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Ankle-brachial index in screening for asymptomatic carotid and intracranial atherosclerosis
Atherosclerosis 233 (2014) 72e75
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Ankle-brachial index in screening for asymptomatic carotid and intracranial atherosclerosis M. Jiménez a, L. Dorado a, M. Hernández-Pérez a, M.T. Alzamora b, G. Pera b, P. Torán b, M. Gomis a, N. Pérez de la Ossa a, M. Millán a, D. Escudero a, A. Dávalos a, J.F. Arenillas c, E. López-Cancio a, * a b c
Department of Neurosciencies, Hospital Germans Trias i Pujol, Universitat Autónoma Barcelona, Badalona, Spain Unitat de Suport a la Recerca Metropolitana Nord, IDIAP Jordi Gol, Santa Coloma de Gramenet, Barcelona, Spain Department of Neurology, Stroke Unit, Hospital Clínico Universitario, Valladolid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 July 2013 Received in revised form 18 December 2013 Accepted 19 December 2013 Available online 4 January 2014
Objective: To evaluate usefulness of ankle-brachial index (ABI) in the screening for asymptomatic cervico-cerebral atherosclerosis (CCA) against traditional vascular risk assessment. Methods: This study included a random population sample of 933 Caucasians without prior cardiovascular disease but with a moderate and high vascular risk (REGICOR score 5e9% and 10%). Presence and degree of CCA was evaluated by color-coded duplex and significant stenosis >50% (SCCA) confirmed by MRA. Results: Prevalence of significant carotid and/or intracranial stenosis was 6% in the whole population, but increased up to 25% among those subjects with ABI 0.9 regardless of REGICOR score. Using REGICOR 10%, the likelihood ratio (LR) for the detection of SCCA was 1.8, while using ABI 0.90 the LR was 6.0. After multivariate regression analysis, low ABI was independently associated with SCCA whereas REGICOR score was not. Less than 40% of subjects with SCCA were taking antiplatelet drugs or statins at the moment of diagnosis. Conclusion: ABI emerged as a useful and simple tool in identifying asymptomatic SCCA in our population. This finding may be important for improving stroke primary prevention strategies. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Subclinical atherosclerosis Carotid stenosis Intracranial stenosis Primary prevention
1. Introduction Carotid and intracranial atherosclerosis is one of the most common causes of ischemic stroke worldwide and it is associated with a high morbidity and mortality. However, due to its long silent course, cervico-cerebral atherosclerosis (CCA) is commonly diagnosed after stroke. At that time, permanent sequelae may have occurred, and the risk of stroke recurrence or other vascular events occurrence is high even under secondary preventive measures [1,2]. Primary prevention strategies firstly require the identification of factors that can discriminate in-risk asymptomatic subjects in whom screening would be cost-effective. There is not a general accepted consensus in the screening for asymptomatic carotid stenosis so far [3], while screening for asymptomatic intracranial stenosis has never been proposed.
Ankle-brachial index (ABI) has been previously reported as a surrogate marker of carotid or coronary atherosclerosis and predictor of future ischemic events. A few previous studies including symptomatic patients with ischemic stroke reported the association of low ABI with the presence of intracranial stenosis [4e6]. However, there are no studies focusing on this particular association in asymptomatic subjects without known cardiovascular disease. Our objective is to evaluate the usefulness of ankle-brachial index (ABI) in the screening for asymptomatic carotid and intracranial atherosclerosis and to compare it to traditional vascular risk assessment. 2. Methods 2.1. Subjects
* Corresponding author. Departamento de Neurociencias, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Barcelona, Spain. Tel.: þ34 934978911; fax: þ34 934978742. E-mail address: [email protected] (E. López-Cancio). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.021
This is a secondary analysis of the Barcelona- AsIA study (Asymptomatic Intracranial Atherosclerosis study), an ongoing population-based and longitudinal study that included a random
M. Jiménez et al. / Atherosclerosis 233 (2014) 72e75
