- Email: [email protected]
Risk Stratification for Cardiovascular Disease in Women in the Primary Care Setting
ATHEROSCLEROSIS RISK STRATIFICATION
Risk Stratification for Cardiovascular Disease in Women in the Primary Care Setting Ranjini R. Roy, MD, R. Todd Hurst, MD, Steven J. Lester, MD, Christopher Kendall, BS, RDCS, Christy Baxter, BS, RDCS, Qing Wu, ScD, Jill Borovansky, MD, Julia Files, MD, Prasad Panse, MD, and Susan Wilansky, MD, Phoenix and Scottsdale, Arizona
Background: Traditional risk assessment tools classify the majority of middle-aged women at low risk despite cardiovascular (CV) disease’s affecting >50% of women and remaining the leading cause of death. Ultrasound-determined carotid intima-media thickness (CIMT) and/or computed tomographic coronary artery calcium score (CACS) quantify subclinical atherosclerosis and add incremental prognostic value. The aim of this study was to assess the utility of CIMT and CACS to detect subclinical atherosclerosis in younger women. Methods: Asymptomatic women aged 50 to 65 years with at least one CV risk factor and low Framingham risk scores were identified prospectively at primary care and cardiology clinics. Mean intimal thickness, plaque on CIMT, and Agatston calcium score for CACS were obtained. Results: Of 86 women (mean age, 58 6 4.6 years; mean Framingham risk score, 1.9 6 1.2; mean low-density lipoprotein cholesterol level, 138.9 6 37.0 mg/dL), 53 (62%) had high-risk CIMT (51% plaque, 11% CIMT > 75th percentile). In contrast, three women (3.5%) had CACS > 100, all of whom had plaque by CIMT. Of the 58 women with CACS of 0, 32 (55%) had high-risk CIMT (48% plaque, 7% CIMT > 75th percentile). Conclusions: In patients referred by their physicians for assessment of CV risk, CIMT in asymptomatic middleaged women with at least one CV risk factor and low risk by the Framingham risk score identified a large number with advanced subclinical atherosclerosis despite low CACS. Our results suggest that CIMT may be a more sensitive method for CV risk assessment than CACS or traditional risk tools in this population. Further studies are needed to determine if earlier detection would be of clinical benefit. (J Am Soc Echocardiogr 2015;28:1232-9.) Keywords: Carotid ultrasound, Calcium score, Women, Risk
Fifty-six percent of adult women in the United States will develop clinical cardiovascular disease (CVD) in their lifetimes,1 and CVD remains the number one cause of mortality in women, resulting in one death per minute in the United States.2-4 Importantly, in up to 45% of women, their first presentation of CVD may be sudden death, which occurs without antecedent symptoms, further emphasizing the importance of primary prevention of CVD.4-7 Although effective means for preventing CVD are available, current methods for identifying those at risk before events occur are From the Division of Cardiovascular Diseases, Department of Internal Medicine, University of Arizona College of Medicine, Maricopa Medical Center, Phoenix, Arizona (R.R.R.); and the Division of Cardiovascular Diseases (R.T.H., S.J.L., C.K., C.B., S.W.), College of Medicine, Biostatistics, Division of Health Sciences Research (Q.W.), Department of Internal Medicine (J.B., J.F.); and Department of Radiology (P.P.), Mayo Clinic College of Medicine, Scottsdale, Arizona. This research was funded by a Mayo Clinic CR5 grant. Reprint requests: Susan Wilansky, MD, Mayo Clinic College of Medicine, Department of Internal Medicine, Division of Cardiovascular Diseases, 13400 East Shea Boulevard, Scottsdale, AZ 85259 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.06.015
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limited.8,9 Population-based risk algorithms such as the Framingham risk score (FRS), Reynolds risk score (RRS), and pooled cohort equation are used to assess cardiovascular risk, yet 75% of myocardial infarction and CVD deaths occur in the low- and intermediate-risk populations.7-13 Both computed tomographic coronary artery calcium score (CACS) and carotid intima-media thickness (CIMT) and plaque detection on ultrasound measure subclinical atherosclerosis and have been shown to independently add incremental predictive value to traditional risk factors, although the correlation between the two is weak.10-12 In this study, we evaluated the prevalence of advanced subclinical atherosclerosis as assessed by CACS and carotid ultrasound in middle-aged women with at least one cardiovascular risk factor but low FRS. METHODS This protocol was approved by the Mayo Clinic Institutional Review Board. Asymptomatic women between 50 and 65 years of age with at least one cardiovascular risk factor (hyperlipidemia, hypertension, family history of premature coronary disease, current tobacco use, or elevated high-sensitivity C-reactive protein) and classified at low risk by the FRS were included in the study. Women were identified by their
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primary care physicians or cardiologists at the Mayo Clinic Arizona ASCVD = Atherosclerotic from December 1, 2010, to cardiovascular disease January 31, 2013. The initial history, physical examination, and CACS = Coronary artery laboratory testing was performed calcium score by the referring physician and CAD = Coronary artery was accessible via the electronic disease medical record. Informed consent CI = Confidence interval was obtained by the Protocol Development Office. FRS were CIMT = Carotid intima-media calculated for all participants, thickness and only those at low risk CVD = Cardiovascular (<10% risk for a cardiovascular disease event over 10 years) were included. The RRS was also calcuFRS = Framingham risk score lated when data were available, HR = Hazard ratio and the race- and sex-specific pooled cohort equation to calcuRRS = Reynolds risk score late the 10-year atherosclerotic CVD (ASCVD) risk estimate13 was calculated for all patients. Hyperlipidemia was defined as a low-density lipoprotein cholesterol level $ 100 mg/dL; hypertension as systolic blood pressure $ 140 mm Hg, diastolic blood pressure $ 90 mm Hg, or use of antihypertensive therapy; and family history of premature coronary disease as a first-degree male relative <55 years of age or a female first-degree relative <65 years of age with a cardiac event. Subjects were excluded if they were on lipid-lowering therapy, had histories of coronary artery disease (CAD) or CAD equivalent such as peripheral vascular disease, cerebrovascular disease, or diabetes mellitus. Patients were assessed for waist circumference, body mass index, current tobacco use, family history, and hypertension. Laboratory studies including a fasting lipid profile, plasma glucose, and highsensitivity C-reactive protein were performed and CIMT assessment was performed in all subjects. Low-risk CIMT was classified as <50th percentile, intermediate-risk CIMT as 50th to 75th percentile, and high-risk CIMT as >75th percentile or the presence of plaque. Computed tomography for CACS was also performed, and an Agatston score was assigned on the basis of age- and sex-matched control subjects.14 CIMT was defined as the distance between the lumen-intima interface and the media-adventitia interface. All patients were scanned by one of two experienced cardiac sonographers (C.K. and C.B.) using a multifrequency linear-array transducer in fundamental frequency > 7 MHz on a high-resolution B-mode ultrasound system (Siemens Acuson Sequoia C512; Acuson Inc, Mountain View, CA). All studies followed the CIMT protocol approved by the Mayo Clinic Arizona echocardiography laboratory and included screening for carotid artery plaque and common CIMTanalysis. For the carotid artery plaque screen, the transverse and longitudinal axes of the right and left common carotid arteries, the carotid bulb, and the proximal internal and external carotid arteries were imaged. Measurements for CIMTwere obtained at the distal 1-cm far wall of the common carotid artery at end-diastole (within one or two frames of the onset of the electrocardiographic Q wave) averaged over three cardiac cycles from two separate angles of insonation (Figure 1A). All CIMT images were transferred and stored digitally on a server for analysis using Arterial Health Package (Siemens Syngo Ultrasound Workplace; Siemens Medical Inc, Malvern, PA). Plaque was defined as a focal intima-media thickening of the arterial wall that was $1.5 mm thick and/or >50% thicker than the surrounding arterial wall (Figure 1B). If plaque was identified, the locaAbbreviations
