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Presence of external carotid artery plaque independently predicts mortality in patients without internal carotid artery atherosclerosis Esther SH Kim, Damien M Marycz, Devon Archinal, Heather L Gornik, Mehdi H Shishehbor and John R Bartholomew Vasc Med published online 28 August 2014 DOI: 10.1177/1358863X14546159 The online version of this article can be found at: http://vmj.sagepub.com/content/early/2014/08/28/1358863X14546159

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VMJ0010.1177/1358863X14546159Vascular MedicineKim et al.

Original Article

Presence of external carotid artery plaque independently predicts mortality in patients without internal carotid artery atherosclerosis

Vascular Medicine 1­–5 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1358863X14546159 vmj.sagepub.com

Esther SH Kim1, Damien M Marycz2, Devon Archinal1, Heather L Gornik1, Mehdi H Shishehbor1 and John R Bartholomew1

Abstract Background: The presence of plaque in the external carotid artery (ECA) detected on carotid duplex ultrasound (CDU) is of unknown clinical significance and may not be reported in routine clinical practice. We hypothesize that ECA plaque in the absence of plaque in the other cervical vessels is a risk factor for increased all-cause mortality. Objectives: To determine the significance of ECA plaque on all-cause mortality in the absence of internal carotid artery (ICA) or common carotid artery (CCA) plaque. Methods: We queried the Non-Invasive Vascular Laboratory database for all CDUs performed between 1 January 2005 and 31 December 2005. All images were reviewed for the presence of plaque. Studies were included if plaque was absent in both the CCA and the ICA. Chart review was performed to obtain demographic and clinical information. All-cause mortality was determined using the Social Security Death Index. Results: A total of 500 patient studies met the inclusion criteria; 64 patients (12.8%) had plaque in one or both ECAs. There was no significant difference in age (mean 58.1 ± 14.8 years), race (82.5% white), or sex (64.4% male) between those with and without ECA plaque. There was a significant difference in all-cause mortality between patients with and without isolated ECA plaque after adjustment for age, sex, low-density lipoprotein cholesterol, smoking, hypertension, body mass index, and surgery within 30 days of CDU (adjusted hazard ratio 2.60, 95% CI 1.46–4.66, p1.5 mm14 (Figure 1). The origin of the ECA was considered to start at the flow divider, and plaque which extended from the carotid bulb into the ECA were considered CCA plaque and excluded from final analysis.

Figure 1.  Plaque in the external carotid artery on B-mode ultrasonography. A B-mode ultrasound image of the origin of the external carotid artery showing focal thickening of the far wall (white arrow) at least 50% greater than the adjacent vessel walls with protrusion into the lumen consistent with atherosclerotic plaque.

multiple CDUs performed during that timeframe, only the first study was included in the analysis. Ultrasound examinations reporting no significant stenosis or plaque in both the common carotid artery (CCA) and ICA (0–19% in our institution) bilaterally were eligible for re-review of all study images for the presence of plaque. Any studies with plaque identified on re-review in either the CCA or ICA were excluded such that only studies with isolated ECA plaque were included in the analysis. The laboratory is accredited by the Intersocietal Accreditation Commission – Vascular Testing Division. Demographic, clinical, laboratory and medication information within 1 year before or after the date of CDU were obtained through review of the electronic medical record. Demographic information included age, race, sex and body mass index (BMI). Charts were reviewed for history of smoking, diabetes, and hypertension, and laboratory values were obtained for total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), total triglycerides, serum creatinine and hemoglobinA1C (HbA1c). The use of aspirin, statins, antihypertensive medications and other cholesterol-lowering medications were also included to assess for any statistical significance between those with isolated ECA plaque versus those without. Query of the Social Security Death Index was used to assess for all-cause mortality. This study was approved by the Institutional Review Board prior to investigation.