sample of 933 subjects older than 50 years selected from our reference population with a moderate to high vascular risk (REGICOR >5%) and without previous history of stroke, coronary or peripheral artery disease. Complete study protocol has been reported in detail elsewhere [7]. 2.2. Vascular risk assessment Vascular risk was calculated using the REGICOR score, which is the Framingham Risk Score adapted and validated for Spanish population. REGICOR evaluates the risk (%) of having a coronary event in 10 years based on a compute of the following traditional risk factors: gender, age, diabetes, smoking, hypertension and cholesterol levels. REGICOR <5% indicates low risk, 5e9% moderate risk, and >10% high risk [8]. 2.3. Assessment of ankle-brachial index Ankle-brachial index (ABI) measurement was carried out by two nurses trained in the technique, using a portable Doppler equipment (Mini-Dopplex D 900-P, Huntleigh Healthcare) [9]. ABI was calculated in each side (right and left) dividing the higher of the two systolic pressure measurements (posterior tibial and pedial) by the higher systolic pressure measured in both arms. The lower index of both sides was considered for analysis. A cut-off point of ABI 0.90 was considered abnormal for primary analyses. 2.4. Assessment of carotid and intracranial atherosclerosis All cervical and transcranial color-coded duplex ultrasound studies were performed at baseline in the same lab by two neurologists using a General Electric Vivid/Pro equipment (Horten, Norway). Presence of carotid plaques, carotid stenosis and intracranial stenosis was assessed as previously described in AsIA study protocol [7]. Severity of stenosis was defined following peak systolic velocities (PSV). Subjects with a significant extracranial carotid stenosis (50%, PSV 125 cm/s) and/or a moderate to severe intracranial stenosis (PSV 220 cm/s for middle cerebral artery; 155 cm/s for anterior cerebral artery and carotid siphon; 145 cm/s for posterior cerebral and basilar arteries and 120 cm/s for vertebral artery) underwent a confirmatory MRA study with a 1.5 T equipment (Philips). Cervico-cerebral atherosclerosis (CCA) was defined as the presence of at least one carotid plaque or one intracranial stenosis of any degree. Significant cervico-cerebral atherosclerosis (SCCA) was defined as the presence of at least one significant carotid (50%) or one moderate to severe intracranial stenosis. 3. Statistical analysis Statistics were performed with the SPSS 15.0 statistical package. Association of baseline variables, REGICOR and ABI with CCA and SCCA was analyzed by Pearson’s c2 test for categorical variables and ManneWhitney U test or Student-t test for continuous variables. We calculated sensitivity, specificity, PPV and NPV of both ABI 0.90 and REGICOR 10 for detecting the presence of SCCA. We also calculated likelihood ratio (LR ¼ sensitivity/(1-specificity)), pre-test and post-test probabilities in the detection of SCCA using both approaches. Logistic regression analyses adjusted for REGICOR, ABI, age, sex, hypertension, diabetes and dyslipidemia were performed to study the independent association of REGICOR score and ABI with the presence of CCA and SCCA. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI).
73
4. Results AsIA study included 933 asymptomatic subjects: 63.7% men, mean age 66 years, median REGICOR score 7. A REGICOR 10%, equivalent to high vascular risk, was present in 244 subjects (26.2%). An ABI 0.90 was found in 65 subjects (7.0%). Neurosonologic study at baseline showed CCA of any degree in 484 subjects (52%). SCCA was present in 56 subjects (6.0%), located in extracranial carotid (n ¼ 25), intracranial arteries (n ¼ 27) or both locations (n ¼ 4). Baseline variables and their distribution among subjects with and without CCA are shown in Table 1. Of note, only 33.9% and 39.2% of subjects in whom SCCA was detected at baseline were taking antiplatelet drugs and statins, respectively. Prevalence of SCCA was significantly higher in subjects with REGICOR 10% and in those with low ABI compared to subjects with REGICOR <10% and ABI <0.9 (Fig. 1, superior panel A, both p < 0.001). Combining both risk measures, prevalence of SCCA was around 25% in those with abnormal ABI regardless the REGICOR score (Fig. 1, inferior panel B). Using REGICOR 10%, likelihood ratio (LR) for the detection of SCCA was 1.8 (pre-test probability 0.06 and post-test probability 0.10). Using ABI 0.90, LR was 6.0 (pre-test probability 0.06 and post-test probability 0.27). We also evaluated a cut-off point of ABI <1.0 that was found in 220 subjects. Prevalence of SCCA in this group was 12.7%, which was lower than the 26.2% found in the 65 subjects with an ABI 0.90. LR using ABI <1.0 was 2.2 so this approach would be less cost-effective than ABI 0.90 in screening for asymptomatic stenosis. After multivariate logistic regression analysis, ABI 0.90 was independently associated with the presence of asymptomatic SCCA, increasing more than 5-fold the risk of having a significant stenosis of the extracranial or intracranial arteries. In the same model, REGICOR did not remain independently associated with SCCA (Supplementary Table I). Out of the individual vascular risk factors included in the model, only diabetes had an independent association with SCCA (OR 2.3, data not shown). Analyses for separated locations of significant stenosis (extracranial or intracranial) showed similar results (see Supplementary Table II). Sensitivity, specificity, PPV and NPV of ABI 0.90 for diagnosing SCCA was 0.3 (0.18e0.42), 0.95 (0.93e0.96), 0.26 (0.15e0.37) and 0.95 (0.94e0.97), respectively. AUC (C-statistic) for the adjusted model was 0.79 (0.73e0.85).
