European Heart Journal

European Heart Journal Advance Access originally published online on October 29, 2007
European Heart Journal 2007 28(24):2967-2971; doi:10.1093/eurheartj/ehm487

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Comparative performance of subclinical atherosclerosis tests in predicting coronary heart disease in asymptomatic individuals

Alain Simon^*, Gilles Chironi and Jaime Levenson

AP-HP, Hôpital Européen Georges Pompidou, Centre de Médecine Préventive Cardiovasculaire, 75015 Paris, France
Faculté de Médecine Paris Descartes, 75270 Paris, France

Received 18 April 2007; revised 13 September 2007; accepted 26 September 2007; online publish-ahead-of-print 29 October 2007.

^* Corresponding author. Tel: +33 1 43 95 93 91; fax: +33 1 45 39 11 93. E-mail address: alain.simon{at}brs.ap-hop-paris.fr

	Abstract

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The prognostic performance of subclinical atherosclerosis in predicting coronary heart disease (CHD) needs to be clarified because of the existence of many non-invasive tests available for its detection in the clinical setting: ultrasound measurement of carotid intima–media thickness (IMT) and plaque, cardiac computed tomography assessment of coronary artery calcium, Doppler stethoscope measurement of ankle–arm index pressure (AAI), and mechanographic or Doppler determination of aortic pulse wave velocity (PWV). Data analysis of the main prospective studies in asymptomatic populations allows the establishment of a dose–response relationship between subclinical atherosclerosis burden and cumulative incidence of future CHD event (absolute risk). Negative subclinical atherosclerosis testing conveys a low 10-year CHD risk inferior to 10% whatever the test considered, i.e. IMT less than the 1st tertile or 1st quintile, AAI 0.90, PWV less than the first tertile, no discernible carotid plaque, or zero coronary calcium score. Positive testing for IMT (>95th percentile or 5th quintile), AAI (<0.90), or PWV (>3rd tertile) conveys a moderately high 10-year CHD risk between 10 and 20%. Positive testing for carotid plaque (focal protrusion >1.5 mm or mineralization) or coronary calcium (total score >300 or 400 units) conveys a high 10-year CHD risk superior to 20%. Therefore, positive subclinical atherosclerosis measurement seems to have its place in the context of existing prediction models, namely for intermediate risk classification. It also remains to be established whether individuals with negative subclinical atherosclerosis may be considered at low CHD risk and receive conservative management.

Key Words: Primary prevention • Intima–media thickness • Plaque • Atherosclerosis • Arterial stiffness • Coronary calcium • Cardiovascular risk

	Introduction

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Better identification of asymptomatic individuals at high risk of future coronary heart disease (CHD) and who should therefore receive aggressive risk reduction therapy is an important challenge for primary prevention of cardiovascular disease.¹ Despite their aetiological importance in atherosclerosis, cardiovascular risk factors have a poor performance in predicting asymptomatic subjects who will or will not develop CHD.² A large overlap exists in the distributions of both the major risk factors, serum cholesterol and blood pressure, in men who died of CHD and in those who did not.² Moreover, more than half of subjects with CHD have no major risk factor, or only one.³ Conversely, the well-established high prognostic performance of clinically overt arterial disease^4,5 has supported the idea of extrapolating the prognostic performance of clinical arterial disease to subclinical disease.¹ The observation that arterial disease does not begin with the first clinical event but develops long before without symptoms has motivated much biotechnological medical research for the detection of subclinical disease^6–8. The more commonly used subclinical vascular markers in the clinical setting are carotid intima–media thickness (IMT) and plaque measured by ultrasound, coronary artery calcium detected by cardiac computed tomography (CT), ankle–arm index pressure (AAI) measured by distal pressure Doppler measurement, and aortic pulse wave velocity (PWV) measured from carotid and femoral pressure wave recordings with a Doppler or mechanographic device.¹ For individuals at intermediate risk, e.g. 10–20% 10-year Framingham risk of fatal and non-fatal CHD⁴ or 3–5% European SCORE⁹ risk of fatal cardiovascular disease, clinicians may consider testing for subclinical atherosclerosis and, in those with a positive test, aggressive risk reduction intervention may be appropriate.^8–11 Nevertheless, the implementation of subclinical atherosclerosis testing in the risk management of patients is dependent on a better knowledge of the comparative prognostic performance of various tests of atherosclerosis currently available.

