Stroke. 2006;37:2904-2909
Published online before print November 2, 2006,
doi: 10.1161/01.STR.0000248764.51601.bb
(Stroke. 2006;37:2904.)
© 2006 American Heart Association, Inc.
Risk of Coronary and Other Nonstroke Vascular Death in Relation to the Presence and Extent of Atherosclerotic Disease at the Carotid Bifurcation
Emmanuel Touzé, MD;
Charles P. Warlow, MD, FRCP
Peter M. Rothwell, MD, PhD, FRCP
From the Stroke Prevention Research Unit (E.T., P.M.R.), University Department of Clinical Neurology, Radcliffe Infirmary, Oxford, England; Faculté de Médecine René Descartes (E.T.), Université Paris 5, France; and the Department of Clinical Neuroscience (C.P.W.), Edinburgh University, Western General Hospital, Crewe Road, Edinburgh, England.
Correspondence to P.M. Rothwell, Stroke Prevention Research Unit, University Department of Clinical Neurology, Radcliffe Infirmary, Oxford OX2 6HE, UK. E-mail peter.rothwell{at}clneuro.ox.ac.uk
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Abstract
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Background and Purpose— It has been proposed that purely
unilateral carotid stenosis is due mainly to local hemodynamic
factors, whereas more diffuse disease reflects a systemic as
well as a local predisposition and should therefore be associated
with higher rates of arterial disease in the other territories.
However, few studies have tested this hypothesis.
Methods— We studied angiograms from 2741 patients with a recently symptomatic carotid stenosis from the European Carotid Surgery Trial and categorized them as showing purely unilateral disease (no convincing plaque in the contralateral carotid artery) or bilateral disease. We related the presence and extent of plaque at both bifurcations to the prevalence of past atherothrombotic disease in other arterial territories and the risk of future nonstroke vascular events.
Results— The degree of symptomatic carotid stenosis was unrelated to either the prevalence of symptomatic arterial disease in other territories at baseline or to the risk of nonstroke vascular death during follow-up, whereas there were strong associations with the presence of bilateral carotid disease. In multivariate analyses, bilateral carotid disease (n=2076) was associated with previous myocardial infarction (odds ratio [OR]=1.7; 95% CI, 1.2 to 2.4) or peripheral vascular disease (OR=1.5; 95% CI, 1.2 to 2.0) and with subsequent nonstroke vascular death (hazard ratio=2.0; 95% CI, 1.5 to 2.6). The 5-year risk of nonstroke vascular death ranged from 2.7% (95% CI, 1.5% to 4.6%) in patients with no history of coronary or peripheral arterial disease at baseline and purely unilateral carotid disease to 21.4% (95% CI, 17.6% to 26.1%) in those with bilateral carotid disease and a history of either coronary or peripheral arterial disease (P<0.0001).
Conclusions— Bilateral carotid disease is associated with higher rates of symptomatic arterial disease in other territories, suggesting a systemic predisposition to atherosclerosis and hence, the need for more aggressive preventive treatment, whereas purely unilateral carotid disease indicates a mainly local hemodynamic etiology.
Key Words: stroke • carotid artery • atherosclerosis • prognosis • systemic factors • myocardial infarction
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Introduction
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Atherosclerosis is strongly related to systemic risk factors,
such as lipids, smoking, and inflammation.
1,2 Both pathological
and imaging studies have shown that disease is often present
in multiple arterial territories,
3–5 and clinical studies
have shown that disease in 1 territory predicts events in other
territories.
6–8 However, plaques often develop very focally,
as indicated by the frequent asymmetry of disease at the carotid
bifurcations.
9–11 Such focal disease is usually explained
on the basis of local anatomic and hemodynamic factors,
9,12,13 whereas more symmetrical disease has been attributed to systemic
factors.
14–16
If development of bilateral carotid disease does indicate the presence of a systemic predisposition to disease, patients with such lesions would be expected to have a higher prevalence of arterial disease in the other territories than those with unilateral lesions. Two small studies found that bilateral asymptomatic carotid plaques but not unilateral plaques were associated with prevalent coronary artery disease (CAD)17 or with vascular risk factors and hospitalization for vascular diseases.18 However, those studies were not specifically designed to assess this question. The potential prognostic value of atherosclerosis in 1 rather than both carotid arteries has not been taken into account in previous models for the prediction of CAD in patients with symptomatic or asymptomatic carotid artery stenosis19–22 and is not mentioned in the recent American Heart Association/American Stroke Association statement emphasizing the importance of the evaluation of coronary risk in stroke patients.6 Moreover, it is uncertain whether it is simply the presence of plaque at both bifurcations, irrespective of the extent or severity of stenosis, that is of prognostic value or whether the risk of CAD increases with extent and severity. We therefore selected 2741 patients with bilateral carotid arterial angiograms from the European Carotid Surgery Trial (ECST) and related the presence and extent of plaque at both bifurcations to the prevalence of past atherothrombotic disease in other territories and the risk of future nonstroke vascular events.