Table 1 Baseline characteristics of subjects among groups of CCA. Baseline variables
Non CCA n ¼ 449
Age (years) 64.1 7.7 Sex (%male) 56.0 Smoking habit (%) 21.4 Hypertension (%) 47.5 Diabetes (%) 18.8 Dyslipidemia (%) 50.4 BMI (kg/m2) 28.7 (4.3) CRP mg/dl 2.6 (1.6e4.5) REGICOR 10 (%) 17.2 ABI 0.90 (%) 3.1 Medical therapies at baseline Antiplatelets (%) 10 Statins (%) 31.6 Anti-hypertensives 43.9 (%)
CCA (any degree) n ¼ 484
SCCA n ¼ 56
68.3 8.1** 70.9** 26.7* 64.6** 34.3** 58.3* 28.7 (4.2) 2.8 (1.7e4.9) 34.5** 10.6**
71.1 8.8** 71.4** 23.2 76.8** 53.6** 60.7* 28.7 (4.3) 2.8 (1.9e5.9) 44.6** 30.4**
21.5** 40.5* 60.5*
33.9** 39.2* 69.6*
Results expressed as percentages when indicated, mean (SD) or median (IQR). CCA: cervico-cerebral atherosclerosis; SCAA: significant cervico-cerebral atherosclerosis; BMI: body mass index; CRP: C reactive protein; ABI: ankle-arm index; *p < 0.05 and **p < 0.01 for comparisons among CCA and SCAA with non-CCA (control group).
74
M. Jiménez et al. / Atherosclerosis 233 (2014) 72e75
Fig. 1. Superior panel A: Prevalence of cervico-cerebral atherosclerosis (CCA) of any degree (dark) and prevalence of significant CCA (SCCA) (light) among groups of REGICOR score (REG) and ankle-brachial index (ABI). Inferior panel B: Prevalence of SCCA combining REGICOR score and ABI.
5. Discussion In this population-based study in Caucasian subjects without history of cardiovascular disease, ABI emerged as a simple tool to identify subjects with a high risk of having subclinical significant carotid or intracranial atherosclerosis. This tool was equally useful in both groups of subjects with moderate and high vascular risk calculated by means of REGICOR score. ABI is a non-invasive and easy-to-perform test that can be used by primary care providers in routine clinical settings together with vascular risk functions. Following the last European guidelines on cardiovascular disease prevention, ABI measurement should be considered for cardiovascular risk assessment in subjects at intermediate vascular risk [10]. Currently, routine screening for asymptomatic carotid stenosis is controversial and recommendations are vague. In the last American guidelines on the management of patients with extracranial carotid artery disease, screening with duplex ultrasonography is considered in subjects who have two or more major vascular risk factors for atherosclerosis and in those with a carotid bruit [3]. However, the sensitivity and specificity of carotid bruit is low [11], and population with two or more vascular risk factors is too large to recommend general screening. Besides this, there are no specific recommendations on screening for asymptomatic intracranial atherosclerosis since this particular location has received much less attention. Still, intracranial atherosclerosis is also a major cause of stroke worldwide [12] and may be depicted together with carotid disease using the same non-invasive test (color-coded duplex, MR angiography). Early diagnosis of CCA would favor a correct management of the disease from its asymptomatic stage. Primary preventive measures
in CCA include aspirin and statins. Revascularization procedures in some selected cases of asymptomatic carotid stenosis may also be indicated [11]. In our study, only 34% and 39% of subjects with SCCA were on those therapies at the moment of diagnosis (Table 1). Although AsIA study is observational, our findings allowed us to recommend adequate medical treatment in more than 60% of subjects with SCCA. Additionally, a periodic control of progression of stenosis with non-invasive methods, together with evaluation of hemodynamic reserve or microembolic signal monitoring, may guide best treatment in subjects with asymptomatic significant CCA. Doing so, a carotid stenting was performed in one subject with progressive bilateral high grade carotid stenosis and impaired cerebral vasomotor reactivity. Moreover, detection of SCCA may give us the opportunity to instruct patients about alarm symptoms associated with their disease. In our cohort, we performed a carotid endarterectomy in one subject with an asymptomatic carotid stenosis>70% at baseline after complaining of amaurosis fugax 1.5 years after inclusion. In our population with moderate to high atherosclerotic risk, prevalence of significant asymptomatic carotid or intracranial stenosis is 6%, so screening of all subjects with REGICOR 5% would not be cost-effective. However, by means of ABI, we found a relatively small target population with a high prevalence of the disease that might benefit from a non-invasive test to detect subclinical CCA. Low ABI increased 5-fold the probability of having SCCA, after adjustment for vascular risk factors and REGICOR score. In fact, we found that SCCA was equally prevalent in both groups of moderate and high atherosclerotic risk (REGICOR 5e9 and 10 respectively), supporting the idea that we should investigate new methods to improve the traditional vascular risk stratification, especially in individuals at intermediate risk [13,14].