tion was noted, and a three-beat clip that best demonstrated the plaque was obtained. Measurements were performed using semiautomated border detection software and obtained from two optimal angles of incidence (middle, anterior, and posterior). Three measurements at each angle were evaluated at end-diastole (within one or two frames of the Q wave on the electrocardiogram) for a total of 12 measurements, resulting in a composite mean CIMT measurement. There were two independent cardiologists experienced in reading CIMT studies, to minimize interobserver variability. Electron-beam computed tomography with 3-mm slice thickness was used to assess for coronary artery calcification (Figure 2). If coronary artery calcium was detected, using the Agatston method, an automated score was generated.15 CACS were based on ageand sex-matched control patients.14 A CACS of 0 was suggestive of no disease, 1 to 99 of mild disease, 100 to 399 of moderate disease, and >400 of severe disease. Carotid ultrasound was compared with CACS in the detection of subclinical atherosclerosis. Patients were classified with low-risk CIMT (<50th percentile), intermediate-risk CIMT (50th to 75th percentile), or high-risk CIMT (>75th percentile or the presence of plaque) for CVD on the basis of age-, sex-, and race-matched percentile.16 A CACS Agatston score was assigned to age- and sex-matched patients. SAS version 9.2 (SAS Institute Inc, Cary, NC) was used for data analysis. Continuous variables are presented as mean 6 SD. Categorical variables are presented as counts and percentages. Sample size calculation was performed by our Department of Biostatistics. A sample of 70 patients was found to have 80% power if the percentage of patients at high risk by CIMT and by CACS differed by 25 points (i.e., 63% vs 38%). With additional patients, the power would be greater to detect a difference. RESULTS Baseline Data A total of 90 patients were assessed and four excluded. Exclusions included a screen failure due to lipid-lowering therapy (n = 1), one subject at intermediate risk by FRS, and two subjects who later refused computed tomography. Thus, 86 women were included in the study (mean age, 58 6 4.6 years) with an average FRS of 1.9 6 1.2, an average RRS of 2.2 6 2.1, and an average 10-year ASCVD risk estimate of 3.1 6 2.0. Eighty-two of 86 women (95%) had 10-year ASCVD risk < 7.5%. Ninety-five percent of women were Caucasian, three were Asian-Pacific Islanders, and one was African American. The average body mass index was 26.1 6 4.9 kg/m2, waist circumference 93.1 6 12.9 cm, systolic blood pressure 117.6 6 15.2 mm Hg, fasting glucose 92.7 6 13.3 mg/dL, and lowdensity lipoprotein cholesterol level 138.9 6 37.0 mg/dL (Table 1). Thirty-two patients (37.2%) had family histories of CAD, 11 (12.8%) were smokers, and 23 (26.7%) were on antihypertensive medications. The mean high-sensitivity C-reactive protein level was 2.9 mg/L. CIMT Findings Of the participating women, 44 (51.2%) had evidence of plaque on CIMT, with an additional nine subjects (10.5%) demonstrating high risk CIMT > 75th percentile for age-, gender-, and race-matched control subjects. Figure 3 illustrates the CIMT percentile breakdown among those with plaque. Of the four women who had 10-year ASCVD risk estimates $ 7.5%, three had plaque on CIMT, and the fourth had high-risk CIMT falling into the >75th percentile. Thus, 53 of participants (61.6%) were found to have either plaque on
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Figure 1 CIMT. (A) Middle left common carotid artery at end-diastole demonstrating normal thickness. (B) Presence of plaque in the right common carotid artery (yellow arrow).
Figure 2 Electron-beam computed tomography with 3-mm slice thickness demonstrating no coronary artery calcification. (A) Axial image at the level of left main (yellow arrow) and left anterior descending (blue arrow) arteries. (B) Axial image from the same patient at the level of proximal right coronary (yellow arrow) and left circumflex (blue arrow) arteries. CIMT or a high-risk CIMT scan. Eight patients (9.3%) were categorized as <25th percentile for age- and gender-matched control subjects, 32 (37.2%) were in the 25th to 49th percentile, 27 (31.4%) were in the 50th to 75th percentile, and 19 (22.1%) were >75th percentile by CIMT (Figure 4A). The composite mean thickness on CIMT was 0.6 6 0.12 mm. Of those with plaque, the mean plaque thickness was 1.9 6 0.46 mm. CACS Findings Regarding the Agatston score for coronary artery calcium, 58 subjects (67.4%) were found to have CACS of 0, and 25 (29.0%) had CACS of 1 to 99 (Figure 4A). Interestingly, of the four women who had 10year ASCVD risk estimates $ 7.5%, three had CACS of 0 and the fourth had a CACS of 1. Only three patients (3.6%) had CACS of 100 to 399, and there were no patients with CACS > 400. The percentile breakdown for CT calcium scoring is illustrated in Figure 4 but reveals a similar trend, with a majority of patients demonstrating low-risk CACS scans. The breakdown by CIMT percentile in patients with >75th percentile CACS is illustrated in Table 2.
CIMT Compared with CACS Overall, more patients were found to have low-risk scans by CACS than by CIMT, with 58 subjects (67.4%) identified with CACS of 0 compared with eight subjects (9.3%) falling into the <25th percentile range of CIMT (Figure 4). Of the 58 subjects with CACS of 0, 28 (48.2%) were found to have plaque by CIMT, and an additional four were >75th percentile by CIMT. Thirty-two patients (55%) with CACS of 0 had CIMT in the 50th percentile or greater. Only five patients (5.6%) with CACS of 0 had CIMT in the <25th percentile range (Table 3). Conversely, 14 participants (16.5%) were found to have CACS in the >75th percentile, of whom nine (64%) were known to have plaque by CIMT. Three of the remaining five subjects without plaque on CIMT but still >75th percentile by CACS were deemed to be >75th percentile by CIMT. Thus, there were only two patients identified as being >75th percentile by CACS but with low-risk findings on CIMT. Of those with plaque or high-risk CIMT > 75th percentile (n = 53), 32 (60.3%) were found to have CACS of 0, 18 (34.0%) were found to have CACS of 1 to 99, and three (5.7%) were found to have CACS of 100 to 399. There were
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Table 1 Baseline characteristics (n = 86) Variable
Age (y) Caucasian Waist circumference (cm) Systolic blood pressure (mm Hg)
Value
57.5 6 4.2 95% 93.1 6 12.9 117.6 6 15.2
Diastolic blood pressure(mm Hg)
69.7 6 10.6
On antihypertensive medication
23 (26.7%)
On aspirin
14 (16.3%)
Current cigarette smoker
11 (12.8%)
Family history of premature CAD
32 (37.2%)
Mean FRS
1.9 6 1.2
Mean RRS
2.2 6 2.1
Mean ASCVD 10-y risk estimate
3.1 6 2.0
Laboratory results Total cholesterol (mg/dL)
232.1 6 40.0
Triglycerides (mg/dL)
117.9 6 53.5
HDL cholesterol (mg/dL)
68.5 6 22.7
LDL cholesterol (mg/dL)
138.9 6 37.0
Glucose (mg/dL) hs-CRP (mg/L)
92.7 6 13.3 2.9 6 4.0
HDL, High-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein. Data are expressed as mean 6 SD or as number (percentage).
no patients with either high-risk CIMT (>75th percentile) or plaque by CIMT who had CACS > 400 (Table 4). All 3 patients with CACS > 100 had plaque by CIMT. There were 25 patients who had CACS of 1 to 99, of whom 13 had plaque by CIMT. Of the remaining 12 patients with CACS of 1 to 99 suggestive of mild disease, five (42%) had high-risk CIMT (>75th percentile). There were seven patients with CACS of 1 to 99 and CIMT < 50th percentile. Follow-Up Data Six month follow-up was available on 84 of the 86 subjects included in this study. Two subjects were unable to be reached by telephone. Lipid-lowering therapy was recommended by physicians for 51 participants (61%) on the basis of the results of the CIMT and/or CACS scans. Physicians recommended the initiation of statin therapy in 48 patients, ezetimibe in one patient, fenofibrate in one patient, and niacin in one patient. The use of aspirin also increased from 16.3% at baseline to 24.1% at 6-month follow-up. Of the 51 patients who were started on lipid-lowering therapy, 18 had high-risk CIMT (>75th percentile), 13 had CIMT in the 50th to 75th percentiles, 16 had CIMT in the 25th to 49th percentiles, and four had CIMT < 25th percentile (Table 5). Of the four patients with CIMT in the <25th percentile, two patients had plaque by CIMT. The other two patients with CIMT < 25th percentile and no plaque by CIMT had CACS > 0 (4 and 64) with elevated CACS percentiles (64th and 84th percentiles) and so were advised to receive lipid-lowering therapy. Of the 16 patients with CIMT in the 25th to 49th percentiles, 14 patients had plaque by CIMT. The other two patients who did not have plaque by CIMT had also had CACS > 0 (9 and 28) and were in elevated percentiles by CACS (58th and 84th percentiles) and were thus recommended
Figure 3 CIMT percentile breakdown among those with plaque. lipid-lowering therapy. All patients in the 50th to 75th percentiles had plaque by CIMT, and 10 of 18 patients with high-risk CIMT > 75th percentile had plaque. Further breakdown by CACS score is illustrated in Table 5.
