santis G, Verhegghe B, Pirrelli S, Odero A. Impact of carotid stent cell design on vessel scaffolding: a case study comparing experimental investigation and numerical simulations. J Endovasc Ther. 2011 Jun;18(3):397-406. doi: 10.1583/10-3338.1.
citation: Auricchio F, Conti M, Ferrara A, Morganti S, Reali A. Patient-specific finite element analysis of carotid artery stenting: a focus on vessel modeling. Int J Numer Method Biomed Eng. 2013 Jun;29(6):645-64. doi: 10.1002/cnm.2511. Epub 2012 Sep 29.
citation: De Santis G, Conti M, Trachet B, De Schryver T, De Beule M, Degroote J, Vierendeels J, Auricchio F, Segers P, Verdonck P, Verhegghe B. Haemodynamic impact of stent-vessel (mal)apposition following carotid artery stenting: mind the gaps! Comput Methods Biomech Biomed Engin. 2013;16(6):648-59. doi: 10.1080/10255842.2011.629997. Epub 2011 Dec 8.
citation: De Santis G, Trachet B, Conti M, De Beule M, Morbiducci U, Mortier P, Segers P, Verdonck P, Verhegghe B. A computational study of the hemodynamic impact of open- versus closed-cell stent design in carotid artery stenting. Artif Organs. 2013 Jul;37(7):E96-106. doi: 10.1111/aor.12046. Epub 2013 Apr 12.
citation: Hathcock JJ. Flow effects on coagulation and thrombosis. Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1729-37. doi: 10.1161/01.ATV.0000229658.76797.30. Epub 2006 Jun 1.
citation: Davies PF. Overview: temporal and spatial relationships in shear stress-mediated endothelial signalling. J Vasc Res. 1997 May-Jun;34(3):208-11. doi: 10.1159/000159224. No abstract available.
citation: Bohm M, Cotton D, Foster L, Custodis F, Laufs U, Sacco R, Bath PM, Yusuf S, Diener HC. Impact of resting heart rate on mortality, disability and cognitive decline in patients after ischaemic stroke. Eur Heart J. 2012 Nov;33(22):2804-12. doi: 10.1093/eurheartj/ehs250. Epub 2012 Aug 26.
citation: Irvine CD, Gardner FV, Davies AH, Lamont PM. Cognitive testing in patients undergoing carotid endarterectomy. Eur J Vasc Endovasc Surg. 1998 Mar;15(3):195-204. doi: 10.1016/s1078-5884(98)80176-7.
citation: Hayase H, Tokunaga K, Nakayama T, Sugiu K, Nishida A, Arimitsu S, Hishikawa T, Ono S, Ohta M, Date I. Computational fluid dynamics of carotid arteries after carotid endarterectomy or carotid artery stenting based on postoperative patient-specific computed tomography angiography and ultrasound flow data. Neurosurgery. 2011 Apr;68(4):1096-101; discussion 1101. doi: 10.1227/NEU.0b013e318208f1a0.
citation: Marshall RS, Lazar RM, Liebeskind DS, Connolly ES, Howard G, Lal BK, Huston J 3rd, Meschia JF, Brott TG. Carotid revascularization and medical management for asymptomatic carotid stenosis - Hemodynamics (CREST-H): Study design and rationale. Int J Stroke. 2018 Dec;13(9):985-991. doi: 10.1177/1747493018790088. Epub 2018 Aug 22.
citation: Howard VJ, Meschia JF, Lal BK, Turan TN, Roubin GS, Brown RD Jr, Voeks JH, Barrett KM, Demaerschalk BM, Huston J 3rd, Lazar RM, Moore WS, Wadley VG, Chaturvedi S, Moy CS, Chimowitz M, Howard G, Brott TG; CREST-2 study investigators. Carotid revascularization and medical management for asymptomatic carotid stenosis: Protocol of the CREST-2 clinical trials. Int J Stroke. 2017 Oct;12(7):770-778. doi: 10.1177/1747493017706238. Epub 2017 May 2.
citation: Schroder J, Heinze M, Gunther M, Cheng B, Nickel A, Schroder T, Fischer F, Kessner SS, Magnus T, Fiehler J, Larena-Avellaneda A, Gerloff C, Thomalla G. Dynamics of brain perfusion and cognitive performance in revascularization of carotid artery stenosis. Neuroimage Clin. 2019;22:101779. doi: 10.1016/j.nicl.2019.101779. Epub 2019 Mar 13.
citation: Piegza M, Wieckiewicz G, Wierzba D, Piegza J. Cognitive Functions in Patients after Carotid Artery Revascularization-A Narrative Review. Brain Sci. 2021 Oct 1;11(10):1307. doi: 10.3390/brainsci11101307.