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European Heart Journal Advance Access originally published online on July 11, 2006
European Heart Journal 2006 27(16):1971-1978; doi:10.1093/eurheartj/ehl136
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Carotid intima–media thickness and the risk of new vascular events in patients with manifest atherosclerotic disease: the SMART study

Joke M. Dijk1,2, Yolanda van der Graaf1, Michiel L. Bots1, Diederick E. Grobbee1, Ale Algra1,3,4,* on behalf of the SMART study group

1 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Huispostnummer Str.6.131, PO Box 85060, 3508 BA Utrecht, The Netherlands
2 Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands
3 Rudolph Magnus Institute for Neuroscience, Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands
4 Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

Received 11 January 2006; revised 22 May 2006; accepted 15 June 2006; online publish-ahead-of-print 11 July 2006.

* Corresponding author. Tel: +31 31 30 2509350; fax: +31 31 30 2505485. E-mail address: a.algra{at}umcutrecht.nl


   Abstract
Top
 Abstract
Introduction
 Methods
 Measurements
 Results
 Discussion
 Appendix
 Acknowledgements
 References
 
Aims Carotid intima–media thickness (CIMT) is an independent predictor of vascular events in the general population. Currently, little is known about the relationship between CIMT and new vascular events in patients with manifest arterial disease. We aimed to assess the strength of this relationship.

Methods and results The study was performed in the first consecutive 2374 patients with manifest arterial disease enrolled in the cohort study SMART (Second Manifestations of ARTerial disease), a cohort study among patients with manifest arterial disease or cardiovascular risk factors. Common CIMT was measured at baseline in both carotid arteries. Vascular events were vascular death, non-fatal myocardial infarction, or stroke, whichever occurred first.

Adjusted for age and sex, an increase in common CIMT of 1 SD (~0.32 mm) was associated with the occurrence of vascular events [hazard ratio (HR) 1.18; 95% confidence interval (95% CI) 1.04–1.32]. Increasing CIMT was most strongly related to ischaemic stroke incidence (HR 1.35; 95% CI 1.16–1.59). Results were similar in the 2177 patients without large common carotid plaques (CIMT <2 mm at all measurements sites). The findings were similar after additional adjustment for risk factors of CIMT and vascular risk.

Conclusion Common CIMT is associated with the occurrence of new vascular events, mostly for ischaemic stroke, in patients with manifest arterial disease. This relation does not appear to depend on the presence of plaques.

Key Words: Intima–media thickness • Epidemiology • Risk factors • Clinical studies • Cardiovascular diseases


   Introduction
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 Abstract
 Introduction
Methods
 Measurements
 Results
 Discussion
 Appendix
 Acknowledgements
 References
 
Increased carotid intima–media thickness (CIMT) is related to various cardiovascular risk factors including hypertension, smoking, hypercholesterolaemia, and diabetes mellitus.1 Moreover, increased CIMT has been related to future myocardial infarction, stroke, and cardiovascular death (Table 1).2–21


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  		Table 1 Summary of prospective studies examining the relationship between CIMT and vascular events

 
In addition, carotid CIMT is related to the presence of atherosclerotic lesions in the legs,22 aorta,23 and elsewhere in the carotid arteries.24,25 On the basis of these findings, CIMT is a well-established measure of generalized atherosclerosis. The availability of CIMT as a measure of atherosclerosis that predicts arterial disease has justified its use as an alternative (surrogate) outcome for risk of vascular events in intervention studies like lipid lowering26 and blood-pressure reducing27 therapy. Change in CIMT as a surrogate outcome increases the efficiency and feasibility of these studies because fewer subjects are needed and the follow-up can be shorter.28 Furthermore, CIMT has been suggested of importance for risk stratification, so optimal treatment can be installed in persons at a high predicted vascular risk.29

Most studies on the relation of CIMT and vascular disease have been performed in patients with end-stage renal disease (ESRD) or in patients without clinically manifest disease (Table 1). Three studies, restricted to patients with coronary artery disease (CAD), did report on patients with manifest arterial disease other than ESRD, but results were conflicting.8,9,13 Thus it is unclear whether an increased CIMT is related to future vascular disease in patients with established arterial disease. This is of importance, as intervention studies in patients with manifest vascular disease can only use CIMT as a surrogate outcome with confidence, if CIMT is related to risk of vascular disease in this population as well. Moreover, CIMT may only improve risk stratification in these patients if a relation with future vascular disease is present.

In addition, the presence of one or more common carotid plaques has been associated with an increased risk of stroke30 and myocardial infarction.31 When an atherosclerotic plaque is present at the site of one of the common CIMT measurements, it is incorporated in the CIMT value. As a common carotid plaque prevalence of 15% has been reported in a healthy elderly population,30 and the presence of plaques is likely to be higher in groups with symptomatic vascular disease, this might influence the association of CIMT and vascular disease in those patients.

