Common Carotid Artery Intima-Media Thickness and the

Risk of Stroke Recurrence

Georgios Tsivgoulis, MD; Konstantinos Vemmos, MD; Christos Papamichael, MD;
Konstantinos Spengos, MD; Efstathios Manios, MD; Kimon Stamatelopoulos, MD;
Demetrios Vassilopoulos, MD, PhD; Nikolaos Zakopoulos, MD
Background and PurposeIncreased common carotid artery intima-media thickness (CCA-IMT) has been associated with
an increased risk of myocardial infarction and stroke. We investigated the relationship between CCA-IMT and recurrent
stroke in a cohort of ischemic stroke patients.
MethodsHigh-resolution B-mode ultrasonographic measurements of the CCA-IMT were performed in a consecutive
series of 238 patients hospitalized in our institution with first-ever ischemic stroke. Stroke risk factors and secondary
prevention therapies were documented. Patients were followed-up prospectively and the outcome event of interest was
recurrent stroke.
ResultsDuring a mean follow-up period of 28.9 months (range: 6 to 60 months), 27 recurrent strokes were documented.
Patients who experienced recurrent cerebrovascular events had significantly (P0.005) higher CCA-IMT values
(1.01 mm, 95% CI:0.92 to 1.11 mm) than subjects who were free of stroke recurrence (0.88 mm, 95% CI:0.85 to
0.91 mm). After adjustment for baseline characteristics, risk factors and stroke subtypes and secondary prevention
therapies increasing CCA-IMT was found to be an independent predictor of stroke recurrence. For each increment of
0.1 mm in CCA-IMT the probability of experiencing recurrent stroke increased by 18.0% (95% CI:2.0% to 36.0%,
P0.027).
ConclusionsIncreased CCA-IMT values are associated with a higher risk of long-term stroke recurrence. (Stroke. 2006;
37:1913-1916.)
Key Words: atherosclerosis carotid arteries recurrence stroke

growing body of evidence supports that the intimamedia thickness of the common carotid artery (CCAIMT) can be regarded as an early marker of atherosclerosis.1
Furthermore, increased CCA-IMT has been associated with
conventional cardiovascular risk factors,2 the presence of
other localizations of atherosclerosis3 and an increased risk of
myocardial infarction4 and stroke.5
However, there are limited data regarding the potential
significance of CCA-IMT in predicting recurrent cerebrovascular events. Assuming that in addition to established risk
factors, increased CCA-IMT may constitute an important risk
marker for recurrent stroke, the present longitudinal study
aimed to evaluate the relationship between CCA-IMT and
stroke recurrence in a cohort of consecutive first-ever ischemic stroke (IS) patients.

Materials and Methods

Study Population
A series of 324 consecutive, first-ever acute stroke patients, admitted
to the acute stroke unit and the general neurology ward of our
institution between January 2000 and December 2003 were screened.

All patients were included in The Athens Stroke Registry, a

computerized prospective observational data bank, gathered in 2
university teaching hospitals.6,7 According to the Trial of Org 10172
in Acute Stroke Treatment (TOAST) criteria, IS was classified based
on etiopathogenetic mechanisms into the following groups: large
artery atherosclerotic stroke (LAA), cardioembolic stroke (CE),
small artery occlusion or lacunar infarction (LAC), infarction of
other determined origin and infarction of undetermined cause
(IUC).8 Height and weight were recorded and body mass index was
calculated as weight to height squared. Risk factors were documented as previously described.6,7

Carotid Ultrasonography Studies

The CCA-IMT of all screened patients was assessed using high
resolution B-mode ultrasonography (Acuson 128XP, equipped with
a 7-MHz linear-array transducer), within the first 5 days of ictus. The
CCA-IMT value was defined as the mean of the IMT of the right and
left IMT of the CCA, calculated from 10 measurements on each side,
taken 10 mm proximal to the carotid bifurcation. The previously
anatomically validated lumen/intima leading edge (I-line) to media/
adventitia leading edge (M-line) method was used.7,9 All ultrosonographic measurements were performed by the same experienced
sonographer (C. P.),7,9 13 who was blinded to any clinical information about the study population.

Received March 7, 2006; accepted April 6, 2006.

