From the Society for Vascular Surgery
Predictors and clinical significance of progression or regression of asymptomatic carotid stenosis Stavros K. Kakkos, MD, PhD, RVT,a Andrew N. Nicolaides, MS, PhD, FRCS,a, Ioanna Charalambous,b Dafydd Thomas, MD, FRCP,c Argyrios Giannopoulos, MD,a A. Ross Naylor, MD, FRCS,d George Geroulakos, MD, PhD,a,e and Anne L. Abbott, MBBS, FRACP, PhD,f,g,h for the Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study Group, London and Leicester, United Kingdom; Nicosia, Cyprus; and Melbourne, Australia Objective: To determine baseline clinical and ultrasonographic plaque factors predictive of progression or regression of asymptomatic carotid stenosis and the predictive value of changes in stenosis severity on risk of first ipsilateral cerebral or retinal ischemic events (including stroke). Methods: A total of 1121 patients with asymptomatic carotid stenosis of 50% to 99% in relation to the bulb diameter (European Carotid Surgery Trial [ECST] method) underwent six monthly clinical assessments and carotid duplexes for up to 8 years (mean follow-up, 4 years). Progression or regression was considered present if there was a change of at least one grade higher or lower, respectively, persisting for at least two consecutive examinations. Results: Regression occurred in 43 (3.8%), no change in 856 (76.4%), and progression in 222 (19.8%) patients. Younger age, high grades of stenosis, absence of discrete white areas in the plaque, and taking lipid lowering therapy were independent baseline predictors of increased incidence of regression. High serum creatinine, male gender, not taking lipid lowering therapy, low grades of stenosis, and increased plaque area were independent baseline predictors of progression. One hundred and thirty first ipsilateral cerebral or retinal ischemic events, including 59 strokes, occurred. Forty (67.8%) of the strokes occurred in patients whose stenosis was unchanged, 19 (32.2%) in those with progression, and zero in those with regression. For the entire cohort, the 8-year cumulative ipsilateral cerebral ischemic stroke rate was zero in patients with regression, 9% if the stenosis was unchanged, and 16% if there was progression (average annual stroke rates of 0%, 1.1%, and 2.0%, respectively; log-rank, P [ .05; relative risk in patients with progression, 1.92; 95% confidence interval, 1.14-3.25). For patients with baseline stenosis 70% to 99% in relation to the distal internal carotid (North American Symptomatic Carotid Endarterectomy Trial [NASCET] method), in the absence of progression (n [ 349), the 8-year cumulative ipsilateral cerebral ischemic stroke rate was 12%. In the presence of progression (n [ 77), it was 21% (average annual stroke rates of 1.5% and 2.6%, respectively; log-rank, P [ .34). Only nine (30%) of the 30 strokes occurred in the progression group. Conclusions: Progressive asymptomatic carotid stenosis identified a subgroup with about twice the risk of ipsilateral stroke compared with those without progression. However, the clinical value of screening for progression simply for selecting patients for carotid procedures is limited because of the low frequency of progression and its relatively low associated stroke rate. The cost effectiveness of screening for change in stenosis severity to better direct current optimal medical treatment needs testing. (J Vasc Surg 2014;59:956-67.)
A number of natural history studies in patients with asymptomatic carotid stenosis have investigated the association between stenosis progression and risk of ipsilateral cerebrovascular events,1-12 and mostly concluded that progression to >80% stenosis in relation to the diameter of the distal internal carotid (North American Symptomatic Carotid Endarterectomy Trial [NASCET] method) was associated with an increased risk of cerebrovascular events. However, these
previous studies had significant limitations such as retrospective design, small sample sizes, short duration of follow-up, suboptimal medical treatment, and often stenosis progression detected after ipsilateral stroke or transient ischemic attack was included in predictive testing. Despite the uncertain clinical significance of progressive asymptomatic carotid stenosis, it remains a common reason for repeated carotid duplex imaging and referral for carotid surgery to reduce stroke risk.
