Accepted Manuscript

Carotid atherosclerosis and risk for ischemic stroke in patients with atrial fibrillation on
oral anticoagulant treatment

Cecilia Becattini, Francesco Dentali, Giuseppe Camporese, Agnese Sembolini, Elena

Rancan, Chiara Tonello, Giorgia Manina, Seena Padayattil, Giancarlo Agnelli

PII: S0021-9150(18)30052-2
DOI: 10.1016/j.atherosclerosis.2018.02.004
Reference: ATH 15375

To appear in: Atherosclerosis

Received Date: 4 March 2017

Revised Date: 27 December 2017
Accepted Date: 2 February 2018

Please cite this article as: Becattini C, Dentali F, Camporese G, Sembolini A, Rancan E, Tonello
C, Manina G, Padayattil S, Agnelli G, Carotid atherosclerosis and risk for ischemic stroke in
patients with atrial fibrillation on oral anticoagulant treatment, Atherosclerosis (2018), doi: 10.1016/
j.atherosclerosis.2018.02.004.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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 ACCEPTED MANUSCRIPT
CAROTID ATHEROSCLEROSIS AND RISK FOR ISCHEMIC STROKE IN PATIENTS WITH ATRIAL

FIBRILLATION ON ORAL ANTICOAGULANT TREATMENT

Cecilia Becattini 1, Francesco Dentali2, Giuseppe Camporese3, Agnese Sembolini1, Elena Rancan2,

Chiara Tonello3, Giorgia Manina1, Seena Padayattil 4, Giancarlo Agnelli1

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1
Internal and Cardiovascular Medicine-Stroke Unit, University of Perugia, Italy. 2Internal Medicine,

University of Insubria, Varese, Italy. 3Unit of Angiology, University Hospital of Padua, Italy.

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4
Cardiology Unit, University Hospital of Padua, Italy.

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Running head: Carotid atherosclerosis and atrial fibrillation
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Keywords Atrial fibrillation, carotid atherosclerosis, carotid stenosis, stroke, anticoagulants
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Word count for the abstract 248

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Word count for the main text 2564

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Total number of figures and tables: 2 Tables 1 figure

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Address for correspondence: Cecilia Becattini, M.D.

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Internal and Cardiovascular Medicine - Stroke Unit

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University of Perugia
cecilia.becattini@unipg.it
Phone 0039.075.5786424
Fax 0039.075.5782436

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Background and Aims Whether carotid atherosclerosis is associated with an increased risk for

ischemic stroke in patients with atrial fibrillation (AF) on anticoagulant treatment is undefined. To

explore this association, patients with AF on treatment with vitamin K antagonists were included

in a multicenter, prospective study.

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Methods At inclusion in the study, patients underwent Doppler-Ultrasonography for the

assessment of carotid atherosclerosis and then were prospectively followed. Ischemic stroke or

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transient ischemic attack (TIA) were the primary study outcomes; death and its causes were

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reported.

Results Overall, 587 patients were included in the study. At ultrasonography, 380 patients had

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carotid atherosclerosis (64.7%) and 45 Internal Carotid (ICA) stenosis ≥ 50% (7.7%). During a mean
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follow-up of 41±15 months, 30 patients had an ischemic stroke or TIA (1.49% per patient-year,
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95% CI 0.96-2.03) and 81 patients died (4.01% per patient-year, 95% CI 3.16-4.86). Carotid

atherosclerosis was associated with a significant increase in the risk for the composite of ischemic
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stroke or TIA or death after adjusting for CHA2DS2VASc (6.0% vs. 3.1% patient-year; HR 1.60, 95%
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CI 0.99-2.59; p=0.05). ICA ≥ 50% was associated with a not significant increase in the risk of
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ischemic stroke or TIA (2.05% vs. 1.45% patient-year; HR 1.39, 95% CI 0.42-4.58) or all-cause death

(6.1% vs. 3.8% patient-year; HR 1.66, 95% CI 0.83-3.32).

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Conclusions In patients with AF, carotid atherosclerosis is a predictor for the composite of
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cerebrovascular events or death while on anticoagulant therapy. In patients with AF and carotid

atherosclerosis, the clinical benefit of a more intense antithrombotic treatment should be

evaluated.

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Introduction

Atrial fibrillation (AF) is associated with increased morbidity, mortality and utilization of health

services (1-3). AF is an independent risk factor for stroke as it increases the annual risk for this

event by fivefold. AF accounts for approximately 15% of all strokes (3).

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Age of 65 years or higher, hypertension, diabetes, congestive heart failure and history of stroke or

transient ischemic attack (TIA) are independent risk factors for ischemic stroke, TIA or systemic

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embolism in patients with AF (4-5). More recently, female gender and history of ischemic heart

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disease, peripheral artery disease and aortic plaque were claimed to be additional risk factors for

stroke or systemic embolism in AF patients (2,6-7). These factors have been included in clinical

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models for the assessment of the risk of stroke or systemic embolism in patients with AF (8-9).
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CHADS2 (Congestive heart failure, Hypertension, Age 75 or older, Diabetes and Stroke) and
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CHA2DS2-VASc (Congestive heart failure, Hypertension, Age 75 or older, Diabetes, Stroke, Vascular

diseases, Age 65 to 74 and Sex) scores are the most commonly recommended models for the
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assessment of the risk for stroke or systemic embolism in patients with AF and they are currently
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used to tailor the indication for anticoagulant therapy (10-11).

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Warfarin reduces ischemic stroke by 64% (range 49 to 74%) compared with no treatment or

placebo (12). Despite anticoagulant treatment, patients with AF have a residual risk for stroke or
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systemic embolism. Identification of patients at high risk for stroke despite anticoagulant
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treatment remains crucial to optimize clinical management and improve patients’ outcome.