From the Department of Neurology (G.T., K.Spengos, D.V.), University of Athens, Eginition Hospital, Athens, Greece; and the Acute Stroke Unit
(K.V., C.P., E.M., K.Stamatelopoulos, N.Z.), Department of Clinical Therapeutics, University of Athens, Alexandra Hospital, Athens, Greece.
Correspondence to Georgios Tsivgoulis, MD, Iofontos 2, 11634 Athens, Greece. E-mail tsivgoulisgiorg@yahoo.gr
2006 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

DOI: 10.1161/01.STR.0000226399.13528.0a

1913
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by MARIA BELLADONNA on January 4, 2015

1914

Stroke

July 2006

Follow-Up
For the needs of the present study only cases fulfilling the following
conditions were recruited (n253): (1) first-ever IS; (2) ultrasonographic measurements of the CCA-IMT (patients who succumbed
during the first 1 to 2 days after admission or patients with unavailable
CCA-IMT measurements because of technical reasons were excluded);
(3) white origin. Secondary stroke prevention therapies (lipid-lowering,
antidiabetic and antihypertensive medications, antiplatelet agents, oral
anticoagulants) were administered in the entire cohort in keeping to the
European Stroke Initiative recommendations.14 All surviving patients
were followed-up prospectively at 1 month, 3 months, 6 months and
every 6 months thereafter by a study investigator and a trained nurse by
as previously reported.15 Follow-up was routinely performed at the
outpatient clinics of our institution. When patients failed to attend their
regular follow-up assessments at the hospital, they were contacted by
telephone calls. Furthermore, we conducted a face-to-face examination
in the patients place of residence in cases with severe residual handicap
and in patients who missed 2 or more scheduled consecutive follow-up
evaluations. The outcome events of interest was recurrent stroke,
defined as cerebrovascular events of sudden onset, lasting for
24 hours, clearly resulting in an increase of an existing or in a new
neurological deficit.15 They were determined after evaluation of all
the available information obtained from hospital records, physicians
notes in private practice, necropsy findings or death certificates, and
the patients clinical presentation at the regular follow-up assessments. A total of 15 patients who were lost during the follow-up
period (8 cases after having moved from their initial place of
residence failed to attend the follow-up evaluations and to return the
telephone calls, 3 cases of immigrant workers returned to their
country of origin in the first months following the index event, 4
cases declined to continue either the clinical or the telephone
follow-up evaluations without providing any specific reasons) were
excluded from further evaluation.

of intracerebral hemorrhage and 4 cases with unspecified type of

recurrence because of lack of follow-up brain imaging) were
documented. Patients who experienced recurrent stroke were
significantly older (P0.035) and had a significantly higher
Baseline Characteristics, Stroke Subtypes, Secondary
Prevention Therapies and Carotid Ultrasonographic
Measurements in Patients With and Without Recurrent Stroke
Stroke Recurrence

Variable

Yes
(n27)

No
(n211)

Baseline Characteristics
Age
Male sex
Body mass index
(kg/m2)

71.2 (11.5)

66.5 (10.8)

0.035

60.7

0.546

66.7
26.9 (3.3)

27.0 (2.5)

0.900

Hypertension

81.5

64.5

0.078

Diabetes mellitus

29.6

28.4

0.897

Hypercholesterolemia

33.3

30.8

0.789

Smoking

25.9

37.0

0.260

Alcohol intake

11.1

8.1

0.590

CHD

29.6

15.2

0.048

Atrial fibrillation

18.5

20.4

0.821

3.7

2.8

0.574

25.9

10.0

0.015

LAA

29.6

24.2

0.536

CE

29.6

25.1

0.613

Heart failure
TIAs
Stroke Subtypes

Statistical Analysis
Statistical comparisons were performed between patients with and
without recurrent stroke in terms of demographic features, stroke risk
factors, secondary prevention therapies and carotid ultrasonographic
measurements using the 2 test (or the Fisher exact test) and the unpaired
t test (or MannWhitney U test) as indicated. We also used ANCOVA
(analysis of covariance) to compare the mean CCA-IMT between the 2
stroke subgroups, after adjusting for baseline characteristics.
To evaluate which factors contribute to long-term recurrence, we
performed Cox proportional hazards analyses. In the initial univariate
analyses the association of demographic characteristics, stroke risk
factors and subtypes, secondary prevention therapies and CCA-IMT
with stroke recurrence was investigated. All factors that contributed to
the outcome in the initial univariate analyses at P0.1 were included in
the multivariate model as candidate variables and then removed by
backward stepwise selection procedure. In the final multivariate analyses, statistical significance was achieved if P0.05. To confirm the
robustness of multivariate models, we repeated all multivariate analyses
using a forward-selection procedure. Associations are presented as
relative risks (RR) with corresponding 95% CI. Kaplan-Meier curves of
groups of stroke patients stratified by CCA-IMT tertiles are also
presented and survival free of stroke recurrence is compared between
the 3 subgroups using the log-rank method. The Statistical Package for
Social Science (SPSS Inc, version 10.0 for Windows) was used for
statistical analyses.