From the Department of Vascular Surgery, Imperial College, Londona; the Vascular Screening and Diagnostic Center, Nicosiab; the Department of Neurology, St. Mary’s Hospital, Londonc; the Department of Vascular Surgery, Leicester Royal Infirmary, Leicesterd; the Department of Vascular Surgery, Ealing Hospital, Londone; the School of Public Health and Preventive Medicine, Monash University, Melbournef; the Preventive Health Division of Baker IDI Heart and Diabetes Institute, Melbourneg; and the Stroke Division of the Florey Institute of Neuroscience and Mental Health, Melbourne.h The full list of investigators appears in the Appendix (online only). Supported by a grant from the European Commission (Biomed II) Program (PL 650629) for the first 3 years and subsequently by a grant from the CDER Trust (United Kingdom). Author conflict of interest: Dr Nicolaides is a consultant to LifeQMedical Limited and own shares with the company.
Presented in a plenary session at the 2013 Vascular Annual Meeting of the Society for Vascular Surgery, San Francisco, Calif, May 30-June 1, 2013. Additional material for this article may be found online at www.jvascsurg.org. Reprint requests: Andrew N. Nicolaides, MS, PhD, FRCS, Vascular Screening and Diagnostic Centre, 30 Weymouth St, London W1G 7BS, UK (e-mail:
[email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Copyright Ó 2014 by the Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jvs.2013.10.073
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Table I. Duplex velocity criteria used in the Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) study16 Angiographic diameter stenosis N%
Duplex velocity criteria
E%
PSVIC18,19
EDVIC18-20
PSVIC/PSVCC21-23
PSVIC/EDVCC24,25
11
50
5.5
CC, Common carotid; E, European Carotid Surgery Trial; EDV, end-diastolic velocity; IC, internal carotid; N, North American Symptomatic Carotid Endarterectomy Trial; PSV, peak systolic velocity.
The Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study was a prospective international cohort study. The primary objective13,14 was to assess the cerebrovascular risk stratification potential of combinations of patients’ baseline clinical and biochemical characteristics, ultrasound-determined degree of stenosis, and plaque morphology. Particularly important were history of contralateral transient ischemic attack or stroke, stenosis severity at baseline, and plaque texture features (grayscale median [GSM], size of plaque area, size of juxtaluminal black area, and presence of discrete white areas [DWAs]), which could stratify stroke risk from less than 1% per year to more than 10% per year.13,14 A secondary objective of the ACSRS study was to assess the stroke risk stratification value of stenosis progression or regression using serial (6-monthly) duplex scanning. The aims of the present report were to determine: 1) The incidence of stenosis progression (with or without progression to occlusion) and regression; 2) the association of baseline clinical, biochemical, and plaque features predictive of stenosis progression or regression; 3) the predictive value of changes in the severity of stenosis in terms of ipsilateral cerebral or retinal ischemic (CORI) events including stroke. Associated with this aim, we determined if stenosis progression is a predictor of cerebrovascular events, is independent of baseline stenosis, and investigated any additional predictive value of change in stenosis severity compared with our previously published “ACSRS Best Baseline Risk Stratification Model for Stroke.”13,14 METHODS The methodology of the ACSRS study regarding inclusion and exclusion criteria, recruitment sources, clinical and biochemical characteristics, duplex examination, image acquisition of plaques, image normalization and analysis, and primary outcome measures and their use in stroke
risk stratification has been previously published.13-15 Only the most relevant methodology is presented. Patient recruitment Inclusion and exclusion criteria. Newly referred ( 70
96 329 555
55 212 328
31 142 201
Numbers at risk Stenosis 50-69 Stenosis 70-89 Stenosis 90-99
15 59 99
C
6
7
8
163 573 244
107 350 138
75 222 77
43 95 36
D 1.00
Lipid Lowering Therapy No Yes
0.98
0.96
0.94
0.98
0.96
0.94
0.92
0.92
0.90
0.90 0
1
2
3
4
5
6
7
8
DWA Absent Present
Regression Free Survival
1.00
Regression Free Survival
5
YEARS
0
1
2
3
YEARS Numbers at risk Lipid lowering therapy No 704 Yes 276
420 175
262 112
4
5
6
7
8
YEARS
117 56
Numbers at risk DWA present DWA absent
344 636
200 395
119 255
57 116
Fig 3. Effect of significant factors in model 3 (Table IV) on regression-free survival. A, Age (log-rank, P ¼ .016). B, Ipsilateral stenosis (log-rank, P ¼ .081). C, Lipid-lowering therapy (log-rank, P ¼ .002). D, Presence of discrete white areas (DWAs; log-rank, P ¼ .032).