DISCUSSION The principal finding in our study was that >60% of asymptomatic women classified at low risk by the FRS and/or RRS had advanced atherosclerosis as determined by ultrasound of the carotid artery. One third of women had detectable calcium on CACS, while only three had calcium scores > 100. Interestingly, all of the women with 10-year ASCVD risk estimates of $7.5% were identified by CIMT as either having plaque or high-risk CIMT (>75th percentile), but three of the four women had CACS of 0 and the fourth woman had a CACS of 1. The 10-year ASCVD risk estimate of $7.5% is the cut point at which it has been recommended to consider moderate- to high-intensity statin therapy.13 Current guidelines suggest using CACS as an adjunctive tool for determining the need for statin therapy in patients in whom the decision for lipid-lowering therapy is less clear. However, in our specific population, CIMT appeared to identify those at a higher cardiovascular risk as ascertained by the ASCVD risk estimate tool, whereas CACS did not. Prevention of CVD in women is paramount given the high lifetime risk for CVD in women, which approaches 56%.1 The use of carotid ultrasound for risk assessment in patients at intermediate risk for CVD has been well established, but its use in the low-risk population is uncertain.17,18 Women in particular are often classified at low risk on the basis of traditional measures of risk assessment such as the FRS and RRS, with 92% of women aged 60 to 69 years being in the lowrisk FRS range.19 Yet these risk assessment tools may be inadequate to accurately assess cardiovascular risk.10,12,20-23 Michos et al.21 studied 2,447 asymptomatic, nondiabetic women and found that of the 20% who had high-risk CACS, 84% were classified at low risk by the FRS, and none were classified at high risk. In another study of women with family histories of premature CAD, 98% were at low risk by the FRS, yet 40% had detectable coronary artery calcium and 17% had CACS >90th percentile.20 The finding in our study of detecting subclinical atherosclerosis in asymptomatic women otherwise classified at low risk by the FRS is in keeping with a study by Postley et al.,24 who screened 715 asymptomatic adults with ultrasound of the carotid and femoral arteries to
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Figure 4 Age- and gender-matched percentile breakdown of CIMT and CACS (A) and Agatston calcium score distribution in women (B). Table 2 Breakdown of CIMT percentile in patients with >75th percentile CACS (n = 15)
Table 4 Agatston calcium score in women with plaque or high-risk CIMT scan (n = 53)
CIMT percentile
CACS Agatston score
Number of patients (%)
Number of patients (%)
<25th
1 (12.5)
0
32 (60.4)
25th to 49th
6 (18.8)
1–99
18 (34.0)
50th to 75th
2 (7.4)
100–399
>75th
6 (31.2)
>400
3 (5.7) 0
Table 3 CIMT percentile in women with calcium scores of 0 (n = 58)
Table 5 Breakdown of CIMT and CACS in patients started on lipid-lowering therapy (n = 51)
CIMT percentile
CACS Agatston score
<25th
Number of patients (%)
Number of patients (%)
CIMT percentile
Number of patients
5 (5.6) 21 (36.2)
0
28
<25th
50th to 75th
22 (38.0)
1–99
20
25th to 49th
>75th
10 (17.2)
100–399
3
50th to 75th
13
>400
0
>75th
18
25th to 49th
detect subclinical atherosclerosis. They found that among cohorts aged 50 to 65 years, 56% of the women had plaque in their femoral arteries. Among low-risk women aged 50 to 64 years, 30.4% had femoral or carotid plaque, and among those at intermediate risk, 56.3% had plaque. Our results demonstrated that 51.2% of women classified at low risk by the FRS had carotid plaque, which is higher than reported by Postley et al. However, smoking is a known risk factor for progression of atherosclerosis, and it is worthwhile to note that in their study, only 3.9% of women were current smokers, compared with 12.8% in our present study, which may have played a role in the higher plaque burden seen in our study. High-risk CIMT or plaque was correlated with an increase in cardiovascular events in several large studies, with hazard ratios (HRs) ranging from 1.81 (95% confidence interval [CI], 1.14–2.87) to 4.15 (95% CI, 1.50–11.47).17,25-31 With every 0.1-mm increase in CIMT, the risk for myocardial infarction increases by 10% to 15% and the risk for stroke increases by 13% to 18%.32 Plaque also correlates with an increase in cardiovascular events and may more accurately assesses risk prediction in women compared with men.22 A systematic review including nine studies and >38,000 patients with carotid plaque determined that in eight of the nine studies, the finding of plaque on carotid ultrasound was predictive of cardiovascular death and/or myocardial infarction.33 Most women’s first cardiovas-
4 16
cular events are stroke, from which the mortality is higher compared with men.34 In the Atherosclerosis Risk in Communities study, 7,289 women underwent CIMT, and the HR for myocardial infarction or coronary heart disease death for high versus low tertiles was 6.69.16 The Cardiovascular Health Study analyzed 5,858 individuals without clinically apparent coronary heart disease and found that the highest quintile of CIMT had a 3.87 relative risk (adjusted for age and sex) of myocardial infarction or stroke compared with those in the lowest quintile.35 More recently, the Cardiovascular Health Study investigators found that CIMT improved risk prediction for stroke and CVD in the older population, predominantly by down-classifying risk in those who did not have events, and they also found that the presence of any plaque improved risk prediction and reclassification.36 In the Atherosclerosis Risk in Communities Stroke study of 7,865 women with no prior clinical cerebrovascular disease, the HR for those with CIMT > 1.0 mm compared with those with CIMT < 0.6 mm was 8.5.37 Bauer et al.38 compared two large population-based studies with subclinical CVD, the Multi-Ethnic Study of Atherosclerosis cohort and the Heinz Nixdorf Recall Study group, and analyzed the association between traditional cardiovascular risk factors and CIMT. They found that there was high consistency between the traditional risk factors, particularly age, male sex, and systolic blood
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pressure, and increased CIMT measurements, thus reaffirming that CIMT may serve as a marker for cardiovascular risk. Thus, early identification of women with subclinical atherosclerosis may allow the early identification of an at-risk population and possibly earlier implementation of preventive strategies. CACS may also help restratify patients for cardiovascular risk assessment.11,13,39 A subgroup analysis of the Multi-Ethnic Study of Atherosclerosis showed that 90% of women aged 45 to 79 years (excluding those with diabetes) were classified at low risk by FRS.39 However, 32% of these women had CACS > 0, and those with scores > 0 were found to be at increased risk for cardiovascular events, with a HR of 5.2 (95% CI, 2.5–10.8). It has been suggested that CACS may be preferred as a method of reclassifying risk in the intermediate-risk population,40 though it is unclear if this would apply to our study population, which was younger, low-risk women. Current guidelines support the use of CACS as a means for further risk-stratifying individuals at intermediate risk.13,18 A CACS of 0 has been associated with a low risk for cardiovascular events,41,42 but in our study, 48.2% of women with CACS of 0 were found to have plaque by CIMT. Although our study did not analyze hard outcomes, the presence of plaque on CIMT has been correlated with an increase in cardiovascular events. Therefore, in our specific patient population of younger women, CIMT may be a useful adjunctive tool for further risk stratification. The three patients found to have CACS of 100 to 399 were all identified as having plaque by CIMT, supporting the presence of subclinical atherosclerosis and probable elevated cardiovascular risk. Note that this study was conducted before the availability of the 10-year ASCVD risk estimator, which has greatly influenced clinician practice with regard to the use of statin therapy. However, it may