In this report, the prognostic performance of subclinical atherosclerosis testing is discussed on the basis of crude CHD incidence (absolute risk) associated with positive and negative subclinical atherosclerosis testing.¹²

	Methods

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Studies and subjects
Using MEDLINE and review articles, we identified published studies in which subclinical atherosclerosis was detected with the most important non-invasive tests currently being used, and in which patients were followed prospectively to determine the occurrence of CHD events (Table 1): Atherosclerosis Risk in Communities (ARIC),¹³ Cardiovascular Health Study (CHS),¹⁴ Kuopio Ischemic Heart Disease (KIHD),¹⁵ South Bay Heart Watch study (SBHW),¹⁶ St Francis Heart study (SFHS),¹⁷ and the Rotterdam Study (ROT).¹⁸ These studies fulfilled the main quality criteria defined by the group Meta-analysis Of Observational Studies in Epidemiology¹⁹ (MOOSE) and listed in the statement for Strengthening the Reporting of Observational studies in Epidemiology²⁰ (STROBE): (i) background, objective, and key elements of study design were clearly defined; (ii) eligibility criteria, participant selection methods without bias, and baseline characteristics of participants were properly described; (iii) precise definition and report of the number of CHD outcomes were provided. Lastly, study participants were free of symptoms and history of clinical cardiovascular disease at inclusion. Age and gender characteristics of the subjects in the included studies are shown in Table 2.

View this table: [in this window] [in a new window]   Table 1 Characteristics of prospective studies in asymptomatic subjects undergoing subclinical atherosclerosis testing at the onset of follow-up

 

View this table: [in this window] [in a new window]   Table 2 Ten-year CHD risk by absence or presence of subclinical atherosclerosis in asymptomatic people

 
Data analysis
Published aggregate data of the studies considered for this review allowed calculation of CHD incidence according to the presence or absence of subclinical atherosclerosis at baseline.^13–18 The CHD incidence rate was calculated as the number of events divided by study persons-time. The cumulative 10-year CHD risk was determined by using an exponential survival model²¹ and assuming the CHD rate to be constant, by means of the formula: 10-year CHD risk = 1 – EXP(–10), being the annual CHD rate deducted from each study. Data are descriptive without specific statistical analysis, with the exception of the relationship between subclinical atherosclerosis determination and CHD risk that was obtained by curve model analysis after having coded the results of subclinical atherosclerosis testing (Figure 1).

View larger version (15K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Dose–response curve between negative and positive subclinical atherosclerosis testing and 10-year CHD risk. Only studies that used the same or similar end-points were included. CAC, coronary artery calcium; IMT, intima–media thickness; PWV, pulse wave velocity.

 

	Results

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Coronary risk of positive subclinical atherosclerosis testing
Carotid IMT and plaque (Table 2)
In middle-aged subjects of the ARIC study,¹³ ultrasound evidence of markedly increased carotid overall mean IMT (average of IMT measures in common carotid, bifurcation, and internal carotid on both sides above the 95th percentile) was associated with 14 and 11% 10-year CHD risk in men and women, respectively. In older subjects of both sexes of the CHS study,¹⁴ a marked increase in the maximal common carotid IMT in the 5th quintile was associated with 15% 10-year CHD risk. In middle-aged men of the KIHD study,¹⁵ ultrasound detection of focal intrusive plaque or mineralization in extracranial carotid arteries was associated with a 10-year risk of myocardial infarction of 25%, which represents a very high risk possibly due to the high CHD prevalence in the male Finnish population.¹⁵ These findings show that the performance of carotid ultrasound testing for predicting subsequent CHD depends on the type of the lesion detected and how far advanced it is.¹⁵ Moreover, it has been suggested that the combination of carotid IMT measurement and plaque detection may add prognostic information with regard to the occurrence of subsequent CHD as compared with categorization according to a single measure of IMT or plaque.²²

AAI and PWV (Table 2)
In elderly subjects of the CHS study, ²³ decreased AAI below 0.9 (that is evidence of asymptomatic peripheral arterial disease) was associated with a 15% 10-year CHD risk. In elderly subjects of the Rotterdam study,¹⁸ a marked increase in aortic PWV in the 3rd tertile adjusted for age and gender (that reflects systemic large arteries stiffening) was associated with a 13% 10-year CHD risk.