M. Jiménez et al. / Atherosclerosis 233 (2014) 72e75
Strengths of this study include a population-based design, evaluation of vascular risk with a specific and validated score in our population (REGICOR), and evaluation of significant CCA in the same ultrasound lab and confirmed with Magnetic Resonance Angiography. Limitations include that results cannot be extrapolated neither to subjects with a low vascular risk (REGICOR <5) nor to other populations different from Caucasians. Also, this is a crosssectional study which does not allow us to infer any causal relationships. Finally, this study is focused on atherosclerosis, so prevention strategies are applicable only to this particular etiology of stroke. However, atherosclerosis causes around 25e30% of all ischemic strokes in our population. In summary, ABI emerged as a useful and non-invasive tool in the prediction of subclinical carotid and intracranial atherosclerosis in a Caucasian population with moderate to high vascular risk and without history of cardiovascular disease. These findings are important for the discussion about the feasibility and costeffectiveness of screening for asymptomatic carotid and intracranial atherosclerosis and may contribute to the development of primary prevention strategies in the stroke field. Disclosures
[4]
[5]
[6]
[7]
[8]
[9]
[10]
None. Appendix A. Supplementary data
[11]
Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.atherosclerosis.2013.12.021.
[12]
References [1] Mantese VA, Timaran CH, Chiu D, Begg RJ, Brott TG, CREST Investigators. The carotid revascularization endarterectomy versus stenting trial (CREST): stenting versus carotid endarterectomy for carotid disease. Stroke 2010 Oct;41(10 Suppl.):S31e4. [2] Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011 Sep 15;365(11): 993e1003. [3] Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of
[13]
[14]
75
patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American college of cardiology foundation/American heart association task force on practice guidelines, and the American stroke association, American association of neuroscience nurses, American association of neurological surgeons, American college of radiology, American society of neuroradiology, congress of neurological surgeons, society of atherosclerosis imaging and prevention, Society for cardiovascular angiography and interventions, society of interventional radiology, society of NeuroInterventional surgery, society for vascular medicine, and society for vascular surgery. Circulation 2011 Jul 26;124(4):489e532. Busch MA, Lutz K, Rohl JE, Neuner B, Masuhr F. Low ankle-brachial index predicts cardiovascular risk after acute ischemic stroke or transient ischemic attack. Stroke 2009 Dec;40(12):3700e5. Ratanakorn D, Keandoungchun J, Tegeler CH. Coexistent extra- and intracranial stenosis, cervical atherosclerosis, and abnormal ankle brachial index in acute ischemic stroke. J Stroke Cerebrovasc Dis 2012 Nov;21(8):782e9. Manzano JJ, De Silva DA, Pascual JL, Chang HM, Wong MC, Chen CP. Associations of ankle-brachial index (ABI) with cerebral arterial disease and vascular events following ischemic stroke. Atherosclerosis 2012 Jul;223(1):219e22. Lopez-Cancio E, Dorado L, Millan M, et al. The population-based barcelonaasymptomatic intracranial atherosclerosis study (ASIA): rationale and design. BMC Neurol 2011 Feb 17;11(1):22. Marrugat J, Subirana I, Comin E, et al. Validity of an adaptation of the framingham cardiovascular risk function: the VERIFICA study. J Epidemiol Community Health 2007 Jan;61(1):40e7. Alzamora MT, Fores R, Baena-Diez JM, et al. The peripheral arterial disease study (PERART/ARTPER): prevalence and risk factors in the general population. BMC Public Health 2010 Jan 27;10:38. Perk J, De Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012): the fifth joint task force of the european society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Atherosclerosis 2012 Jul;223(1):1e68. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American heart association/American stroke association. Stroke 2011 Feb;42(2):517e84. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke 2008 Aug;39(8):2396e9. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation 2010 Dec 21;122(25): 2748e64. Perrone-Filardi P, Achenbach S, Mohlenkamp S, et al. Cardiac computed tomography and myocardial perfusion scintigraphy for risk stratification in asymptomatic individuals without known cardiovascular disease: a position statement of the working group on nuclear cardiology and cardiac CT of the European society of cardiology. Eur Heart J 2011 Aug;32(16). 1986,93, 1993a, 1993b.