be worth noting that in our study, the use of CIMT and/or CACS altered physician management to patient care, with patients being started on lipid-lowering therapy 61% of the time on the basis of the results of these scans. In addition, the most recent guidelines recommend against the routine use of CIMT for risk assessment for a first ASCVD event.13 This recommendation was based largely on the variability of CIMT measurements and difficulty with standardization of these measurements, along with the results of a recent large meta-analysis suggesting that the addition of CIMT did not substantially add to the reclassification of risk class.43 Polak et al.44 conducted a study of 279 patients using CIMT measurements near and below the carotid bulb and found that measurements obtained below the bulb, although smaller, correlated better with risk factors and events compared with measurements obtained near the carotid bulb. These data suggest that even small differences in CIMT measurements may have variable associations with events and thus should be taken into account when analyzing the available literature on CIMT. It is notable that in our study, measurements were obtained at the distal 1-cm far wall of the common carotid artery and not near the bulb, which was found to correlate better with risk factors and events. In addition, Aldridge et al.45 performed a study in which medical residents were rapidly trained in an abbreviated CIMT measurement protocol from the American Society of Echocardiography and found that after training, interobserver variability was low, with 88% agreement with the expert, suggesting that standardization and reproducibility of CIMT of measurements may be feasible. Thus, in a specific population such as ours, CIMT in younger women may be helpful as an adjunctive tool for risk assessment. It is worthwhile to note that the most recent American College of Cardiology and American Heart Association guidelines make a class III recommendation for using common CIMT alone for risk stratification.13 We agree with this recommendation. A complete carotid ultra-
sound study for risk stratification includes a comprehensive plaque assessment, and if no plaque is found, common CIMT should be assessed. It would be most helpful if future guidelines clearly distinguished between a comprehensive carotid ultrasound examination for risk stratification and performing only a common CIMT study without plaque screening. The results of our study suggest that in middle-aged women with at least one cardiovascular risk factor who are otherwise deemed to be at low risk by the FRS or RRS, imaging for risk prediction may add incremental value in identifying subclinical atherosclerosis and reclassifying low-risk women into a higher risk category. On the basis of the findings of our study and the fact that ultrasound does not result in radiation exposure, CIMT may be preferable and a more sensitive detector of subclinical atherosclerotic vascular disease in younger women. However, further studies are needed to determine if earlier detection of subclinical atherosclerosis is beneficial with regard to long-term outcomes. Limitations Our study did not address whether the identification of women with high-risk CACS or CIMT scans led to an increase in cardiovascular events. Previous studies have shown that although both CIMT and CACS are predictive of future CVD events, CACS may be a better predictor for total CVD and CIMT for stroke.31,46 However, prior studies have demonstrated that subclinical atherosclerosis is correlated with an increase in cardiovascular events. Many of the women deemed to have high-risk scans or plaque were initiated on lifestyle modifications and/or pharmacologic therapy, so long-term follow-up for adverse cardiovascular events comparing those who were initiated on therapy with those who were not may be beneficial for future studies. In addition, socioeconomic diversity may be limited because of the nature of the referral practices. In our study, there was no independent arbiter to assess vascular disease to fully investigate the question of whether CIMT was truly a more accurate method of detecting atherosclerosis compared with CACS. It may be that CIMT detected false-positive results or perhaps that CACS detected false-negative results, and without the independent arbiter, we are limited in fully assessing this. Although our sample size was small, our study was sufficient to detect $80% power on the basis of our statistical calculations. CONCLUSIONS Carotid ultrasound in asymptomatic younger women with at least one cardiovascular risk factor but otherwise classified at low risk by the FRS identified a large number with plaque, many of whom did not have high CACS, suggesting that CIMT may be a more sensitive method for detecting subclinical atherosclerosis in this population. REFERENCES 1. Wilkins JT, Ning H, Berry J, Zhao L, Dyer AR, Lloyd-Jones DM. Lifetime risk and years lived free of total cardiovascular disease. JAMA 2012;308: 1795-801. 2. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013;127:e6-245. 3. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, DeSimone G, et al. Heart disease and stroke statistics—2010 update. A report from the American Heart Association. Circulation 2009.
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4. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 2014;129:e28-292. 5. Burke AP, Farb A, Malcom GT, Liang Y, Smialek J, Virmani R. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circ Cardiovasc Qual Outcomes 1998;97:2110-6. 6. Mosca L, Appel LJ, Benjamin EJ, Berra K, Chandra-Strobos N, Fabunmi RP, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 2004;109:672-93. 7. Myerburg RJ, Interian A Jr., Mitrani RM, Kessler KM, Castellanos A. Frequency of sudden cardiac death and profiles of risk. Am J Cardiol 1997; 80:10F-9. 8. Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41: 1475-9. 9. Hecht HS, Superko HR. Electron beam tomography and National Cholesterol Education Program guidelines in asymptomatic women. J Am Coll Cardiol 2001;37:1506-11. 10. Lester SJ, Eleid MF, Kahndheria BK, Hurst RT. Carotid intima-media thickness and coronary artery calcium score as indications of subclinical atherosclerosis. Mayo Clin Proc 2009;84:229-33. 11. Polonsky TS, McClelland RL, Jorgensen NW, Bild DE, Burke GL, Guerci AD, et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. Jama 2010;303:1610-6. 12. Naqvi TZ, Mendoza F, Rafii F, Gransar H, Guerra M, Lepor N, et al. High prevalence of ultrasound detected carotid atherosclerosis in subjects with low Framingham risk score: potential implications for screening for subclinical atherosclerosis. J Am Soc Echocardiogr 2010;23:809-15. 13. Goff DC Jr., Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB Sr., Gibbons R, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circ Cardiovasc Qual Outcomes 2013. 14. Hoff JA, Chomka EV, Krainik AJ, Daviglus M, Rich S, Kondos GT. Age and gender distributions of coronary artery calcium detected by electron beam tomography in 35,246 adults. Am J Cardiol 2001;87:1335-9. 15. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr., Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827-32. 16. Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol 1997;146:483-94. 17. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, 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 189-90. 18. Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2010;122:e584-636. 19. Ford ES, Giles WH, Mokdad AH. The distribution of 10-year risk for coronary heart disease among US adults: findings from the National Health and Nutrition Examination Survey III. J Am Coll Cardiol 2004;43: 1791-6. 20. Michos ED, Vasamreddy CR, Becker DM, Yanek LR, Moy TF, Fishman EK, et al. Women with a low Framingham risk score and a family history of premature coronary heart disease have a high prevalence of subclinical coronary atherosclerosis. Am Heart J 2005;150:1276-81. 21. Michos ED, Nasir K, Braunstein JB, Rumberger JA, Budoff MJ, Post WS, et al. Framingham risk equation underestimates subclinical atherosclerosis risk in asymptomatic women. Atherosclerosis 2006;184:201-6.