Reduced incidence of progression has been seen in patients on lipid-lowering therapy, which is compatible with a previous report of reduction in progression of carotid plaque area.34
Elevated creatinine, low GSM indicating a hypoechoic plaque, severe ipsilateral stenosis, contralateral stenosis, and male gender were associated with progression to occlusion. Previous studies have demonstrated the association
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Table V. The incidence of ipsilateral cerebral or retinal ischemic (CORI) events in relation to changes in severity of stenosis Stenosis change
No events, No. (%)
Regression No change Progression Total RR 95% CI
43 768 180 991
Amaurosis fugax, No. (%)
TIA, No. (%)
Stroke, No. (%)
0 16 (1.9) 6 (2.7) 22 (2.0) 1.52 0.60-3.84
0 32 (3.7) 17 (7.7) 49 (4.4) 2.15 1.22-3.80
0 40 (4.7) 19 (8.6) 59 (5.3) 1.92 1.14-3.25
(100) (90) (81) (88) -
Total, No. (%) 43 856 222 1121
All events, No. (%)
(100) (100) (100) (100) -
0 88 (10) 42 (19) 130 (12) 1.93 1.38-2.71
CI, Confidence interval; RR, relative risk; TIA, transient ischemic attack. Progression in this table includes progression to occlusion. RR is the relative risk of events in patients with progression in relation to the rest of the patients.
A
B 1.0
1.00 Changes in Stenosis
Regression No Change Progression
0.9
0.8
0.90
0.7
0.85
0.6
0.80 0
1
2
3
4
5
6
7
8
Regression No Change Progression
0.95
Stroke Free Survival
CORI Event Free Survival
Changes in Stenosis
0
1
2
3
YEARS Numbers at risk Regression No change Progression
38 740 205
28 455 129
4
5
6
7
8
YEARS 19 282 87
5 134 39
Numbers at risk Regression No change Progression
38 740 205
28 455 129
19 282 87
5 134 39
Fig 4. A, Effect of changes in stenosis on ipsilateral cerebrovascular or retinal ischemic (CORI) events (log-rank overall, P < .001). B, Effect of changes in stenosis on ipsilateral hemispheric stroke (log-rank overall, P ¼ .050). Note: Only 19 strokes occurred in the group of patients that had progression of stenosis; the remaining 40 strokes occurred in the group that had no change in stenosis.
between ipsilateral progression and type I (hypoechoic) plaque,7 ipsilateral stenosis,5,6,11 or contralateral stenosis.6 However, this is the first time the incidence of progression to occlusion has been shown to be associated with elevated creatinine and male gender. The prediction of progression to occlusion using the significant risk factors (GSM, ipsilateral stenosis, contralateral stenosis, and male gender) in a Cox proportional hazards model (model 2; Table IV) was high as indicated by the area under the ROC curve (0.793), and it may have a clinical application. Future studies need to investigate whether in the presence of the above risk factors patients should receive a more aggressive risk factor modification than what is proposed in current guidelines.
Increasing age and DWAs were associated with a low incidence of regression. Increased age is often associated with a higher incidence of plaque calcification and/or higher collagen content and such plaques are unlikely to remodel and regress. DWAs indicate the presence of plaques that have neovascularization as shown by plaque perfusion studies35 that may also be resistant to regression. Lipid-lowering therapy was associated with increased incidence of regression. The association between lipidlowering therapy and plaque regression in patients with asymptomatic carotid stenosis has already been demonstrated,36 and is a well-established action of statins, reported to occur independently of the baseline cholesterol levels.36 Our two observations on the reduced likelihood
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Table VI. Proportional hazards model with stenosis and progression as covariates and stroke as the dependent variable
b
HR
95% CI
P
.295
1.343
1.068-1.687
.011
.616
1.85
1.072-3.202
.027
Variable Ipsilateral stenosis (10% increase) Progression
CI, Confidence interval; HR, hazard ratio.
Table VII. Progression of stenosis added as covariate in a proportional hazards model of our previously published report shown to predict the risk of future events Variable
b
Ipsilateral stenosis (10% increase) Log (GSM þ 40) Plaque area1/3 (mm2) DWA History of contralateral TIA or stroke Progression
HR
95% CI
.017
1.017
1.002-1.032
.023
2.464 .63 .725 .661
0.085 1.878 2.065 1.938
0.042-0.171 1.463-2.413 1.292-3.302 1.321-2.842