In this prospective study, we evaluated whether common CIMT is related to the occurrence of new vascular events in patients with clinically manifest arterial disease and whether this relation is independent of the presence of common carotid plaques.


   Methods
Top
 Abstract
 Introduction
 Methods
Measurements
 Results
 Discussion
 Appendix
 Acknowledgements
 References
 
Study population
We used data from patients enrolled in the SMART study (Second Manifestations of ARTerial disease). The SMART study is an ongoing prospective single-centre cohort study in patients with manifest arterial disease or cardiovascular risk factors. Starting in September 1996, consecutive patients aged 18–80, referred to the University Medical Center Utrecht (UMCU) with manifest arterial disease or a cardiovascular risk factor, underwent a vascular screening including a questionnaire, blood chemistry, and ultrasonography. Written informed consent was obtained from all participants. The study was approved by the medical Ethics Committee of the hospital. The rationale and design of the SMART-study have been described in detail elsewhere.32

For the current study, the data of the first consecutive 2437 participants with manifest arterial disease [cerebral, coronary, or peripheral artery disease; renal artery stenosis; or an aneurysm of the abdominal aorta (AAA)] who were included in SMART before 1 March 2003 were considered. The arterial disease manifestation renal artery stenosis was based on medical history and inclusion diagnosis. Definitions of other included manifestations of arterial disease were described previously.33 In 63 participants, CIMT measurements were missing for logistic reasons. Data of 2374 participants were analysed.


   Measurements
Top
 Abstract
 Introduction
 Methods
 Measurements
Results
 Discussion
 Appendix
 Acknowledgements
 References
 
Common CIMT
The left and right common carotid arteries were examined in anterolateral, posterolateral and mediolateral directions with an ATL Ultramark 9 (Advanced Technology Laboratories, Bethel, WA, USA) equipped with a 10-MHz linear array transducer as previously described.34 Measurements were performed 1 cm proximal to the beginning of the dilatation of the carotid bulb. On an R-wave-triggered frozen longitudinal image of the far wall, the sonographer traced the leading edges corresponding to the transition zones between lumen–intima and media–adventitia over a length of 1 cm proximal to the carotid bulb. The total intima–media surface of this selected area was calculated automatically. The mean CIMT of the six measurements in each patient was calculated. An interobserver variability study on CIMT measurements among 25 volunteers showed a coefficient of variation of 11.7%. The intraobserver variability was slightly lower than the interobserver variability.35 Validation studies, in which ultrasonographically measured CIMT was compared with histologically determined CIMT, showed that the far wall CIMT can be accurately measured by ultrasound.36

Common carotid plaque
In general, a >50% locally widened vessel wall relative to adjacent segments, with protrusion into the lumen, is considered a plaque.30 As in other studies on CIMT, when an atherosclerotic plaque was present at the site of one of the common CIMT measurements, it was incorporated in the CIMT value. Presence of common carotid artery plaques was not assessed in this study. To be able to study the relation of CIMT without common carotid artery plaques incorporated, a CIMT of ≥2 mm measured at one of the six measurement sites was considered to reflect presence of a plaque. A ≥2 mm is likely to be a >50% local widening of the vessel wall when the mean CIMT of 0.95 mm is taken into account and is ~3 SDs higher than the mean CIMT.

Vascular screening
Vascular screening was conducted on a single day at the UMCU. Blood samples were collected after an overnight fast. Glucose, total cholesterol, triglycerides, and HDL-cholesterol were measured. LDL-cholesterol was calculated with Friedewald's formula. Height and weight were measured without shoes and heavy clothing. Blood pressure was measured in supine position at the right brachial artery every 4 min during the arterial stiffness measurement with a semi-automatic oscillometric device (Omega 1400, Invivo Research Laboratories Inc., Broken Arrow, OK, USA). Medical history, use of current medication, and current and past cigarette smoking behaviour were derived from a questionnaire described elsewhere.32

Follow-up
Patients were asked biannually to complete a questionnaire on hospitalizations and outpatient clinic visits in the preceding 6 months. Events of interest for this study were ischaemic stroke (definite and probable), coronary ischaemic events, vascular death, and the composite of all vascular events. Definitions of the events are given in Table 2.32 When a possible event was recorded by the participant, hospital discharge letters and results of relevant laboratory and radiology examinations were collected. On the basis of this information, all events were audited by three members of the Outcome Event Committee. In case of disagreement, the opinion of other members of the Outcome Event Committee was sought and final adjudication was based on the majority of the classifications obtained.