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22. Nambi V, Chambless L, Folsom AR, He M, Hu Y, Mosley T, et al. Carotid intima-media 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 2010;55:1600-7. 23. 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;297:611-9. 24. Postley JE, Perez A, Wong ND, Gardin JM. Prevalence and distribution of sub-clinical atherosclerosis by screening vascular ultrasound in low and intermediate risk adults: the New York Physicians Study. J Am Soc Echocardiogr 2009;22:1145-51. 25. Hunt KJ, Evans GW, Folsom AR, Sharrett AR, Chambless LE, Tegeler CH, et al. Acoustic shadowing on B-mode ultrasound of the carotid artery predicts ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2001;32:1120-6. 26. Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb 1991;11:1245-9. 27. Kitamura A, Iso H, Imano H, Ohira T, Okada T, Sato S, et al. Carotid intima-media thickness and plaque characteristics as a risk factor for stroke in Japanese elderly men. Stroke 2004;35:2788-94. 28. 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;257:430-7. 29. 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. Circ Cardiovasc Qual Outcomes 2004;109:1089-94. 30. Prabhakaran S, Rundek T, Ramas R, Elkind MS, Paik MC, Boden-Albala B, Sacco RL. Carotid plaque surface irregularity predicts ischemic stroke: the northern Manhattan study. Stroke 2006;37:2696-701. 31. Folsom AR, Kronmal RA, Detrano RC, O’Leary DH, Bild DE, Bluemke DA, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med 2008;168:1333-9. 32. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2007; 115:459-67. 33. Wyman RA, Mays ME, McBride PE, Stein JH. Ultrasound-detected carotid plaque as a predictor of cardiovascular events. Vasc Med 2006;11:123-30. 34. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293-304. 35. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14-22. 36. Gardin JM, Bartz TM, Polak JF, O’Leary DH, Wong ND. What do carotid intima-media thickness and plaque add to the prediction of stroke and cardiovascular disease risk in older adults? The cardiovascular health study. J Am Soc Echocardiogr 2014;27:998-10052. 37. Chambless LE, Folsom AR, Clegg LX, Sharrett AR, Shahar E, Nieto FJ, et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2000;151: 478-87. 38. Bauer M, Delaney JA, Mohlenkamp S, Heinz Jockel K, Kronmal RA, Lehmann N, et al. Comparison of factors associated with carotid intimamedia thickness in the Multi-ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR). J Am Soc Echocardiogr 2013;26:667-73. 39. Lakoski SG, Greenland P, Wong ND, Schreiner PJ, Herrington DM, Kronmal RA, et al. Coronary artery calcium scores and risk for cardiovascular events in women classified as ‘‘low risk’’ based on Framingham risk score: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med 2007;167:2437-42.
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40. Yeboah J, McClelland RL, Polonsky TS, Burke GL, Sibley CT, O’Leary DH, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012;308:788-95. 41. Sarwar A, Shaw LJ, Shapiro MD, Blankstein R, Hoffman U, Cury RC, et al. Diagnostic and prognostic value of absence of coronary artery calcification. JACC Cardiovasc Imaging 2009;2:675-88. 42. Budoff MJ, Mohlenkamp S, McClelland R, Delaney JA, Bauer M, Jockel HK, et al. A comparison of outcomes with coronary artery calcium scanning in unselected populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and Heinz Nixdorf RECALL study (HNR). J Cardiovasc Comput Tomogr 2013;7:182-91. 43. Den Ruijter HM, Peters SA, Anderson TJ, Britton AR, Dekker JM, Eijkemans MJ, et al. Common carotid intima-media thickness measure-
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ments in cardiovascular risk prediction: a meta-analysis. JAMA 2012; 308:796-803. 44. Polak JF, Post WS, Carr JJ, Szklo M, O’Leary DH. Associations of common carotid intima-media thickness with coronary heart disease risk factors and events vary with distance from the carotid bulb. J Am Soc Echocardiogr 2014;27:991-7. 45. Aldridge ME, Do K, Oo T, Naqvi TZ. Carotid intima-media thickness and plaque assessment by trained medical residents: validation and preliminary testing of a training protocol. J Am Soc Echocardiogr 2013;26:1457-64. 46. Gepner AD, Young R, Delaney JA, Tettersall MC, Blaha MJ, Post WS, et al. Comparison of coronary artery calcium presence, carotid plaque presence, and carotid intima-media thickness for cardiovascular disease prediction in the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Imaging 2015;8:e002262.
Risk Stratification for Cardiovascular Disease in Women in the Primary Care Setting Ranjini R. Roy, MD, R. Todd Hurst, MD, Steven J. Lester, MD, Christopher Kendall, BS, RDCS, Christy Baxter, BS, RDCS, Qing Wu, ScD, Jill Borovansky, MD, Julia Files, MD, Prasad Panse, MD, and Susan Wilansky, MD, Phoenix and Scottsdale, Arizona
Background: Traditional risk assessment tools classify the majority of middle-aged women at low risk despite cardiovascular (CV) disease’s affecting >50% of women and remaining the leading cause of death. Ultrasound-determined carotid intima-media thickness (CIMT) and/or computed tomographic coronary artery calcium score (CACS) quantify subclinical atherosclerosis and add incremental prognostic value. The aim of this study was to assess the utility of CIMT and CACS to detect subclinical atherosclerosis in younger women. Methods: Asymptomatic women aged 50 to 65 years with at least one CV risk factor and low Framingham risk scores were identified prospectively at primary care and cardiology clinics. Mean intimal thickness, plaque on CIMT, and Agatston calcium score for CACS were obtained. Results: Of 86 women (mean age, 58 6 4.6 years; mean Framingham risk score, 1.9 6 1.2; mean low-density lipoprotein cholesterol level, 138.9 6 37.0 mg/dL), 53 (62%) had high-risk CIMT (51% plaque, 11% CIMT > 75th percentile). In contrast, three women (3.5%) had CACS > 100, all of whom had plaque by CIMT. Of the 58 women with CACS of 0, 32 (55%) had high-risk CIMT (48% plaque, 7% CIMT > 75th percentile). Conclusions: In patients referred by their physicians for assessment of CV risk, CIMT in asymptomatic middleaged women with at least one CV risk factor and low risk by the Framingham risk score identified a large number with advanced subclinical atherosclerosis despite low CACS. Our results suggest that CIMT may be a more sensitive method for CV risk assessment than CACS or traditional risk tools in this population. Further studies are needed to determine if earlier detection would be of clinical benefit. (J Am Soc Echocardiogr 2015;28:1232-9.) Keywords: Carotid ultrasound, Calcium score, Women, Risk
Fifty-six percent of adult women in the United States will develop clinical cardiovascular disease (CVD) in their lifetimes,1 and CVD remains the number one cause of mortality in women, resulting in one death per minute in the United States.2-4 Importantly, in up to 45% of women, their first presentation of CVD may be sudden death, which occurs without antecedent symptoms, further emphasizing the importance of primary prevention of CVD.4-7 Although effective means for preventing CVD are available, current methods for identifying those at risk before events occur are From the Division of Cardiovascular Diseases, Department of Internal Medicine, University of Arizona College of Medicine, Maricopa Medical Center, Phoenix, Arizona (R.R.R.); and the Division of Cardiovascular Diseases (R.T.H., S.J.L., C.K., C.B., S.W.), College of Medicine, Biostatistics, Division of Health Sciences Research (Q.W.), Department of Internal Medicine (J.B., J.F.); and Department of Radiology (P.P.), Mayo Clinic College of Medicine, Scottsdale, Arizona. This research was funded by a Mayo Clinic CR5 grant. Reprint requests: Susan Wilansky, MD, Mayo Clinic College of Medicine, Department of Internal Medicine, Division of Cardiovascular Diseases, 13400 East Shea Boulevard, Scottsdale, AZ 85259 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.06.015
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limited.8,9 Population-based risk algorithms such as the Framingham risk score (FRS), Reynolds risk score (RRS), and pooled cohort equation are used to assess cardiovascular risk, yet 75% of myocardial infarction and CVD deaths occur in the low- and intermediate-risk populations.7-13 Both computed tomographic coronary artery calcium score (CACS) and carotid intima-media thickness (CIMT) and plaque detection on ultrasound measure subclinical atherosclerosis and have been shown to independently add incremental predictive value to traditional risk factors, although the correlation between the two is weak.10-12 In this study, we evaluated the prevalence of advanced subclinical atherosclerosis as assessed by CACS and carotid ultrasound in middle-aged women with at least one cardiovascular risk factor but low FRS. METHODS This protocol was approved by the Mayo Clinic Institutional Review Board. Asymptomatic women between 50 and 65 years of age with at least one cardiovascular risk factor (hyperlipidemia, hypertension, family history of premature coronary disease, current tobacco use, or elevated high-sensitivity C-reactive protein) and classified at low risk by the FRS were included in the study. Women were identified by their