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Ankle-brachial index in screening for asymptomatic carotid and intracranial atherosclerosis M. Jiménez a, L. Dorado a, M. Hernández-Pérez a, M.T. Alzamora b, G. Pera b, P. Torán b, M. Gomis a, N. Pérez de la Ossa a, M. Millán a, D. Escudero a, A. Dávalos a, J.F. Arenillas c, E. López-Cancio a, * a b c
Department of Neurosciencies, Hospital Germans Trias i Pujol, Universitat Autónoma Barcelona, Badalona, Spain Unitat de Suport a la Recerca Metropolitana Nord, IDIAP Jordi Gol, Santa Coloma de Gramenet, Barcelona, Spain Department of Neurology, Stroke Unit, Hospital Clínico Universitario, Valladolid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 July 2013 Received in revised form 18 December 2013 Accepted 19 December 2013 Available online 4 January 2014
Objective: To evaluate usefulness of ankle-brachial index (ABI) in the screening for asymptomatic cervico-cerebral atherosclerosis (CCA) against traditional vascular risk assessment. Methods: This study included a random population sample of 933 Caucasians without prior cardiovascular disease but with a moderate and high vascular risk (REGICOR score 5e9% and 10%). Presence and degree of CCA was evaluated by color-coded duplex and significant stenosis >50% (SCCA) confirmed by MRA. Results: Prevalence of significant carotid and/or intracranial stenosis was 6% in the whole population, but increased up to 25% among those subjects with ABI 0.9 regardless of REGICOR score. Using REGICOR 10%, the likelihood ratio (LR) for the detection of SCCA was 1.8, while using ABI 0.90 the LR was 6.0. After multivariate regression analysis, low ABI was independently associated with SCCA whereas REGICOR score was not. Less than 40% of subjects with SCCA were taking antiplatelet drugs or statins at the moment of diagnosis. Conclusion: ABI emerged as a useful and simple tool in identifying asymptomatic SCCA in our population. This finding may be important for improving stroke primary prevention strategies. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Subclinical atherosclerosis Carotid stenosis Intracranial stenosis Primary prevention
1. Introduction Carotid and intracranial atherosclerosis is one of the most common causes of ischemic stroke worldwide and it is associated with a high morbidity and mortality. However, due to its long silent course, cervico-cerebral atherosclerosis (CCA) is commonly diagnosed after stroke. At that time, permanent sequelae may have occurred, and the risk of stroke recurrence or other vascular events occurrence is high even under secondary preventive measures [1,2]. Primary prevention strategies firstly require the identification of factors that can discriminate in-risk asymptomatic subjects in whom screening would be cost-effective. There is not a general accepted consensus in the screening for asymptomatic carotid stenosis so far [3], while screening for asymptomatic intracranial stenosis has never been proposed.
Ankle-brachial index (ABI) has been previously reported as a surrogate marker of carotid or coronary atherosclerosis and predictor of future ischemic events. A few previous studies including symptomatic patients with ischemic stroke reported the association of low ABI with the presence of intracranial stenosis [4e6]. However, there are no studies focusing on this particular association in asymptomatic subjects without known cardiovascular disease. Our objective is to evaluate the usefulness of ankle-brachial index (ABI) in the screening for asymptomatic carotid and intracranial atherosclerosis and to compare it to traditional vascular risk assessment. 2. Methods 2.1. Subjects
* Corresponding author. Departamento de Neurociencias, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Barcelona, Spain. Tel.: þ34 934978911; fax: þ34 934978742. E-mail address: [email protected] (E. López-Cancio). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.021
This is a secondary analysis of the Barcelona- AsIA study (Asymptomatic Intracranial Atherosclerosis study), an ongoing population-based and longitudinal study that included a random
M. Jiménez et al. / Atherosclerosis 233 (2014) 72e75
sample of 933 subjects older than 50 years selected from our reference population with a moderate to high vascular risk (REGICOR >5%) and without previous history of stroke, coronary or peripheral artery disease. Complete study protocol has been reported in detail elsewhere [7]. 2.2. Vascular risk assessment Vascular risk was calculated using the REGICOR score, which is the Framingham Risk Score adapted and validated for Spanish population. REGICOR evaluates the risk (%) of having a coronary event in 10 years based on a compute of the following traditional risk factors: gender, age, diabetes, smoking, hypertension and cholesterol levels. REGICOR <5% indicates low risk, 5e9% moderate risk, and >10% high risk [8]. 