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  		Table 2 Definitions of events

 
Data analysis
Cox proportional hazards analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the occurrence of vascular events associated with an increase of 1 SD of CIMT (~0.32 mm). If a patient had multiple events, the first was taken. Three models were used. The unadjusted association of common CIMT and vascular events was examined in model I. In model II, it was adjusted for age and sex. In model III, we additionally adjusted for systolic blood pressure, diastolic blood pressure, diabetes mellitus, cigarette smoking, and use of antihypertensive medication at baseline. Other risk factors for atherosclerosis (body mass index, triglycerides, HDL-cholesterol, LDL-cholesterol, and use of lipid-lowering medication) were not included in the model, as these variables did not change the magnitude or the direction of the associations. To examine the association of CIMT with outcome independent of common carotid plaque presence, it was additionally studied in patients who had a CIMT <2 mm at all six measurement sites. Analyses were carried out in all patients and additionally in patients with CAD, cerebrovascular disease, or peripheral arterial disease (PAD) separately. Because of the limited number of patients, no separate analyses were done for patients with an AAA or a renal artery stenosis. The proportional hazards assumption was satisfied on the basis of logminlog plots for tertiles of CIMT. Whether corrections for multiple testing should be made to account for the inflation of experimentwise Type I error, is a matter of debate. We belong to the school that believes such corrections should not be done.37,38 P-values were two-sided and P<0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Measurements
 Results
Discussion
 Appendix
 Acknowledgements
 References
 
Baseline characteristics of the study population are given in Table 3. The 2374 patients in this study had a mean age of 60.0 and were predominantly male (76%). The common CIMT ranged from 0.36 to 4.52 mm, with a mean of 0.95 mm (SD 0.32 mm). Table 4 shows the coincidence of manifestations of arterial disease in individual patients at baseline. In 424 patients, two manifestations of arterial disease were present, 69 patients had three and eight patients had four manifestations.


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  		Table 3 Baseline characteristics of the study population

 

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  		Table 4 Coinciding of manifestations of arterial disease at base line

 
During a median follow-up of 2.8 years (range: 0.1–6.5 years), 225 patients experienced a new vascular event, of whom 125 died of a vascular cause. In Table 5, the HRs of different vascular events are given for 1 SD increase in common CIMT. Adjusted for age and sex, increased CIMT was related to an increased risk of any vascular event (HR 1.18, 95% CI 1.04–1.32). When the vascular events were separated into ischaemic stroke and coronary ischaemic events, the relative risk of stroke [1.35 (1.16–1.59)] associated with 1 SD increase in CIMT appeared higher than that of ischaemic coronary events [1.19 (CI 1.02–1.38)]. After adjustment for vascular risk factors for increased CIMT and cardiovascular risk, the strengths of the relations attenuated slightly. Additionally, in Table 5, the relation of CIMT with vascular events is given for the 2177 patients with a CIMT <2 mm at all six measurement sites. The relation between CIMT and stroke [46 events, HR 2.07 (1.38–3.11)] appeared stronger relative to the findings in the total population, whereas the association with vascular death and other vascular events was not materially altered. As shown in Table 6, examining the relation in patients with CAD, PAD, and stroke or TIA separately generally produced similar results as in the total population.


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  		Table 5 Relation of common CIMT with vascular events

 

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  		Table 6 Relation of common CIMT with vascular events in strata of manifestations of vascular disease

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Measurements
 Results
 Discussion
Appendix
 Acknowledgements
 References
 
The results of our study show that in patients with manifest vascular disease, increased common CIMT is associated with a higher risk of vascular events (Table 5). The relative risk for ischaemic stroke apparently is greater than that of other vascular events. The associations are largely independent of age and sex and are present in patients with previous CAD, PAD, and stroke or TIA.

Increased CIMT reflects the severity of arterial damage brought about by classical vascular risk factors.1 CIMT thus may be considered an intermediate in the causal pathway between vascular risk factors and clinical manifest arterial disease. Therefore, these classical risk factors are no confounders and should not be controlled for in the analysis. Nevertheless, when the main interest is to assess whether the novel risk factors are related to new vascular events independent of these classical risk factors, one may want to additionally adjust for these factors.

That we observed a weaker relation in comparison with other studies is probably due to the fact that those studies were performed in the general population or in patients with vascular risk factors (Table 1). As the absolute risk of a vascular event is higher in our population of patients with manifest arterial disease, the relative risk consequently tends to be lower. In addition, patients with manifest arterial disease are likely to have higher levels of CIMT,3–6,8,9,11,14 and as it has been shown that the increase in relative risk is smaller at higher levels of CIMT,5 this also may partly explain the strengths of our relations.