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primary care physicians or cardiologists at the Mayo Clinic Arizona ASCVD = Atherosclerotic from December 1, 2010, to cardiovascular disease January 31, 2013. The initial history, physical examination, and CACS = Coronary artery laboratory testing was performed calcium score by the referring physician and CAD = Coronary artery was accessible via the electronic disease medical record. Informed consent CI = Confidence interval was obtained by the Protocol Development Office. FRS were CIMT = Carotid intima-media calculated for all participants, thickness and only those at low risk CVD = Cardiovascular (<10% risk for a cardiovascular disease event over 10 years) were included. The RRS was also calcuFRS = Framingham risk score lated when data were available, HR = Hazard ratio and the race- and sex-specific pooled cohort equation to calcuRRS = Reynolds risk score late the 10-year atherosclerotic CVD (ASCVD) risk estimate13 was calculated for all patients. Hyperlipidemia was defined as a low-density lipoprotein cholesterol level $ 100 mg/dL; hypertension as systolic blood pressure $ 140 mm Hg, diastolic blood pressure $ 90 mm Hg, or use of antihypertensive therapy; and family history of premature coronary disease as a first-degree male relative <55 years of age or a female first-degree relative <65 years of age with a cardiac event. Subjects were excluded if they were on lipid-lowering therapy, had histories of coronary artery disease (CAD) or CAD equivalent such as peripheral vascular disease, cerebrovascular disease, or diabetes mellitus. Patients were assessed for waist circumference, body mass index, current tobacco use, family history, and hypertension. Laboratory studies including a fasting lipid profile, plasma glucose, and highsensitivity C-reactive protein were performed and CIMT assessment was performed in all subjects. Low-risk CIMT was classified as <50th percentile, intermediate-risk CIMT as 50th to 75th percentile, and high-risk CIMT as >75th percentile or the presence of plaque. Computed tomography for CACS was also performed, and an Agatston score was assigned on the basis of age- and sex-matched control subjects.14 CIMT was defined as the distance between the lumen-intima interface and the media-adventitia interface. All patients were scanned by one of two experienced cardiac sonographers (C.K. and C.B.) using a multifrequency linear-array transducer in fundamental frequency > 7 MHz on a high-resolution B-mode ultrasound system (Siemens Acuson Sequoia C512; Acuson Inc, Mountain View, CA). All studies followed the CIMT protocol approved by the Mayo Clinic Arizona echocardiography laboratory and included screening for carotid artery plaque and common CIMTanalysis. For the carotid artery plaque screen, the transverse and longitudinal axes of the right and left common carotid arteries, the carotid bulb, and the proximal internal and external carotid arteries were imaged. Measurements for CIMTwere obtained at the distal 1-cm far wall of the common carotid artery at end-diastole (within one or two frames of the onset of the electrocardiographic Q wave) averaged over three cardiac cycles from two separate angles of insonation (Figure 1A). All CIMT images were transferred and stored digitally on a server for analysis using Arterial Health Package (Siemens Syngo Ultrasound Workplace; Siemens Medical Inc, Malvern, PA). Plaque was defined as a focal intima-media thickening of the arterial wall that was $1.5 mm thick and/or >50% thicker than the surrounding arterial wall (Figure 1B). If plaque was identified, the locaAbbreviations
tion was noted, and a three-beat clip that best demonstrated the plaque was obtained. Measurements were performed using semiautomated border detection software and obtained from two optimal angles of incidence (middle, anterior, and posterior). Three measurements at each angle were evaluated at end-diastole (within one or two frames of the Q wave on the electrocardiogram) for a total of 12 measurements, resulting in a composite mean CIMT measurement. There were two independent cardiologists experienced in reading CIMT studies, to minimize interobserver variability. Electron-beam computed tomography with 3-mm slice thickness was used to assess for coronary artery calcification (Figure 2). If coronary artery calcium was detected, using the Agatston method, an automated score was generated.15 CACS were based on ageand sex-matched control patients.14 A CACS of 0 was suggestive of no disease, 1 to 99 of mild disease, 100 to 399 of moderate disease, and >400 of severe disease. Carotid ultrasound was compared with CACS in the detection of subclinical atherosclerosis. Patients were classified with low-risk CIMT (<50th percentile), intermediate-risk CIMT (50th to 75th percentile), or high-risk CIMT (>75th percentile or the presence of plaque) for CVD on the basis of age-, sex-, and race-matched percentile.16 A CACS Agatston score was assigned to age- and sex-matched patients. SAS version 9.2 (SAS Institute Inc, Cary, NC) was used for data analysis. Continuous variables are presented as mean 6 SD. Categorical variables are presented as counts and percentages. Sample size calculation was performed by our Department of Biostatistics. A sample of 70 patients was found to have 80% power if the percentage of patients at high risk by CIMT and by CACS differed by 25 points (i.e., 63% vs 38%). With additional patients, the power would be greater to detect a difference. RESULTS Baseline Data A total of 90 patients were assessed and four excluded. Exclusions included a screen failure due to lipid-lowering therapy (n = 1), one subject at intermediate risk by FRS, and two subjects who later refused computed tomography. Thus, 86 women were included in the study (mean age, 58 6 4.6 years) with an average FRS of 1.9 6 1.2, an average RRS of 2.2 6 2.1, and an average 10-year ASCVD risk estimate of 3.1 6 2.0. Eighty-two of 86 women (95%) had 10-year ASCVD risk < 7.5%. Ninety-five percent of women were Caucasian, three were Asian-Pacific Islanders, and one was African American. The average body mass index was 26.1 6 4.9 kg/m2, waist circumference 93.1 6 12.9 cm, systolic blood pressure 117.6 6 15.2 mm Hg, fasting glucose 92.7 6 13.3 mg/dL, and lowdensity lipoprotein cholesterol level 138.9 6 37.0 mg/dL (Table 1). Thirty-two patients (37.2%) had family histories of CAD, 11 (12.8%) were smokers, and 23 (26.7%) were on antihypertensive medications. The mean high-sensitivity C-reactive protein level was 2.9 mg/L. CIMT Findings Of the participating women, 44 (51.2%) had evidence of plaque on CIMT, with an additional nine subjects (10.5%) demonstrating high risk CIMT > 75th percentile for age-, gender-, and race-matched control subjects. Figure 3 illustrates the CIMT percentile breakdown among those with plaque. Of the four women who had 10-year ASCVD risk estimates $ 7.5%, three had plaque on CIMT, and the fourth had high-risk CIMT falling into the >75th percentile. Thus, 53 of participants (61.6%) were found to have either plaque on
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Figure 1 CIMT. (A) Middle left common carotid artery at end-diastole demonstrating normal thickness. (B) Presence of plaque in the right common carotid artery (yellow arrow).
Figure 2 Electron-beam computed tomography with 3-mm slice thickness demonstrating no coronary artery calcification. (A) Axial image at the level of left main (yellow arrow) and left anterior descending (blue arrow) arteries. (B) Axial image from the same patient at the level of proximal right coronary (yellow arrow) and left circumflex (blue arrow) arteries. CIMT or a high-risk CIMT scan. Eight patients (9.3%) were categorized as <25th percentile for age- and gender-matched control subjects, 32 (37.2%) were in the 25th to 49th percentile, 27 (31.4%) were in the 50th to 75th percentile, and 19 (22.1%) were >75th percentile by CIMT (Figure 4A). The composite mean thickness on CIMT was 0.6 6 0.12 mm. Of those with plaque, the mean plaque thickness was 1.9 6 0.46 mm. CACS Findings Regarding the Agatston score for coronary artery calcium, 58 subjects (67.4%) were found to have CACS of 0, and 25 (29.0%) had CACS of 1 to 99 (Figure 4A). Interestingly, of the four women who had 10year ASCVD risk estimates $ 7.5%, three had CACS of 0 and the fourth had a CACS of 1. Only three patients (3.6%) had CACS of 100 to 399, and there were no patients with CACS > 400. The percentile breakdown for CT calcium scoring is illustrated in Figure 4 but reveals a similar trend, with a majority of patients demonstrating low-risk CACS scans. The breakdown by CIMT percentile in patients with >75th percentile CACS is illustrated in Table 2.