Ultrasound In compliance with IAC (Intersocietal Accreditation Commission – formerly the Intersocietal Commission for the Accreditation of Vascular Laboratories (ICAVL)) standards,13 the CDU protocol in our laboratory includes spectral Doppler waveforms taken from the proximal, mid, and distal portions of bilateral common and internal carotid arteries. Limited Doppler assessment of the ECA is also performed of at least one site in the origin or proximal segment of the vessel, and transverse and longitudinal B-mode imaging is routinely

Statistical analysis Statistical analysis was performed using STATA.15 Twotailed t-tests and chi-squared tests were used in bivariate analysis of baseline variables. Multivariable cox proportional hazards regression modeling was used to estimate survival for those with and without ECA plaque using traditional cardiovascular risk factors as covariates: age, sex, LDL cholesterol, smoking, and hypertension. BMI and having surgery within 30 days of CDU were also included in the multivariable analysis because of a statistically significant difference in BMI between those with ECA plaque and those without plaque in bivariate analysis and the large proportion of CDUs performed for pre-operative evaluation.

Results The database query resulted in a total of 687 patients with carotid ultrasound studies that met all the inclusion criteria. Of these, 97 were excluded due to the presence of plaque in the CCA or ICA on imaging re-review, 56 were excluded due to inadequate B-mode imaging of the ECA, 33 due to inability to re-review the images, and one due to carotid stent placement. Of the 500 studies meeting all inclusion criteria, 64 had the presence of plaque in one or both ECAs (12.8%). There were 42 of 64 (65.6%) patients with ECA plaque visualized on blinded image re-review that were not reported to have plaque on the original clinical CDU report. The mean age of all patients studied was 58.1 ± 14.8 years, with 64.4% being male. The indications for CDU referral were as follows: asymptomatic bruit (n=199, 39.8%), TIA (transient ischemic attack)/CVA (cerebrovascular accident) (n=25, 5.0%), surveillance of known cerebrovascular disease (n=21, 4.2%), pre-operative examination (n=215, 43.0%), and other not otherwise listed (n=40, 8.0%). Of the 211 patients who underwent surgery at our institution within 30 days of the CDU, 128 (60.7%) underwent cardiac surgery, 53 (25.1%) underwent vascular surgery, and 30 (14.2%) underwent non-cardiovascular surgery. There were no statistically significant differences in demographic or clinical variables between those with and without ECA plaque (Table 1). BMI was lower in those with ECA plaque versus those without (26.0 vs 28.6, p=0.001); however, there was no significant relationship between BMI and all-cause mortality in multivariate analysis. During a

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Kim et al. Table 1.  Patient characteristics.  

ECA plaque absent Mean (SD) n=436

ECA plaque present Mean (SD) n=64

p-value

Age (years) Male (%) Caucasian (%) Body mass index Hypertension (%) Smoking (%) Diabetes (%) Statins (%) Antihypertensive therapy (%) Aspirin (%) LDL HDL HbA1c Total cholesterol Triglyceride Creatinine

57.35 ± 13.11 64.91 80.96 28.58 ± 5.91 54.59 40.83 13.99 44.27 69.04 56.42 93.47 ± 31.80 52.49 ± 16.83 5.92 ± 1.38 172.11 ± 44.98 138.27 ± 179.16 1.16 ± 1.04

60.61 ± 14.07 60.94 95.31 25.96 ± 4.51 53.13 37.50 17.19 45.31 68.75 56.25 89.05 ± 30.41 55.09 ± 20.12 5.925 ± 1.17 169.15 ± 44.00 128.74 ± 79.44 1.21 ± 1.17

0.97 0.54 0.055 0.001 0.83 0.61 0.50 0.87 0.96 0.98 0.15 0.85 0.50 0.32 0.35 0.65

ECA, external carotid artery; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HbA1c, hemoglobin A1c.

Figure 2.  Adjusted survival functions by the presence of ECA plaque. During a median follow-up of 4.9 years, there was a statistically significant difference in mortality between patients with and without isolated ECA plaque with an adjusted hazard ratio of 2.60 for all-cause mortality in those with ECA plaque compared to those without ECA plaque (95% CI 1.46 to 4.66). Survival function was adjusted for age, sex, LDL cholesterol, smoking, hypertension, BMI, and surgery within 30 days of CDU.

median follow-up of 4.9 years from the date of the ultrasound study, there were 61 deaths with a statistically significant difference in all-cause mortality between patients with and without isolated ECA plaque (Figure 2), with an adjusted hazard ratio (HR) of 2.60 for all-cause mortality in those with ECA plaque compared to those without ECA plaque (95% CI 1.46 to 4.66). Of the 61 deaths, a cause of death could be determined through the electronic medical record for only 21 (13 died due to a cardiovascular cause, two died postoperatively, and six died from other causes).