Results
The final studied population fulfilling all the above-mentioned
inclusion criteria consisted of 238 first-ever IS patients. The
distribution of IS subtypes was as follows: LAA 24.8% (n59),
CE 25.6% (n61), LAC 29.4% (n70) and IUC 20.2%
(n48). During the follow-up period (mean: 28.9 months, range:
6 to 60 months), 51 (21.4%) deaths and 27 (11.3%) recurrent
cerebrovascular events (21 cases of IS [8 cases of LAA, 5 cases
of IUC, 4 cases of CE and 4 cases of lacunar infarction], 2 cases

LAC

25.9

29.9

0.673

IUC

14.8

20.9

0.462

0.641

Secondary Prevention
Therapies
Antiplatelet agents

85.2

81.5

Oral anticoagulants

14.8

18.5

0.641

Lipid-lowering
medications

33.3

30.8

0.789

Blood sugarlowering
medications

29.6

28.4

0.897

Diuretics

35.7

41.9

0.532

7.1

15.7

0.229

Calcium antagonists

17.9

20.5

0.746

Angiotensin-converting
enzyme inhibitors

35.7

27.6

0.373

Angiotensin II receptor
blocker

3.6

11.0

0.223

Direct vasodilator

7.1

1.0

0.538

-blocking agents

Carotid Ultrasonographic
Measurements
CCA-IMT (mean, 95% CI)

1.03 (0.941.12)

0.86 (0.830.90)

0.002

Adjusted CCA-IMT
(mean, 95% CI)*

1.01 (0.921.11)

0.88 (0.850.91)

0.005

Continuous variables are presented as mean (SD), unless stated. Noncontinuous variables are presented as percentages.
*CCA-IMT values were adjusted for baseline characteristics by means of
analysis of covariance (ANCOVA).

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Tsivgoulis et al
frequency of coronary heart disease (CHD; P0.048) and of
transient ischemic attacks (TIAs; P0.015) before the IS in
comparison to subjects with no recurrent stroke during the
observation period (Table). Patients in the recurrence group had
significantly (P0.005) higher CCA-IMT values (1.01 mm,
95% CI: 0.92 to 1.11 mm) than subjects who were free of stroke
recurrence (0.88 mm, 95% CI: 0.85 to 0.91 mm) even after
adjustment for demographic characteristics and stroke risk
factors.
The association of baseline characteristics, stroke subtypes,
secondary prevention therapies and CCA-IMT with stroke recurrence was evaluated using univariate Cox proportional hazards analyses. The following variables were significantly related
to stroke recurrence and were therefore selected for entry into the
final multiple-variable model: age (RR per 10-year increase:1.83, 95% CI: 1.21 to 2.75; P0.004), CHD (RR: 2.59,
95% CI: 1.13 to 5.94; P0.024), hypertension (RR:2.13, 95%
CI: 0.91 to 5.12; P0.098), history of TIAs (RR: 2.82, 95% CI:
1.19 to 6.67; P0.018), CCA-IMT (RR per 0.1 mm increase:
1.20, 95% CI: 1.08 to 1.34; P0.001). The multivariate Cox
regression analyses (performed both with the backwardselection and forward-selection procedure) revealed only increasing age (RR per 10-year increase: 2.31, 95% CI: 1.23 to
4.34; P0.009), history of TIAs (RR: 3.15, 95% CI: 1.10 to
9.01; P0.033) and increasing CCA-IMT as independent outcome predictors. For each increment of 0.1 mm in CCA-IMT the
probability of experiencing recurrent stroke increased by 18.0%
(95% CI: 2.0% to 36.0%; P0.027). Kaplan-Meier curves of
groups stratified by CCA-IMT tertiles are presented in the
Figure. Subjects with CCA-IMT measurements within the lower
tertile had the lowest recurrence rate in comparison to the
subgroups of patients with CCA-IMT values within the median
or higher CCA-IMT tertile (log rank test: 18.83; P0.0001).
Because CCA-IMT is a marker of atherosclerosis and has
not been associated with a cardiac source of embolism, we
repeated all cox regression analyses after having excluded the
CE subgroup. A more robust relationship between increased
CCA-IMT and the risk of recurrent stroke (RR per 0.1 mm

CCA-IMT and Stroke Recurrence

1915

increase: 1.27, 95% CI: 1.11 to 1.46; P0.003) was documented. Moreover, we included the patients who were lost
during the follow-up period in the multivariable Cox proportional hazards model and performed the analyses based on the
worst-case scenario (assuming that all 15 patients had experienced recurrent stroke). The association between CCA-IMT
and stroke recurrence retained its statistical significance (RR
per 0.1 mm increase: 1.15, 95% CI: 1.01 to 1.42; P0.042).
Finally, the relationship between CCA-IMT and the different
recurrent IS subgroups was investigated separately for each
subtype of cerebral infarction. Increased CCA-IMT was an
independent predictor of recurrent LAA stroke (RR per
0.1 mm increase: 1.25, 95% CI: 1.03 to 1.53; P0.020),
whereas its association with recurrent LAC (P0.134), CE
(P0.578) and IUC (P0.369) failed to reach the level of
statistical significance.