CIMT Compared with CACS Overall, more patients were found to have low-risk scans by CACS than by CIMT, with 58 subjects (67.4%) identified with CACS of 0 compared with eight subjects (9.3%) falling into the <25th percentile range of CIMT (Figure 4). Of the 58 subjects with CACS of 0, 28 (48.2%) were found to have plaque by CIMT, and an additional four were >75th percentile by CIMT. Thirty-two patients (55%) with CACS of 0 had CIMT in the 50th percentile or greater. Only five patients (5.6%) with CACS of 0 had CIMT in the <25th percentile range (Table 3). Conversely, 14 participants (16.5%) were found to have CACS in the >75th percentile, of whom nine (64%) were known to have plaque by CIMT. Three of the remaining five subjects without plaque on CIMT but still >75th percentile by CACS were deemed to be >75th percentile by CIMT. Thus, there were only two patients identified as being >75th percentile by CACS but with low-risk findings on CIMT. Of those with plaque or high-risk CIMT > 75th percentile (n = 53), 32 (60.3%) were found to have CACS of 0, 18 (34.0%) were found to have CACS of 1 to 99, and three (5.7%) were found to have CACS of 100 to 399. There were
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Table 1 Baseline characteristics (n = 86) Variable
Age (y) Caucasian Waist circumference (cm) Systolic blood pressure (mm Hg)
Value
57.5 6 4.2 95% 93.1 6 12.9 117.6 6 15.2
Diastolic blood pressure(mm Hg)
69.7 6 10.6
On antihypertensive medication
23 (26.7%)
On aspirin
14 (16.3%)
Current cigarette smoker
11 (12.8%)
Family history of premature CAD
32 (37.2%)
Mean FRS
1.9 6 1.2
Mean RRS
2.2 6 2.1
Mean ASCVD 10-y risk estimate
3.1 6 2.0
Laboratory results Total cholesterol (mg/dL)
232.1 6 40.0
Triglycerides (mg/dL)
117.9 6 53.5
HDL cholesterol (mg/dL)
68.5 6 22.7
LDL cholesterol (mg/dL)
138.9 6 37.0
Glucose (mg/dL) hs-CRP (mg/L)
92.7 6 13.3 2.9 6 4.0
HDL, High-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein. Data are expressed as mean 6 SD or as number (percentage).
no patients with either high-risk CIMT (>75th percentile) or plaque by CIMT who had CACS > 400 (Table 4). All 3 patients with CACS > 100 had plaque by CIMT. There were 25 patients who had CACS of 1 to 99, of whom 13 had plaque by CIMT. Of the remaining 12 patients with CACS of 1 to 99 suggestive of mild disease, five (42%) had high-risk CIMT (>75th percentile). There were seven patients with CACS of 1 to 99 and CIMT < 50th percentile. Follow-Up Data Six month follow-up was available on 84 of the 86 subjects included in this study. Two subjects were unable to be reached by telephone. Lipid-lowering therapy was recommended by physicians for 51 participants (61%) on the basis of the results of the CIMT and/or CACS scans. Physicians recommended the initiation of statin therapy in 48 patients, ezetimibe in one patient, fenofibrate in one patient, and niacin in one patient. The use of aspirin also increased from 16.3% at baseline to 24.1% at 6-month follow-up. Of the 51 patients who were started on lipid-lowering therapy, 18 had high-risk CIMT (>75th percentile), 13 had CIMT in the 50th to 75th percentiles, 16 had CIMT in the 25th to 49th percentiles, and four had CIMT < 25th percentile (Table 5). Of the four patients with CIMT in the <25th percentile, two patients had plaque by CIMT. The other two patients with CIMT < 25th percentile and no plaque by CIMT had CACS > 0 (4 and 64) with elevated CACS percentiles (64th and 84th percentiles) and so were advised to receive lipid-lowering therapy. Of the 16 patients with CIMT in the 25th to 49th percentiles, 14 patients had plaque by CIMT. The other two patients who did not have plaque by CIMT had also had CACS > 0 (9 and 28) and were in elevated percentiles by CACS (58th and 84th percentiles) and were thus recommended
Figure 3 CIMT percentile breakdown among those with plaque. lipid-lowering therapy. All patients in the 50th to 75th percentiles had plaque by CIMT, and 10 of 18 patients with high-risk CIMT > 75th percentile had plaque. Further breakdown by CACS score is illustrated in Table 5.
DISCUSSION The principal finding in our study was that >60% of asymptomatic women classified at low risk by the FRS and/or RRS had advanced atherosclerosis as determined by ultrasound of the carotid artery. One third of women had detectable calcium on CACS, while only three had calcium scores > 100. Interestingly, all of the women with 10-year ASCVD risk estimates of $7.5% were identified by CIMT as either having plaque or high-risk CIMT (>75th percentile), but three of the four women had CACS of 0 and the fourth woman had a CACS of 1. The 10-year ASCVD risk estimate of $7.5% is the cut point at which it has been recommended to consider moderate- to high-intensity statin therapy.13 Current guidelines suggest using CACS as an adjunctive tool for determining the need for statin therapy in patients in whom the decision for lipid-lowering therapy is less clear. However, in our specific population, CIMT appeared to identify those at a higher cardiovascular risk as ascertained by the ASCVD risk estimate tool, whereas CACS did not. Prevention of CVD in women is paramount given the high lifetime risk for CVD in women, which approaches 56%.1 The use of carotid ultrasound for risk assessment in patients at intermediate risk for CVD has been well established, but its use in the low-risk population is uncertain.17,18 Women in particular are often classified at low risk on the basis of traditional measures of risk assessment such as the FRS and RRS, with 92% of women aged 60 to 69 years being in the lowrisk FRS range.19 Yet these risk assessment tools may be inadequate to accurately assess cardiovascular risk.10,12,20-23 Michos et al.21 studied 2,447 asymptomatic, nondiabetic women and found that of the 20% who had high-risk CACS, 84% were classified at low risk by the FRS, and none were classified at high risk. In another study of women with family histories of premature CAD, 98% were at low risk by the FRS, yet 40% had detectable coronary artery calcium and 17% had CACS >90th percentile.20 The finding in our study of detecting subclinical atherosclerosis in asymptomatic women otherwise classified at low risk by the FRS is in keeping with a study by Postley et al.,24 who screened 715 asymptomatic adults with ultrasound of the carotid and femoral arteries to
1236 Roy et al
Journal of the American Society of Echocardiography October 2015
Figure 4 Age- and gender-matched percentile breakdown of CIMT and CACS (A) and Agatston calcium score distribution in women (B). Table 2 Breakdown of CIMT percentile in patients with >75th percentile CACS (n = 15)
Table 4 Agatston calcium score in women with plaque or high-risk CIMT scan (n = 53)
CIMT percentile
CACS Agatston score
Number of patients (%)
Number of patients (%)
<25th
1 (12.5)
0
32 (60.4)
25th to 49th
6 (18.8)
1–99
18 (34.0)
50th to 75th
2 (7.4)
100–399
>75th
6 (31.2)
>400
3 (5.7) 0
Table 3 CIMT percentile in women with calcium scores of 0 (n = 58)
Table 5 Breakdown of CIMT and CACS in patients started on lipid-lowering therapy (n = 51)
CIMT percentile
CACS Agatston score
<25th
Number of patients (%)
Number of patients (%)
CIMT percentile
Number of patients
5 (5.6) 21 (36.2)
0
28
<25th
50th to 75th
22 (38.0)
1–99
20
25th to 49th
>75th
10 (17.2)
100–399
3
50th to 75th
13
>400
0
>75th
18
25th to 49th
detect subclinical atherosclerosis. They found that among cohorts aged 50 to 65 years, 56% of the women had plaque in their femoral arteries. Among low-risk women aged 50 to 64 years, 30.4% had femoral or carotid plaque, and among those at intermediate risk, 56.3% had plaque. Our results demonstrated that 51.2% of women classified at low risk by the FRS had carotid plaque, which is higher than reported by Postley et al. However, smoking is a known risk factor for progression of atherosclerosis, and it is worthwhile to note that in their study, only 3.9% of women were current smokers, compared with 12.8% in our present study, which may have played a role in the higher plaque burden seen in our study. High-risk CIMT or plaque was correlated with an increase in cardiovascular events in several large studies, with hazard ratios (HRs) ranging from 1.81 (95% confidence interval [CI], 1.14–2.87) to 4.15 (95% CI, 1.50–11.47).17,25-31 With every 0.1-mm increase in CIMT, the risk for myocardial infarction increases by 10% to 15% and the risk for stroke increases by 13% to 18%.32 Plaque also correlates with an increase in cardiovascular events and may more accurately assesses risk prediction in women compared with men.22 A systematic review including nine studies and >38,000 patients with carotid plaque determined that in eight of the nine studies, the finding of plaque on carotid ultrasound was predictive of cardiovascular death and/or myocardial infarction.33 Most women’s first cardiovas-
4 16