2.3. Assessment of ankle-brachial index Ankle-brachial index (ABI) measurement was carried out by two nurses trained in the technique, using a portable Doppler equipment (Mini-Dopplex D 900-P, Huntleigh Healthcare) [9]. ABI was calculated in each side (right and left) dividing the higher of the two systolic pressure measurements (posterior tibial and pedial) by the higher systolic pressure measured in both arms. The lower index of both sides was considered for analysis. A cut-off point of ABI 0.90 was considered abnormal for primary analyses. 2.4. Assessment of carotid and intracranial atherosclerosis All cervical and transcranial color-coded duplex ultrasound studies were performed at baseline in the same lab by two neurologists using a General Electric Vivid/Pro equipment (Horten, Norway). Presence of carotid plaques, carotid stenosis and intracranial stenosis was assessed as previously described in AsIA study protocol [7]. Severity of stenosis was defined following peak systolic velocities (PSV). Subjects with a significant extracranial carotid stenosis (50%, PSV 125 cm/s) and/or a moderate to severe intracranial stenosis (PSV 220 cm/s for middle cerebral artery; 155 cm/s for anterior cerebral artery and carotid siphon; 145 cm/s for posterior cerebral and basilar arteries and 120 cm/s for vertebral artery) underwent a confirmatory MRA study with a 1.5 T equipment (Philips). Cervico-cerebral atherosclerosis (CCA) was defined as the presence of at least one carotid plaque or one intracranial stenosis of any degree. Significant cervico-cerebral atherosclerosis (SCCA) was defined as the presence of at least one significant carotid (50%) or one moderate to severe intracranial stenosis. 3. Statistical analysis Statistics were performed with the SPSS 15.0 statistical package. Association of baseline variables, REGICOR and ABI with CCA and SCCA was analyzed by Pearson’s c2 test for categorical variables and ManneWhitney U test or Student-t test for continuous variables. We calculated sensitivity, specificity, PPV and NPV of both ABI 0.90 and REGICOR 10 for detecting the presence of SCCA. We also calculated likelihood ratio (LR ¼ sensitivity/(1-specificity)), pre-test and post-test probabilities in the detection of SCCA using both approaches. Logistic regression analyses adjusted for REGICOR, ABI, age, sex, hypertension, diabetes and dyslipidemia were performed to study the independent association of REGICOR score and ABI with the presence of CCA and SCCA. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI).
73
4. Results AsIA study included 933 asymptomatic subjects: 63.7% men, mean age 66 years, median REGICOR score 7. A REGICOR 10%, equivalent to high vascular risk, was present in 244 subjects (26.2%). An ABI 0.90 was found in 65 subjects (7.0%). Neurosonologic study at baseline showed CCA of any degree in 484 subjects (52%). SCCA was present in 56 subjects (6.0%), located in extracranial carotid (n ¼ 25), intracranial arteries (n ¼ 27) or both locations (n ¼ 4). Baseline variables and their distribution among subjects with and without CCA are shown in Table 1. Of note, only 33.9% and 39.2% of subjects in whom SCCA was detected at baseline were taking antiplatelet drugs and statins, respectively. Prevalence of SCCA was significantly higher in subjects with REGICOR 10% and in those with low ABI compared to subjects with REGICOR <10% and ABI <0.9 (Fig. 1, superior panel A, both p < 0.001). Combining both risk measures, prevalence of SCCA was around 25% in those with abnormal ABI regardless the REGICOR score (Fig. 1, inferior panel B). Using REGICOR 10%, likelihood ratio (LR) for the detection of SCCA was 1.8 (pre-test probability 0.06 and post-test probability 0.10). Using ABI 0.90, LR was 6.0 (pre-test probability 0.06 and post-test probability 0.27). We also evaluated a cut-off point of ABI <1.0 that was found in 220 subjects. Prevalence of SCCA in this group was 12.7%, which was lower than the 26.2% found in the 65 subjects with an ABI 0.90. LR using ABI <1.0 was 2.2 so this approach would be less cost-effective than ABI 0.90 in screening for asymptomatic stenosis. After multivariate logistic regression analysis, ABI 0.90 was independently associated with the presence of asymptomatic SCCA, increasing more than 5-fold the risk of having a significant stenosis of the extracranial or intracranial arteries. In the same model, REGICOR did not remain independently associated with SCCA (Supplementary Table I). Out of the individual vascular risk factors included in the model, only diabetes had an independent association with SCCA (OR 2.3, data not shown). Analyses for separated locations of significant stenosis (extracranial or intracranial) showed similar results (see Supplementary Table II). Sensitivity, specificity, PPV and NPV of ABI 0.90 for diagnosing SCCA was 0.3 (0.18e0.42), 0.95 (0.93e0.96), 0.26 (0.15e0.37) and 0.95 (0.94e0.97), respectively. AUC (C-statistic) for the adjusted model was 0.79 (0.73e0.85).