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Subjects and Methods
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The methods and results of the ECST and the details of the angiographic
technique have been published previously.
23,24 In brief, patients
with recently symptomatic carotid bifurcation stenosis defined
on an angiogram were randomly assigned to carotid endarterectomy
or best medical treatment alone. Past history of myocardial
infarction (MI) or peripheral vascular disease (PVD) (defined
by a history of intermittent claudication or peripheral vascular
surgery or angioplasty) was ascertained by a physician at the
time of the randomization from the patient’s history and
clinical records. Patients were followed up at 4 months and
annually thereafter.
Of the 3018 patients randomized, 3007 (99.6%) had an angiogram of the symptomatic carotid artery. The maximum degree of stenosis at both carotid bifurcations was measured by 2 independent observers by the ECST method, who were blinded to past and future medical history. Details of the reproducibility of this measurement and the equivalence to other methods have been published elsewhere.24 The angiogram of the contralateral artery was available for 2308 (77%) patients with at least 20% stenosis at the symptomatic carotid bifurcation. The measurement of the degree of stenosis on the contralateral artery was available from the original radiological report for an additional 433 other patients. Thus, 2741 (91%) patients were available for the study.
Patients were classified as having purely unilateral disease if there was no evidence of any convincing plaque in the contralateral carotid artery. Slight surface irregularities without lumen narrowing were not considered as plaque. On both sides, the severity of carotid artery stenosis was classified into 3 categories (<50%, 50% to 79%, and 
80%),25 and the plaque surface morphology of the symptomatic artery as smooth or irregular.24 The local extent of atherosclerotic disease at each carotid bifurcation was also evaluated by assessment of (1) the total length of the angiographically visible plaque from its proximal origin in the common carotid artery or carotid bulb (quantified as a ratio to the diameter of a disease-free segment of the common carotid artery); (2) significant stenosis (30%) of 2 or more bifurcation vessels; ie, common, internal, and external carotid arteries).
At each follow-up time, details were obtained for any strokes, nonfatal MIs, or deaths. Clinical details, results of any investigations, and any necropsy findings were sent to the main trial center for classification by an independent audit committee unaware of treatment allocation or assessment of the carotid angiograms. Nonstroke vascular death was defined as death not due to acute stroke or the consequences of a previous stroke, which was proven or judged very likely to have been due to a vascular cause. These deaths were subdivided into those due to proven acute MI (based on clinical, ECG, and enzyme elevations or necropsy),26 sudden deaths (no other cause of death at necropsy and past history of CAD or evidence of coronary artery atheroma at necropsy), and other nonstroke vascular deaths (eg, sudden deaths without necropsy, cardiac failure, ruptured aortic aneurysm). Audit of nonfatal MI was discontinued in 1991. Our primary analyses were therefore restricted to fatal outcomes, although we also report data on nonfatal MIs.
Statistical Analysis
The association between the presence of bilateral carotid lesions and baseline characteristics was assessed by calculation of crude and adjusted odds ratios (ORs) in logistic-regression models. The risks of vascular events on follow-up between groups were compared by use of Kaplan-Meier survival analysis. The significance of any differences was calculated by the log-rank test. Hazard ratios (HRs) were determined by the use of Cox proportional-hazards models. Multivariate models were adjusted for treatment group, age, sex, past MI, past PVD, smoking, cardiac failure, diabetes, systolic blood pressure, cholesterol, and degree of stenosis and plaque surface morphology of the symptomatic carotid artery. The same analyses were performed in patients with symptomatic stenosis 50% and in patients without a history of MI or PVD at baseline. All analyses were done with SPSS, version 11.0.
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Results
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The mean degree of stenosis was 63% (SD, 19.4) for the symptomatic
carotid artery and 40% (SD, 26.5) for the contralateral artery.
At baseline, 665 (24%) patients had no lesion on the contralateral
artery. These patients were younger, more often male, and had
slightly lower mean systolic blood pressure, lower mean cholesterol
concentration, and less severe stenosis on the symptomatic side
(
Table 1).