Coronary calcium score (Table 2)
In the middle-aged predominantly male population of the SBHW study,¹⁶ cardiac CT detection of massive coronary calcium deposit, evidenced by a total coronary calcium score >300 units, was associated with a 20% 10-year CHD risk. In older men and women of the SFHS study,¹⁷ a coronary calcium score >400 units was associated with a 28% 10-year CHD risk.

Coronary risk of negative subclinical atherosclerosis testing
Carotid IMT and plaque (Table 2)
In middle-aged subjects of the ARIC study,¹³ the lowest values of carotid overall mean IMT (in the 1st tertile) were associated with a 10-year CHD risk of 3% in men and 1% in women. In older subjects of both sexes of the CHS study,¹⁴ the lowest values of maximal common carotid IMT (in the 1st quintile) were associated with a 4% 10-year CHD risk. In middle-aged men of the KIHD study,¹⁵ absence of any plaque and wall thickening in extracranial carotid arteries was associated with a 8% 10-year CHD risk.

AAI and PWV (Table 2)
In elderly subjects of the CHS study²³, normal AAI (0.90) was associated with an 8% 10-year CHD risk and, in elderly subjects of the Rotterdam study,¹⁸ the lowest values of PWV (in the 1st tertile) were associated with a 4% 10-year CHD risk.

Coronary calcium score (Table 2)
In the middle-aged predominantly male population of the SBHW study,¹⁶ the absence of coronary calcium deposit evidenced by a zero calcium score at cardiac CT was associated with a 6% 10-year CHD risk. In older men and women of the SFHS study,¹⁷ evidence of a zero calcium score was associated with a 1% 10-year CHD risk.

Dose–response curve between atherosclerosis and CHD risk
A dose–response curve relating the absence and presence of subclinical atherosclerosis with 10-year CHD risk was obtained by pooling the results of studies with a similar CHD end-point (e.g. combined myocardial infarction or CHD death, as well as combined myocardial infarction, CHD death, or revascularization) (Figure 1). Negative subclinical atherosclerosis testing, whatever the test used, was associated with a <10% ten-year CHD risk (Figure 1). Conversely, positive subclinical atherosclerosis testing was associated with a 10-year CHD risk of between 10 and 30% (Figure 1). Moreover, CHD risk depended on the type of test used, with a maximum risk of 30% associated with cardiac CT-assessed massive coronary calcium deposit (Figure 1). The graded relationship between absolute CHD risk and atherosclerosis burden provides evidence that subclinical arterial disease is a true risk marker of a future CHD event in asymptomatic individuals.²⁴

However, such prognostic information is limited in several ways: data are lacking in younger individuals who should benefit most from ultrasound assessment of carotid arteries for early detection of high CHD risk; also, data on carotid plaque and coronary calcium were obtained in exclusively or predominantly male populations and may not be extrapolated as such to women.

	Discussion

Top Abstract Introduction Methods Results Discussion Study limitations References

 
Positive testing for subclinical atherosclerosis is associated with a moderately high to high CHD risk, but the different types of subclinical atherosclerosis tests have a different prognostic performance (Figure 1). Positive testing for IMT, AAI, or PWV conveys a 10-year CHD risk between 10 and 20%, whereas positive testing for carotid plaque or coronary calcium conveys a 10-year CHD risk superior to 20%. In contrast, negative testing for subclinical atherosclerosis conveys a low CHD risk inferior to 10% whatever the test considered. These observations lead to consideration of the use of subclinical atherosclerosis testing as an option for advanced risk assessment,⁸ especially in subjects in an intermediate risk class according to classical risk factor scoring. Indeed, a certain proportion of these subjects may be misclassified by traditional risk prediction,²⁵ and subclinical atherosclerosis testing may help to re-classify some of them either into the low risk class (negative test) or into the high risk class (positive test). To this end, algorithms have been proposed that integrate scoring of risk factors and subclinical atherosclerosis testing.^26,27

However, the place of subclinical atherosclerosis testing in the context of models for CHD prediction is debated. Indeed, studies having assessed the incremental benefit of subclinical atherosclerosis testing in the prediction of CHD are still scarce and give inconsistent results. Ultrasound measurement of carotid IMT or plaque in population-based elderly subjects of the CHS does not seem to increase significantly the ability to predict a cardiovascular event for an individual patient.²⁸ The increase in the area under the receiver operating characteristic (ROC) curve for a model with cardiovascular risk factors and addition of carotid atherosclerosis is modest, compared with the ROC curve area for a model with risk factors alone.²⁹ In contrast, most prognostic studies of coronary calcium score have shown an incremental prognostic value of adding coronary calcium to risk factors, compared with conventional risk factors alone.²⁹ The area under the ROC curve was notably greater for the model with Framingham score plus coronary calcium score than for the model using Framingham risk score alone.²⁹ Finally, proper data concerning the incremental prognostic value of other subclinical atherosclerosis tests are lacking.