Table 1 Baseline characteristics of subjects among groups of CCA. Baseline variables
Non CCA n ¼ 449
Age (years) 64.1 7.7 Sex (%male) 56.0 Smoking habit (%) 21.4 Hypertension (%) 47.5 Diabetes (%) 18.8 Dyslipidemia (%) 50.4 BMI (kg/m2) 28.7 (4.3) CRP mg/dl 2.6 (1.6e4.5) REGICOR 10 (%) 17.2 ABI 0.90 (%) 3.1 Medical therapies at baseline Antiplatelets (%) 10 Statins (%) 31.6 Anti-hypertensives 43.9 (%)
CCA (any degree) n ¼ 484
SCCA n ¼ 56
68.3 8.1** 70.9** 26.7* 64.6** 34.3** 58.3* 28.7 (4.2) 2.8 (1.7e4.9) 34.5** 10.6**
71.1 8.8** 71.4** 23.2 76.8** 53.6** 60.7* 28.7 (4.3) 2.8 (1.9e5.9) 44.6** 30.4**
21.5** 40.5* 60.5*
33.9** 39.2* 69.6*
Results expressed as percentages when indicated, mean (SD) or median (IQR). CCA: cervico-cerebral atherosclerosis; SCAA: significant cervico-cerebral atherosclerosis; BMI: body mass index; CRP: C reactive protein; ABI: ankle-arm index; *p < 0.05 and **p < 0.01 for comparisons among CCA and SCAA with non-CCA (control group).
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M. Jiménez et al. / Atherosclerosis 233 (2014) 72e75
Fig. 1. Superior panel A: Prevalence of cervico-cerebral atherosclerosis (CCA) of any degree (dark) and prevalence of significant CCA (SCCA) (light) among groups of REGICOR score (REG) and ankle-brachial index (ABI). Inferior panel B: Prevalence of SCCA combining REGICOR score and ABI.
5. Discussion In this population-based study in Caucasian subjects without history of cardiovascular disease, ABI emerged as a simple tool to identify subjects with a high risk of having subclinical significant carotid or intracranial atherosclerosis. This tool was equally useful in both groups of subjects with moderate and high vascular risk calculated by means of REGICOR score. ABI is a non-invasive and easy-to-perform test that can be used by primary care providers in routine clinical settings together with vascular risk functions. Following the last European guidelines on cardiovascular disease prevention, ABI measurement should be considered for cardiovascular risk assessment in subjects at intermediate vascular risk [10]. Currently, routine screening for asymptomatic carotid stenosis is controversial and recommendations are vague. In the last American guidelines on the management of patients with extracranial carotid artery disease, screening with duplex ultrasonography is considered in subjects who have two or more major vascular risk factors for atherosclerosis and in those with a carotid bruit [3]. However, the sensitivity and specificity of carotid bruit is low [11], and population with two or more vascular risk factors is too large to recommend general screening. Besides this, there are no specific recommendations on screening for asymptomatic intracranial atherosclerosis since this particular location has received much less attention. Still, intracranial atherosclerosis is also a major cause of stroke worldwide [12] and may be depicted together with carotid disease using the same non-invasive test (color-coded duplex, MR angiography). Early diagnosis of CCA would favor a correct management of the disease from its asymptomatic stage. Primary preventive measures
in CCA include aspirin and statins. Revascularization procedures in some selected cases of asymptomatic carotid stenosis may also be indicated [11]. In our study, only 34% and 39% of subjects with SCCA were on those therapies at the moment of diagnosis (Table 1). Although AsIA study is observational, our findings allowed us to recommend adequate medical treatment in more than 60% of subjects with SCCA. Additionally, a periodic control of progression of stenosis with non-invasive methods, together with evaluation of hemodynamic reserve or microembolic signal monitoring, may guide best treatment in subjects with asymptomatic significant CCA. Doing so, a carotid stenting was performed in one subject with progressive bilateral high grade carotid stenosis and impaired cerebral vasomotor reactivity. Moreover, detection of SCCA may give us the opportunity to instruct patients about alarm symptoms associated with their disease. In our cohort, we performed a carotid endarterectomy in one subject with an asymptomatic carotid stenosis>70% at baseline after complaining of amaurosis fugax 1.5 years after inclusion. In our population with moderate to high atherosclerotic risk, prevalence of significant asymptomatic carotid or intracranial stenosis is 6%, so screening of all subjects with REGICOR 5% would not be cost-effective. However, by means of ABI, we found a relatively small target population with a high prevalence of the disease that might benefit from a non-invasive test to detect subclinical CCA. Low ABI increased 5-fold the probability of having SCCA, after adjustment for vascular risk factors and REGICOR score. In fact, we found that SCCA was equally prevalent in both groups of moderate and high atherosclerotic risk (REGICOR 5e9 and 10 respectively), supporting the idea that we should investigate new methods to improve the traditional vascular risk stratification, especially in individuals at intermediate risk [13,14].