Discussion
To the best of our knowledge, no previous study has assessed the
prognostic impact of CCA-IMT in predicting stroke recurrence
after adjusting for established cardiovascular risk factors, stroke
subtypes and secondary prevention therapies. Carotid IMT has
been associated with incident cardiovascular4 and cerebrovascular disease5 in previously healthy people. Moreover, 2 studies
have identified CCA-IMT as an independent predictor of recurrent cardiovascular disease in patients who had undergone
coronary artery bypass surgery16 or had prevalent CHD.17 It
should be noted though that the association between CCA-IMT
and stroke recurrence was not investigated in any of the former
studies. Hence, the present analyses confirm and extend the
findings of previous investigations regarding the prognostic
significance of CCA-IMT.
Interestingly, we also noted that increased CCA-IMT correlated more strongly with the risk of recurrent LAA stroke than
with other IS subtypes. Because CCA-IMT is a marker of the
total atherosclerotic burden of the vascular tree,1,3,12 it is conceivable that increased CCA-IMT values may reflect a higher
risk of recurrent IS caused by an underlying atherothrombotic

Kaplan-Meier curves of patients surviving

free from stroke recurrence according to
tertiles of CCA-IMT values.

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1916

Stroke

July 2006

mechanism. However, the limited number of patients in the

subgroups of recurrent IS should be taken into consideration
when interpreting our data.
Increased CCA-IMT values have been related to a variety of
vascular risk factors such as older age, hypertension, diabetes
mellitus, hyperlipidemia and cigarette smoking.2 Thus, it can be
argued that if IMT reflects exposure to cardiovascular risk
factors, it can be considered as an intermediate factor in the
causal pathway between risk factors and stroke. Interestingly, in
our report increasing CCA-IMT values remained an independent
predictor of stroke recurrence after adjustment for conventional
risk factors. This suggests that besides being an intermediate
phenotype between vascular risk factors and cerebrovascular
disease, CCA-IMT may be a risk factor itself. In favor of this
assumption is the strong evidence supporting a genetic component to IMT variability, with genetic factors contributing to 38%
of the interindividual differences in IMT.18
Finally, certain limitations of the present report should be
addressed. First, a number of risk factors like smoking and
hypertension were defined as binary variables although duration
and severity are important. Second, the potential observers bias
during follow-up, affecting the documentation of recurrent
cerebrovascular events, represents an additional limiting factor
of our study. Of note though, the recurrent strokes were mostly
devastating or fatal (8 cases) and in most cases confirmed by
means of hospital records, brain imaging and autopsy findings.
Third, although the same experienced sonographer performed
the IMT studies, it should be acknowledged that they were
conducted by a hand-held transducer and not by semi-automated
software. Fourth, association does not meet causality and our
study having an observational nature cannot prove a causal
relationship of CCA-IMT with stroke recurrence.
In the present study we provide evidence that increased
CCA-IMT is an adverse prognostic factor for recurrent stroke
in addition to established cardiovascular risk factors. New
therapeutic approaches to carotid atherosclerosis underline
the potential clinical implications of our work. Antihypertensive drugs (especially angiotensin-converting enzyme inhibitors, and -blockers) and statin treatment have been shown
to reduce the development of atherosclerosis measured as
CCA-IMT.19 Thus, CCA-IMT may be a useful noninvasive
adjunctive tool in assessing the risk of recurrent stroke and in
distinguishing IS patients that may benefit the most from
more aggressive secondary prevention treatment strategies.

Acknowledgments
The authors would like to thank Miss Mary Batsara for her valuable
help in data collection.

Disclosures
None.

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Common Carotid Artery Intima-Media Thickness and the Risk of Stroke Recurrence
Georgios Tsivgoulis, Konstantinos Vemmos, Christos Papamichael, Konstantinos Spengos,
Efstathios Manios, Kimon Stamatelopoulos, Demetrios Vassilopoulos and Nikolaos Zakopoulos
Stroke. 2006;37:1913-1916; originally published online May 25, 2006;
doi: 10.1161/01.STR.0000226399.13528.0a
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2006 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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