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TABLE 1. Clinical and Angiographic Characteristics at Randomization of Patients With Bilateral vs Unilateral Carotid Lesions
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Univariate and multivariate analyses did not show any correlation between the severity of stenosis of the symptomatic carotid artery and past MI or PVD (Table 2). However, the presence of bilateral disease was significantly associated with past MI (adjusted OR=1.7; 95% CI, 1.2 to 2.4) and PVD (OR=1.5; 95% CI, 1.2 to 2.0). In patients with symptomatic carotid stenosis 50%, ORs associated with bilateral disease were 1.5 (95% CI, 1.0 to 2.2) for past MI and 2.0 (95% CI, 1.4 to 2.9) for past PVD. In patients with bilateral disease, the strength of the association with past MI did not increase with the severity of stenosis on the contralateral side, but a significant trend was present for past PVD (Table 2). We did not find any correlation between past MI or PVD and the local extent (length of the plaque and stenosis of 2 or more vessels) of the disease at either bifurcation (data not shown).
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TABLE 2. Association Between a History of Symptomatic Disease in Other Territories and the Presence and Severity of Carotid Disease
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During follow-up, there were 406 nonstroke vascular deaths, 215 nonvascular deaths, and 29 deaths of unknown cause. The degree of stenosis of the symptomatic carotid artery did not independently predict the risk of nonstroke vascular death (Table 3). However, the risk of nonstroke vascular death was increased in patients with bilateral disease (Figure 1 and Tables 3 and 4
). This association remained significant after correction for baseline clinical and angiographic characteristics (HR=2.0; 95% CI, 1.5 to 2.6; Table 3) and was consistent in the different components of this composite outcome (Table 4). No similar association was observed for the risk of nonvascular death or nonfatal MI. The strength of the association with subsequent nonstroke vascular death increased gradually with the severity of stenosis of the contralateral carotid artery, but the association was weaker than that for the presence versus absence of any disease on the contralateral artery (Table 3). The risk of nonstroke vascular death and that of nonfatal MI were not correlated with the local extent of disease at either bifurcation (data not shown).
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Figure 1. Kaplan-Meier hazard of nonstroke vascular death and its component outcomes according to the presence of bilateral or unilateral carotid disease. Thin line is bilateral carotid stenoses; thick line is unilateral carotid stenosis. Because all events were fatal and because nonstroke vascular death included all other events, the numbers of patients at risk at each time were similar in all survival analyses. Number of patients at risk at 2, 4, 6, 8, and 10 years were, respectively, 1851, 1517, 1000, 527, and 142 for bilateral carotid disease and 618, 538, 388, 204, and 66 for unilateral disease.
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TABLE 4. Incidence of Fatal and Nonfatal Events According to the Presence of Bilateral or Unilateral Carotid Disease
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Patients with purely unilateral carotid artery disease and without past MI or PVD had a very low 5-year risk of nonstroke vascular death (2.7%; 95% CI, 1.5% to 4.6%; Figure 2). Patients with bilateral carotid artery disease and without past MI or PVD had a risk of nonstroke vascular death very close to that of those with unilateral carotid stenosis and past MI or PVD. Patients with bilateral lesions and past MI or PVD had the highest risk (21.4%; 95% CI, 17.6% to 26.1%). After adjustment in a Cox model, the presence of bilateral carotid disease remained an independent predictor of nonstroke vascular death irrespective of whether there was a past history of MI or PVD and whatever the severity of the stenosis on the symptomatic side (supplemental Figure I, available online at http://stroke.ahajournals.org). However, the association was stronger in patients without a previous MI or PVD (P for heterogeneity=0.009).
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Figure 2. Absolute 5-year risk of nonstroke vascular death according to the presence of unilateral or bilateral carotid disease and past history of symptomatic atherothrombotic disease in other territories. Error bars indicate 95% CI. Log-rank test comparing the 4 groups=137.39; P<0.0001.
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Figure I. Relative risk of nonstroke vascular death (bilateral vs unilateral) according to previous symptomatic arterial disease in other territories and to the severity of stenosis of the symptomatic artery. p(het) indicates probability value for heterogeneity.
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Discussion
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We have shown that patients with bilateral carotid disease are
more likely to have had a previous MI or PVD and are more likely
to die as a consequence of MI or other nonstroke vascular death
and that the presence of bilateral disease is a better predictor
than the extent and severity of disease at either bifurcation.
The prognostic value of bilateral disease was greater in patients
without any past history of MI or PVD at baseline. Patients
with unilateral symptomatic carotid artery stenosis and without
any history of MI or PVD had a very low risk of nonstroke vascular
death, even though they had a recently symptomatic carotid stenosis.
The presence of bilateral carotid disease led to the same relative
increase in risk as a history of MI or PVD.