M. Jiménez et al. / Atherosclerosis 233 (2014) 72e75
Strengths of this study include a population-based design, evaluation of vascular risk with a specific and validated score in our population (REGICOR), and evaluation of significant CCA in the same ultrasound lab and confirmed with Magnetic Resonance Angiography. Limitations include that results cannot be extrapolated neither to subjects with a low vascular risk (REGICOR <5) nor to other populations different from Caucasians. Also, this is a crosssectional study which does not allow us to infer any causal relationships. Finally, this study is focused on atherosclerosis, so prevention strategies are applicable only to this particular etiology of stroke. However, atherosclerosis causes around 25e30% of all ischemic strokes in our population. In summary, ABI emerged as a useful and non-invasive tool in the prediction of subclinical carotid and intracranial atherosclerosis in a Caucasian population with moderate to high vascular risk and without history of cardiovascular disease. These findings are important for the discussion about the feasibility and costeffectiveness of screening for asymptomatic carotid and intracranial atherosclerosis and may contribute to the development of primary prevention strategies in the stroke field. Disclosures
[4]
[5]
[6]
[7]
[8]
[9]
[10]
None. Appendix A. Supplementary data
[11]
Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.atherosclerosis.2013.12.021.
[12]
References [1] Mantese VA, Timaran CH, Chiu D, Begg RJ, Brott TG, CREST Investigators. The carotid revascularization endarterectomy versus stenting trial (CREST): stenting versus carotid endarterectomy for carotid disease. Stroke 2010 Oct;41(10 Suppl.):S31e4. [2] Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011 Sep 15;365(11): 993e1003. [3] Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of
[13]
[14]
75
patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American college of cardiology foundation/American heart association task force on practice guidelines, and the American stroke association, American association of neuroscience nurses, American association of neurological surgeons, American college of radiology, American society of neuroradiology, congress of neurological surgeons, society of atherosclerosis imaging and prevention, Society for cardiovascular angiography and interventions, society of interventional radiology, society of NeuroInterventional surgery, society for vascular medicine, and society for vascular surgery. Circulation 2011 Jul 26;124(4):489e532. Busch MA, Lutz K, Rohl JE, Neuner B, Masuhr F. Low ankle-brachial index predicts cardiovascular risk after acute ischemic stroke or transient ischemic attack. Stroke 2009 Dec;40(12):3700e5. Ratanakorn D, Keandoungchun J, Tegeler CH. Coexistent extra- and intracranial stenosis, cervical atherosclerosis, and abnormal ankle brachial index in acute ischemic stroke. J Stroke Cerebrovasc Dis 2012 Nov;21(8):782e9. Manzano JJ, De Silva DA, Pascual JL, Chang HM, Wong MC, Chen CP. Associations of ankle-brachial index (ABI) with cerebral arterial disease and vascular events following ischemic stroke. Atherosclerosis 2012 Jul;223(1):219e22. Lopez-Cancio E, Dorado L, Millan M, et al. The population-based barcelonaasymptomatic intracranial atherosclerosis study (ASIA): rationale and design. BMC Neurol 2011 Feb 17;11(1):22. Marrugat J, Subirana I, Comin E, et al. Validity of an adaptation of the framingham cardiovascular risk function: the VERIFICA study. J Epidemiol Community Health 2007 Jan;61(1):40e7. Alzamora MT, Fores R, Baena-Diez JM, et al. The peripheral arterial disease study (PERART/ARTPER): prevalence and risk factors in the general population. BMC Public Health 2010 Jan 27;10:38. Perk J, De Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012): the fifth joint task force of the european society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Atherosclerosis 2012 Jul;223(1):1e68. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American heart association/American stroke association. Stroke 2011 Feb;42(2):517e84. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke 2008 Aug;39(8):2396e9. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation 2010 Dec 21;122(25): 2748e64. Perrone-Filardi P, Achenbach S, Mohlenkamp S, et al. Cardiac computed tomography and myocardial perfusion scintigraphy for risk stratification in asymptomatic individuals without known cardiovascular disease: a position statement of the working group on nuclear cardiology and cardiac CT of the European society of cardiology. Eur Heart J 2011 Aug;32(16). 1986,93, 1993a, 1993b.