cular events are stroke, from which the mortality is higher compared with men.34 In the Atherosclerosis Risk in Communities study, 7,289 women underwent CIMT, and the HR for myocardial infarction or coronary heart disease death for high versus low tertiles was 6.69.16 The Cardiovascular Health Study analyzed 5,858 individuals without clinically apparent coronary heart disease and found that the highest quintile of CIMT had a 3.87 relative risk (adjusted for age and sex) of myocardial infarction or stroke compared with those in the lowest quintile.35 More recently, the Cardiovascular Health Study investigators found that CIMT improved risk prediction for stroke and CVD in the older population, predominantly by down-classifying risk in those who did not have events, and they also found that the presence of any plaque improved risk prediction and reclassification.36 In the Atherosclerosis Risk in Communities Stroke study of 7,865 women with no prior clinical cerebrovascular disease, the HR for those with CIMT > 1.0 mm compared with those with CIMT < 0.6 mm was 8.5.37 Bauer et al.38 compared two large population-based studies with subclinical CVD, the Multi-Ethnic Study of Atherosclerosis cohort and the Heinz Nixdorf Recall Study group, and analyzed the association between traditional cardiovascular risk factors and CIMT. They found that there was high consistency between the traditional risk factors, particularly age, male sex, and systolic blood
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Journal of the American Society of Echocardiography Volume 28 Number 10
pressure, and increased CIMT measurements, thus reaffirming that CIMT may serve as a marker for cardiovascular risk. Thus, early identification of women with subclinical atherosclerosis may allow the early identification of an at-risk population and possibly earlier implementation of preventive strategies. CACS may also help restratify patients for cardiovascular risk assessment.11,13,39 A subgroup analysis of the Multi-Ethnic Study of Atherosclerosis showed that 90% of women aged 45 to 79 years (excluding those with diabetes) were classified at low risk by FRS.39 However, 32% of these women had CACS > 0, and those with scores > 0 were found to be at increased risk for cardiovascular events, with a HR of 5.2 (95% CI, 2.5–10.8). It has been suggested that CACS may be preferred as a method of reclassifying risk in the intermediate-risk population,40 though it is unclear if this would apply to our study population, which was younger, low-risk women. Current guidelines support the use of CACS as a means for further risk-stratifying individuals at intermediate risk.13,18 A CACS of 0 has been associated with a low risk for cardiovascular events,41,42 but in our study, 48.2% of women with CACS of 0 were found to have plaque by CIMT. Although our study did not analyze hard outcomes, the presence of plaque on CIMT has been correlated with an increase in cardiovascular events. Therefore, in our specific patient population of younger women, CIMT may be a useful adjunctive tool for further risk stratification. The three patients found to have CACS of 100 to 399 were all identified as having plaque by CIMT, supporting the presence of subclinical atherosclerosis and probable elevated cardiovascular risk. Note that this study was conducted before the availability of the 10-year ASCVD risk estimator, which has greatly influenced clinician practice with regard to the use of statin therapy. However, it may be worth noting that in our study, the use of CIMT and/or CACS altered physician management to patient care, with patients being started on lipid-lowering therapy 61% of the time on the basis of the results of these scans. In addition, the most recent guidelines recommend against the routine use of CIMT for risk assessment for a first ASCVD event.13 This recommendation was based largely on the variability of CIMT measurements and difficulty with standardization of these measurements, along with the results of a recent large meta-analysis suggesting that the addition of CIMT did not substantially add to the reclassification of risk class.43 Polak et al.44 conducted a study of 279 patients using CIMT measurements near and below the carotid bulb and found that measurements obtained below the bulb, although smaller, correlated better with risk factors and events compared with measurements obtained near the carotid bulb. These data suggest that even small differences in CIMT measurements may have variable associations with events and thus should be taken into account when analyzing the available literature on CIMT. It is notable that in our study, measurements were obtained at the distal 1-cm far wall of the common carotid artery and not near the bulb, which was found to correlate better with risk factors and events. In addition, Aldridge et al.45 performed a study in which medical residents were rapidly trained in an abbreviated CIMT measurement protocol from the American Society of Echocardiography and found that after training, interobserver variability was low, with 88% agreement with the expert, suggesting that standardization and reproducibility of CIMT of measurements may be feasible. Thus, in a specific population such as ours, CIMT in younger women may be helpful as an adjunctive tool for risk assessment. It is worthwhile to note that the most recent American College of Cardiology and American Heart Association guidelines make a class III recommendation for using common CIMT alone for risk stratification.13 We agree with this recommendation. A complete carotid ultra-
sound study for risk stratification includes a comprehensive plaque assessment, and if no plaque is found, common CIMT should be assessed. It would be most helpful if future guidelines clearly distinguished between a comprehensive carotid ultrasound examination for risk stratification and performing only a common CIMT study without plaque screening. The results of our study suggest that in middle-aged women with at least one cardiovascular risk factor who are otherwise deemed to be at low risk by the FRS or RRS, imaging for risk prediction may add incremental value in identifying subclinical atherosclerosis and reclassifying low-risk women into a higher risk category. On the basis of the findings of our study and the fact that ultrasound does not result in radiation exposure, CIMT may be preferable and a more sensitive detector of subclinical atherosclerotic vascular disease in younger women. However, further studies are needed to determine if earlier detection of subclinical atherosclerosis is beneficial with regard to long-term outcomes. Limitations Our study did not address whether the identification of women with high-risk CACS or CIMT scans led to an increase in cardiovascular events. Previous studies have shown that although both CIMT and CACS are predictive of future CVD events, CACS may be a better predictor for total CVD and CIMT for stroke.31,46 However, prior studies have demonstrated that subclinical atherosclerosis is correlated with an increase in cardiovascular events. Many of the women deemed to have high-risk scans or plaque were initiated on lifestyle modifications and/or pharmacologic therapy, so long-term follow-up for adverse cardiovascular events comparing those who were initiated on therapy with those who were not may be beneficial for future studies. In addition, socioeconomic diversity may be limited because of the nature of the referral practices. In our study, there was no independent arbiter to assess vascular disease to fully investigate the question of whether CIMT was truly a more accurate method of detecting atherosclerosis compared with CACS. It may be that CIMT detected false-positive results or perhaps that CACS detected false-negative results, and without the independent arbiter, we are limited in fully assessing this. Although our sample size was small, our study was sufficient to detect $80% power on the basis of our statistical calculations. CONCLUSIONS Carotid ultrasound in asymptomatic younger women with at least one cardiovascular risk factor but otherwise classified at low risk by the FRS identified a large number with plaque, many of whom did not have high CACS, suggesting that CIMT may be a more sensitive method for detecting subclinical atherosclerosis in this population. REFERENCES 1. Wilkins JT, Ning H, Berry J, Zhao L, Dyer AR, Lloyd-Jones DM. Lifetime risk and years lived free of total cardiovascular disease. JAMA 2012;308: 1795-801. 2. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013;127:e6-245. 3. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, DeSimone G, et al. Heart disease and stroke statistics—2010 update. A report from the American Heart Association. Circulation 2009.
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40. Yeboah J, McClelland RL, Polonsky TS, Burke GL, Sibley CT, O’Leary DH, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012;308:788-95. 41. Sarwar A, Shaw LJ, Shapiro MD, Blankstein R, Hoffman U, Cury RC, et al. Diagnostic and prognostic value of absence of coronary artery calcification. JACC Cardiovasc Imaging 2009;2:675-88. 42. Budoff MJ, Mohlenkamp S, McClelland R, Delaney JA, Bauer M, Jockel HK, et al. A comparison of outcomes with coronary artery calcium scanning in unselected populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and Heinz Nixdorf RECALL study (HNR). J Cardiovasc Comput Tomogr 2013;7:182-91. 43. Den Ruijter HM, Peters SA, Anderson TJ, Britton AR, Dekker JM, Eijkemans MJ, et al. Common carotid intima-media thickness measure-
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