Therefore, the crucial question of whether abnormal findings from subclinical atherosclerosis testing may really change the risk category assigned to an individual is unclear. Consequently, it is generally admitted that the use of screening for the detection of subclinical arterial disease on a population-wide basis should be discouraged until the uncertainties still existing about its utility have been better clarified. In contrast, some have recently proposed to screen in a systematic way men aged 45–75 and women aged 55–75 for subclinical atherosclerosis, irrespective of risk factor assessment.²⁷ Ideally, a decision to conduct atherosclerosis testing should be based on a decision-analytic approach taking potential benefit and harm into account, possibly in a randomized trial. Such a trial does not exist to our knowledge, and the decision of whether to carry out subclinical atherosclerosis testing is therefore discussed empirically and selectively by the physician with a view to improving and supplementing (but not replacing) the classical risk prediction assessment, but not to making a diagnosis of cardiovascular disease.⁸ In subjects at low traditional risk, positive subclinical atherosclerosis testing does not contribute to CHD risk management because their treatment on the basis of this test has no support at present,⁸ except perhaps in those in the upper range of the low risk category (e.g. 6–9% Framingham risk) wherein risk factor reduction might be worth intensifying to intermediate target levels (e.g. for low-density lipoprotein cholesterol) but not to the high risk target level. Also, subclinical atherosclerosis detection does not change the clinical management of subjects at high traditional risk because they should have risk factors treated intensively no matter what such detection reveals.⁸ Finally, in subjects with intermediate or uncertain traditional risk, positive subclinical atherosclerosis testing may reasonably allow their re-classification into a higher category of risk and justify treating them more aggressively. In contrast, it is uncertain whether negative subclinical atherosclerosis testing may allow the re-classification of these subjects into a lower category of risk.^8–11 Therefore, further studies are required to establish definitely that negative subclinical atherosclerosis testing may identify low-risk individuals who do not need further cardiac medication and should receive conservative management focusing on lifestyle interventions.⁵

	Study limitations

Top Abstract Introduction Methods Results Discussion Study limitations References

 
First, the calculation of cumulative CHD incidence over a 10-year period from studies with a shorter follow-up duration, especially the 1-year follow-up KIHD study (Table 1), was based on the assumption of a constant CHD rate over 10 years. It is likely that this assumption underestimated CHD risk because of the strong influence of age in prediction models. Secondly, the differences in outcomes across the studies considered for this review constitute a limitation in comparing CHD incidences between studies. Thirdly, the predictions from models using subclinical vascular markers, possibly according to cut-offs, have not yet been validated. Fourthly, individual patient data of the studies were not analysed; only aggregate data in groups of subjects were extracted to derive cumulative CHD incidences according to the reported test result. Also, the Framingham functions were not used for risk assessments; only the 10-year Framingham ATPIII cut-offs⁴ of low (<10%), intermediate (10–20%), and high (>20%) risk of fatal and non-fatal CHD were used for interpreting the clinical relevance of the cumulative CHD incidence rate associated with subclinical markers (Figure 1). Lastly, no validation studies have yet shown whether predicted risks generalize to truly new, external data; also, none of the cut-offs recommended in Table 1 have been validated in new patients.

In conclusion, further studies are needed to define the exact place of subclinical atherosclerosis testing in the context of existing risk factor-based models for CHD prediction and for choosing and standardizing the optimal test(s) required for accurate assessment of atherosclerosis burden. In addition to prognostic performance, other criteria for the choice of subclinical atherosclerosis test, such as simplicity, accuracy, safety, and low cost, need to be taken into account (Table 3). However, it is noteworthy that any subclinical atherosclerosis test currently used does not correctly fulfil all the required criteria for optimal testing (Table 3).

View this table: [in this window] [in a new window]   Table 3 Criteria for choosing subclinical atherosclerosis test

 
Conflict of interest: none declared.

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