Discussion While simple for use in clinical practice, risk prediction scores such as the Framingham risk score16 do have

limitations in their ability to accurately classify risk.17 The addition of biomarkers18,19 and imaging techniques such as coronary artery calcium scoring (CACS)20–22 and CIMT5 may improve risk stratification by direct imaging of the vasculature for early changes of atherosclerosis. Similarly, plaque detection using duplex ultrasonography of the peripheral vasculature can also improve coronary heart disease risk prediction,5,8,9,11 and in this study the presence of isolated ECA plaque was significantly associated with allcause mortality, independent of age, race, sex, LDL cholesterol, smoking history, diabetes, or hypertension. These findings support that the presence of atherosclerotic plaque, even in arterial beds considered to be of minor clinical significance, such as the ECA, may be an indicator of increased risk for all-cause mortality. The American College of Cardiology Foundation and the American Heart Association recognize the potential value of imaging for cardiovascular risk assessment.23 In the 2010 Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults,23 carotid IMT and CACS are each given a Class IIa recommendation for risk assessment in asymptomatic adults at intermediate risk. Other groups have also advocated for the use of imaging for the detection of subclinical atherosclerosis: the Screening for Heart Attack Prevention and Education (SHAPE) Task Force24 guideline recommends that all apparently healthy men aged 45–75 years and women aged 55–75 years without a history of coronary heart disease who have at least one traditional cardiovascular risk factor undergo testing for subclinical atherosclerosis with either CACS or CIMT to more precisely stratify their risk for myocardial infarction. Aggressive secondary prevention is recommended for those with a positive test for subclinical atherosclerosis, which is defined as a CACS ⩾1 or CIMT ⩾50th percentile or the presence of carotid plaque.24 While CACS is a non-invasive test with accepted predictive ability and reproducibility, the advantage

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Vascular Medicine

of CIMT over CACS is the ability to predict risk without radiation exposure. CIMT, however, is a highly technical examination requiring trained and experienced operators and readers. Plaque screening using CDU does not require highly specialized training, and several observational studies have demonstrated that the presence of carotid plaque is similar to, or perhaps even more predictive than, increased CIMT as a marker of risk for cardiovascular events.25–32 The importance of plaque screening during a CIMT examination is well recognized.14 Additionally, the incremental value of plaque screening, when added to IMT, has been demonstrated using the ARIC cohort5 and, more recently, the MESA cohort.6 It is important to note, however, that while plaque screening during CIMT is well accepted to be an integral part of risk stratification, the assessment of plaque usually involves close inspection of the CCA, the carotid bulb, and the ICAs.5,6,14 Few studies have included assessment of the ECA during plaque screening,32 and, to our knowledge, no prior studies have described the importance of plaque isolated to the ECA as an independent risk factor for increased all-cause mortality. In the clinical setting, CDU is most commonly used for the detection of CCA or ICA stenosis, and the presence of plaque within the ECA (particularly in the setting of normal CCA and ICAs) may be regarded as an incidental finding that does not merit further investigation or even clinical reporting. Even in our own laboratory, despite the use of report templates with drop-down box options for plaque reporting, the presence of ECA plaque was reported less than half of the time. Most of the medical literature regarding the significance of ECA atherosclerosis is in the context of its implications for treatment of severe ICA disease,33,34 but there has been a postmortem study demonstrating that atherosclerosis in the ECA and femoral arteries have a stronger correlation with atherosclerosis in the coronary arteries compared to the ICA and CCA.35 While we did not study the relative strength of the association between ECA plaque and mortality compared to plaque in the ICA or CCA, our study emphasizes the importance of vascular plaque presence as an important predictor of increased risk for all-cause mortality (even in ‘minor’ vascular beds) and suggests that patients with plaque in any of the extracranial carotid arteries may warrant a comprehensive review of their overall cardiovascular risk. A potential limitation of this study includes the referral bias inherent to a vascular laboratory at a tertiary medical center. The indication for carotid ultrasound in our study was preoperative evaluation in 43.0% of patients. The high rate of events over 5 years (61 deaths in a population of 500 patients) may be hypothesized to be due in part to the high number of screening CDU examinations performed prior to open heart surgery or vascular surgery at our institution; however, multivariate survival analysis including having surgery within 30 days of the CDU did not change the statistically significant relationship between ECA plaque and overall mortality. The more likely explanation for the high number of events is that ECA plaque is a marker for atherosclerotic disease elsewhere, including the coronary and peripheral arteries. To this extent, another potential limitation of our study is the unknown proportion of patients with coronary and/or peripheral artery disease in our cohort, entities known to be associated with elevated cardiovascular morbidity and mortality.