We found a stronger relation of common CIMT with stroke than with myocardial infarction. This finding is in accordance with previously reported risks.4,18,19 The reason for this difference is unclear. A potential explanation is a stronger relation of CIMT with small vessel disease (causing approximately one-quarter of all strokes),39 than with large vessel disease (the cause of CAD). However, this hypothesis is not supported by two studies examining the relation of CIMT and small- and large-vessel cerebral disease, which show a stronger relation of CIMT with large artery disease.40,41 Another possible explanation is that higher CIMT partly represents a higher prevalence of common carotid plaques that function as a source of emboli and thus may increase stroke risk. Generally, plaque thickness is incorporated in the mean CIMT value when a common carotid plaque is present in a subject. However, CIMT- and plaque-associated risk may differ.10 In our study, the strength of the relation of CIMT with different vascular events did not decrease considerably when restricted to patients with <2 mm at all measurement sites (Table 5). This suggests that the relation was not merely explained by a relation with common carotid plaques. The relation of CIMT with ischaemic stroke was, if anything, even stronger after exclusion of patients with a common carotid plaque, although the number of strokes was relatively small (46). Because exact plaque measurements were not available, patients with a small plaque may still be present among the patients with a <2 mm CIMT. As exclusion of the large plaques did not result in a decrease in risk associated with increased CIMT and the risk appeared to be continuous across the distribution of thickness, plaques are not likely to largely explain the relation between CIMT and vascular risk.

As shown in Table 5, the strength of the relation between CIMT and the occurrence of new vascular events in subgroups of patients according to their clinical manifestation of arterial disease generally was similar to the total population (Table 5). However, there were two remarkable differences. First, the relation of CIMT with vascular death was stronger when studied in strata of manifestations of arterial disease than in the population as a whole. This may be explained by the fact that patients with more than one clinical manifestation of arterial disease fell into more categories and at the same time were at a higher risk of vascular death. Secondly, although CIs are overlapping, in patients with PAD, the risk of coronary ischaemic events appeared higher [HR 1.39 (1.14–1.70)] than in the overall population. CIMT has been shown to be independently related to the extent and severity of CAD,42,43 but never in patients with PAD. Our findings suggest that in patients with PAD, who are known to be at high risk of CAD,44 CIMT is a marker of (asymptomatic) CAD.

CIMT is regarded as a measure of generalized atherosclerosis in asymptomatic subjects, therefore, change in CIMT has been widely used as a surrogate outcome in intervention studies.26–28 That in the SMART study a relation of CIMT with new vascular events was shown in patients with manifest arterial disease justifies its use as a surrogate endpoint also in this population. Use of a surrogate outcome has the advantage of considerable reduction in sample size and a shorter follow-up.28 Other criteria, notably the potential for regression or stabilization of CIMT by treatment, need to be further documented in this population. The use of CIMT as a tool to enhance risk differentiation, awaits further evaluation.

In conclusion, these findings from the SMART study support the view that increased common CIMT is related to an increased risk of vascular death and vascular events in patients with manifest arterial disease. This relation does not appear to depend on the extent to which CIMT thickness is determined by the presence of plaques.


   Appendix
Top
 Abstract
 Introduction
 Methods
 Measurements
 Results
 Discussion
 Appendix
Acknowledgements
 References
 
Members of the SMART study group are (alphabetically) as follows.

A. Algra, Julius Center for Health Sciences and Primary Care and Rudolph Magnus Institute of Neuroscience, Department of Neurology, UMCU, The Netherlands.

J.D. Banga, Department of Vascular Medicine, UMCU, The Netherlands.

P.A. Doevendans, Department of Cardiology, UMCU, The Netherlands.

B.C. Eikelboom, Department of Vascular Surgery, UMCU, The Netherlands.

Y. van der Graaf, Julius Center for Health Sciences and Primary Care, UMCU, The Netherlands.

D.E. Grobbee, Julius Center for Health Sciences and Primary Care, UMCU, The Netherlands.

L.J. Kappelle, Department of Neurology, UMCU, The Netherlands.

H.A. Koomans, Department of Nephrology, UMCU, The Netherlands.

W.P.T.M. Mali, Department of Radiology, UMCU, The Netherlands.

F.L. Moll, Department of Vascular Surgery, UMCU, The Netherlands.

G.E.H.M. Rutten, Julius Center for Health Sciences and Primary Care, UMCU, The Netherlands.

F.L.J. Visseren, Department of Vascular Medicine, UMCU, The Netherlands.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Measurements
 Results
 Discussion
 Appendix
 Acknowledgements
References
 
This study was made possible by grant no. 904-61-154 from NWO, the Netherlands Organization for Scientific Research. We gratefully acknowledge the contribution of the ultrasound technicians of the radiology department, the SMART research nurses, Michael Edlinger, data-manager, the SMART Outcome Event Committee, and the SMART study group.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Measurements
 Results
 Discussion
 Appendix
 Acknowledgements
 References
 

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