Our results confirm the findings of 2 small previous studies showing that bilateral asymptomatic carotid plaques but not unilateral plaques were associated with prevalent CAD17 or with vascular risk factors and hospitalization for vascular diseases18 and with the observation that in patients with documented CAD, the prevalence of carotid artery stenosis increases steeply with the number of diseased coronary arteries.4 However, none of those previous studies specifically addressed that issue, none had enough statistical power to reach definite conclusions, and none proposed any explanation. Taken together, these findings are consistent with the hypothesis of distinct roles for local and systemic factors in the development of carotid atherosclerosis. They also highlight the potential clinical usefulness of bilateral carotid disease in identifying patients at high risk of nonstroke vascular death.
Although stroke patients have a relatively high risk of subsequent MI or vascular death, many will not have such events.6,8 It is therefore crucial to identify highest-risk patients who will benefit most with screening. Patients with purely unilateral symptomatic carotid disease and no history of atherothrombotic disease in other territories presumably lack important systemic factors that promote the development and/or complications of atherosclerosis in the near future. Conversely, patients with bilateral carotid disease probably have a more severe systemic predisposition to atherosclerosis and, at baseline, more extensive CAD, which could require more aggressive strategies of investigation and prevention.6,27 Because we did not find any major differences in the prevalence of traditional risk factors at baseline between patients with unilateral and those with bilateral disease, our results are consistent with the existence of other nonmeasured and/or unknown systemic factors.28,29
Interestingly, in contrast to the presence versus absence of disease of the contralateral carotid artery, at neither bifurcation did the extent and severity of disease predict the risk of future nonstroke vascular events. In other words, the presence of early or limited disease at the carotid bifurcation is as predictive of events in other arterial territories as the presence of severe and extensive carotid disease. This may reflect the fact that in contrast to the risk of stroke, which is strongly related to the severity of carotid stenosis,25 the risk of acute coronary events is much more weakly associated with the severity of vessel stenosis, with many events occurring in patients with nonstenosing lesions.
Although we consider our findings to be valid and convincing, our study has some potential shortcomings. First, although we found a strong correlation between the presence of bilateral carotid lesions and the risk of fatal MI, we did not find such a correlation with nonfatal MI, and it might therefore be argued that the association that we observed with the risk of nonstroke vascular death was due to chance. However, the association was highly statistically significant and consistent across the different elements of the composite outcome. Moreover, the difference between the associations that we observed with fatal and nonfatal MI has a potentially plausible explanation. Disease at the carotid bifurcation is strongly associated with multivessel CAD,4 which is more commonly associated with fatal MI than is single-vessel disease.30,31 Most important, however, we tested our observations before publication in 2 independent populations. In the other trial populations included in the Carotid Endarterectomy Trialists’ Collaboration,25 we found very similar results: patients with bilateral carotid disease were more likely to have had a previous MI or PVD (adjusted OR=1.5; 95% CI, 1.1 to 1.9) and to die as a consequence of nonstroke vascular death (HR=1.7; 95% CI, 1.2 to 2.5; with permission of P.M. Rothwell). Analysis of data from a large population-based study of all patients with transient ischemic attack and stroke also show that patients with bilateral carotid disease are more likely to have had previous CAD or PVD (OR=2.3; 95% CI, 1.4 to 3.8) than those with unilateral lesions (with the permission of P.M. Rothwell).32 Our findings are therefore unlikely to be due to chance, and the replication of our results in a population-based study also excludes the possibility that they are a consequence of some unknown selection biases. Second, the method used to classify patients into the unilateral or bilateral disease groups was subjective. Indeed, because angiography does not show the vessel wall and we did not consider surface irregularities, we could have overestimated the proportion of patients with unilat-eral nonstenotic lesions. However, all assessments were made blinded to the clinical data, so there was no possibility of bias in classification, and any misclassification would have decreased the strength of the observed relation. Third, because all patients included in ECST had had a recent stroke or transient ischemic attack, our results may not be valid in patients with asymptomatic carotid stenosis. However, the previous small studies with similar results were conducted in asymptomatic patients.17,18 Fourth, because patients were included in the trial in the late 1980s and early 1990s, the absolute risks of nonstroke vascular death are higher than would be observed today with more intensive preventive treatments. However, it is unlikely that the relative effects that we observed in association with bilateral carotid disease would be very different. Finally, because the ECST was an international multicenter trial, it is possible that our results were due to some unexpected ecological bias. However, we performed analyses by country and did not find any heterogeneity.
In conclusion, purely unilateral symptomatic carotid stenosis is associated with low rates of symptomatic arterial disease in other territories, suggesting a local hemodynamic etiology, whereas the presence of bilateral carotid disease, though not its extent or severity, is associated with high rates of symptomatic arterial disease in other territories, possibly indicating a stronger systemic predisposition to atherosclerosis.
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Acknowledgments
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Disclosures
None.
Received April 20, 2006;
revision received June 14, 2006;
accepted July 5, 2006.
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Abstract
Introduction