Because we are a tertiary referral center, follow-up information is not available for all patients through the electronic medical record. As such, a cause of death was obtainable for only 21 of the 61 total deaths (34.4%). Some would argue that the use of all-cause mortality is a potential limitation for this type of study; however, in contrast to the use of cardiovascular mortality, all-cause mortality is an unbiased and objective end point of great primary interest to both patients and providers.36 Nonetheless, consideration of the use of cardiovascular mortality, in addition to allcause mortality, would be of value in future studies. Another potential limitation of our study may be misclassification of the presence or absence of ECA plaque as the B-mode grayscale interrogation was limited to the bifurcation of the CCA and the origin of the ECA. As atherosclerotic plaque tends to form at the carotid bifurcation and at the origin of the ICA/ECA, however, misclassification bias is less likely to be a significant issue. Given these limitations, further study is necessary to determine the relative incremental value of adding plaque evaluation of the ECA to CIMT and CCA/ICA plaque screening in large, population-based studies and to assess the reproducibility of plaque assessment in the ECA during CDU. In summary, the presence of atherosclerotic plaque in the external carotid artery is an independent predictor of all-cause mortality and may impart important prognostic information for patients referred for CDU. Conscientious reporting of the presence of ECA plaque, even in the absence of CCA or ICA plaque, should be considered. Further study is required to determine the relative importance of ECA plaque for prognostication when compared to traditional risk scores, biomarkers, and imaging modalities such as CACS, CIMT, and traditional plaque screening of the CCAs and ICAs. Acknowledgements We would like to acknowledge Ms Mariam Khan, Mr Neil Poria, Mr David Rausch and Ms Susan Whitelaw for their assistance with database query and data management.

Declaration of conflicting interest Dr Kim is a consultant for Philips Ultrasound and has received grant support from GE.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References 1. De Weerd M, Buskens E, Bots M. Guidelines for screening of extracranial carotid artery disease: a comment. J Neuroimaging 2008; 18: 105–106. 2. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995; 273: 1421–1428. 3. Eliasziw M, Streifler JY, Fox AJ, Hachinski VC, Ferguson GG, Barnett HJ. Significance of plaque ulceration in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial. Stroke 1994; 25: 304–308. 4. Goessens BM, Visseren FL, Kappelle LJ, Algra A, van der Graaf Y. Asymptomatic carotid artery stenosis and the risk

Downloaded from vmj.sagepub.com at MCGILL UNIVERSITY LIBRARY on October 7, 2014

5

Kim et al. of new vascular events in patients with manifest arterial disease: the SMART study. Stroke 2007; 38: 1470–1475. 5. Nambi V, Chambless L, Folsom AR, et al. Carotid intimamedia thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study. J Am Coll Cardiol 2011; 55: 1600–1607. 6. Polak JF, Szklo M, Kronmal RA, et al. The value of carotid artery plaque and intima-media thickness for incident cardiovascular disease: the multi-ethnic study of atherosclerosis. J Am Heart Assoc 2013; 2: e000087. 7. Greenland P, Smith SC Jr, Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people: role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001; 104: 1863–1867. 8. Belcaro G, Nicolaides AN, Ramaswami G, et al. Carotid and femoral ultrasound morphology screening and cardiovascular events in low risk subjects: a 10-year follow-up study (the CAFES-CAVE study). Atherosclerosis 2001; 156: 379–387. 9. Wilson PW, Kauppila LI, O’Donnell CJ, et al. Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality. Circulation 2001; 103: 1529–1534. 10. Iribarren C, Sidney S, Sternfeld B, Browner WS. Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease. JAMA 2000; 283: 2810–2815. 11. Davidsson L, Fagerberg B, Bergstrom G, Schmidt C. Ultrasound-assessed plaque occurrence in the carotid and femoral arteries are independent predictors of cardiovascular events in middle-aged men during 10 years of follow-up. Atherosclerosis 2010; 209: 469–473. 12. Dalager S, Falk E, Kristensen IB, Paaske WP. Plaque in superficial femoral arteries indicates generalized atherosclerosis and vulnerability to coronary death: an autopsy study. J Vasc Surg 2008; 47: 296–302. 13. http://intersocietal.org/vascular/standards/IACVasc ularTestingStandards2013.pdf (accessed 11 August 2014). 14. Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008; 21: 93–111; quiz 189–190. 15. StataCorp LP. Intercooled Stata 9.0 for Windows. College Station, TX: StataCorp LP, 2005. 16. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837–1847. 17. Schlendorf KH, Nasir K, Blumenthal RS. Limitations of the Framingham risk score are now much clearer. Prev Med 2009; 48: 115–116. 18. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA 2007; 297: 611–619. 19. Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation 2008; 118: 2243–2251. 20. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008; 358: 1336–1345.

21. Divers J, Wagenknecht LE, Bowden DW, et al. Regional adipose tissue associations with calcified atherosclerotic plaque: African American-diabetes heart study. Obesity (Silver Spring) 2010; 18: 2004–2009. 22. Fuster V, Vahl TP. The role of noninvasive imaging in promoting cardiovascular health. J Nucl Cardiol 2010; 17: 781–790. 23. 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. J Am Coll Cardiol 2010; 56: 2182–2199. 24. Naghavi M, Falk E, Hecht HS, et al. From vulnerable plaque to vulnerable patient–Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report. Am J Cardiol 2006; 98: 2H–15H. 25. Kitamura A, Iso H, Imano H, et al. Carotid intimamedia thickness and plaque characteristics as a risk factor for stroke in Japanese elderly men. Stroke 2004; 35: 2788–2794. 26. Rosvall M, Janzon L, Berglund G, Engstrom G, Hedblad B. Incident coronary events and case fatality in relation to common carotid intima-media thickness. J Intern Med 2005; 257: 430–437. 27. Van der Meer IM, Bots ML, Hofman A, del Sol AI, van der Kuip DA, Witteman JC. Predictive value of noninvasive measures of atherosclerosis for incident myocardial infarction: the Rotterdam Study. Circulation 2004; 109: 1089–1094. 28. Hunt KJ, Sharrett AR, Chambless LE, Folsom AR, Evans GW, Heiss G. Acoustic shadowing on B-mode ultrasound of the carotid artery predicts CHD. Ultrasound Med Biol 2001; 27: 357–365. 29. Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb 1991; 11: 1245–1249. 30. Prabhakaran S, Rundek T, Ramas R, et al. Carotid plaque surface irregularity predicts ischemic stroke: the northern Manhattan study. Stroke 2006; 37: 2696–2701. 31. Stork S, van den Beld AW, von Schacky C, et al. Carotid artery plaque burden, stiffness, and mortality risk in elderly men: a prospective, population-based cohort study. Circulation 2004; 110: 344–348. 32. Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke 2002; 33: 2916–2922. 33. Countee RW, Vijayanathan T. External carotid artery in internal carotid artery occlusion. Angiographic, therapeutic, and prognostic considerations. Stroke 1979; 10: 450–460. 34. Nicolosi A, Klinger D, Bandyk D, Towne J. External carotid endarterectomy in the treatment of symptomatic patients with internal carotid artery occlusion. Ann Vasc Surg 1988; 2: 336–339. 35. Molnar S, Kerenyi L, Ritter MA, et al. Correlations between the atherosclerotic changes of femoral, carotid and coronary arteries: a post mortem study. J Neurol Sci 2009; 287: 241– 245. 36. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death in clinical research: time for a reassessment? J Am Coll Cardiol 1999; 34: 618–620.

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Presence of external carotid artery plaque independently predicts mortality in patients without internal carotid artery atherosclerosis.

The presence of plaque in the external carotid artery (ECA) detected on carotid duplex ultrasound (CDU) is of unknown clinical significance and may no...
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