Carotid atherosclerosis is an independent risk factor for ischemic stroke (13-14). Patients with

asymptomatic carotid stenosis have an increased risk of ipsilateral ischemic stroke (13). Among AF

patients, those with significant carotid stenosis are more likely to develop ischemic stroke (15). In

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a retrospective study in AF patients on warfarin, carotid stenosis was an independent predictor for

ischemic stroke or TIA (OR 3.0) (16).

We performed a prospective study in AF patients on anticoagulant treatment to assess the role of

carotid atherosclerosis as a risk factor for ischemic stroke, TIA or systemic embolism. The

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incidence of major bleeding was also reported.

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Patients and Methods

Full description of Materials and Methods are available in the online-only Data Supplement

Study design

This is a prospective, multicenter, cohort study. Patient accrual started on October 2010 and

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follow-up was closed on April 2015.

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The study was approved by the Ethical Committee of the Coordinating center.

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Patients

Ambulatory patients with known AF referred to the anticoagulation clinic of the participating

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study centers were eligible for the study. Patients were excluded if they met one of the following
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criteria: not on treatment with vitamin K antagonists from at least 1 month, age lower than 18

years, impossibility to proceed to study centre to undergo carotid ultrasonography or follow-up or

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refusal of written informed consent. No coexisting disease per se was considered an exclusion
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criteria.
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Results
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Study population

Participation in the study was proposed to 687 consecutive patients referred to the anticoagulation clinic of
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the participating study centers. Main reasons for exclusion from the study were impossibility to proceed to
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the study center for ultrasound assessment (bedridden patients) and refusal of consent. Overall, 587

patients were included in the study. More than half of the patients were 75 years of age or over.

About 17% of the patients was on secondary prevention for stroke or systemic embolism and

about 16% had a history of myocardial infarction or angina. A CHA2DS2VASc score of 0 or 1 was

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reported in 15 and 60 patients, respectively. Table 1 reports the main characteristics of the

patients included in the study.

The mean time in therapeutic range (TTR) was 69%±16 (data available for 414 study patients).

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Findings at carotid ultrasonography

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At ultrasonography, 380 patients had carotid atherosclerosis (64.7%, 95% CI 60.9 to 68.6), that

was bilateral in 312.

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Internal Carotid Artery (ICA) stenosis of at least 50% was found in 45 patients (7.7%; 95% CI 5.5 to

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9.8), 20 in the right (3.4%) and 30 in the left side (5.1%); five patients had ICA occlusion (0.9%).
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Bilateral ICA stenosis was diagnosed in five patients.

The prevalence of either carotid stenosis or carotid atherosclerosis increased by CHADS2 (p=0.002)
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and CHA2DS2VASc (p=0.003) scores (Table 1). Increasing age, a history of previous stroke, transient
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ischemic attack (TIA) or ischemic heart diseases were independent predictors of ICA stenosis at
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multivariable analysis.
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Study outcome events

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An ischemic stroke or TIA occurred in 30 patients during a mean follow-up of 41±15 months (range
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1 to 73 months), corresponding to an incidence of 1.49% per patient-year (95% CI 0.96-2.03). INR

value at the time of ischemic stroke or TIA was retrieved for 19 events and was within the

therapeutic range (1.8-3.2) in nine, under the therapeutic range in eight and supra-therapeutic in

two patients.

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As five patients also had an episode of systemic embolism, the incidence of stroke or systemic

embolism was 1.59% patient-year (95% CI 1.05-2.14).

An episode of major bleeding occurred in 22 patients (1.10% per patient-year), and it was an

intracranial haemorrhage in 11 patients (0.5% per patient-year). INR value at the time of major

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bleeding was within the therapeutic range (1.8-3.2) in 40% and supra-therapeutic in 20% of the

patients (data available for 12 events).

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Eighty-one patients died during follow-up (4.01% per patient-year, 95% CI 3.16-4.86).

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Carotid ultrasonography and ischemic stroke or TIA
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The incidence of ischemic stroke or TIA was 1.69 and 1.14% per patient-year in patients with

carotid atherosclerosis and in patients without it, respectively (HR 1.46, 95% CI 0.65-3.29); the
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incidence of ischemic stroke or TIA in patients with or without carotid atherosclerosis was similar
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after adjusting for CHA2DS2VASc score (HR 1.19, 95% CI 0.52-2.72).

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The primary outcome, ischemic stroke or TIA, occurred in three patients with carotid stenosis

(2.05% per patient-year) and in 27 patients without it (1.45% per patient-year). These features
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accounted for a not significant increase in the risk of ischemic stroke or TIA in patients with carotid
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stenosis (HR 1.39, 95% CI 0.42-4.58) that disappeared after adjusting for CHA2DS2VASc score (HR
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1.03, 95% CI 0.30-3.45).

The incidence of ischemic stroke or TIA or systemic embolism was numerically higher in patients

with carotid stenosis as compared with patients without it (2.71 vs. 1.51% per patient-year; HR

1.78, 95% CI 0.63-5.08) also after adjusting for CHA2DS2VASc score (HR 1.31, 95% CI 0.45-3.81).

Similar figures were obtained concerning the incidence of ischemic stroke or TIA or systemic

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embolism in patients with and without carotid atherosclerosis (1.14 vs. 1.84% per patient-year;

adjusted HR 1.29, 95% CI 0.54-2.79).

TTR was similar in patients with and without carotid stenosis (70±15 vs 69±17) or atherosclerosis

(69±16 vs 68±17). No association was found between the incidence of ischemic stroke or TIA and

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TTR (mean values 69±30 vs 68±16 in patients with and without ischemic stroke or TIA,

respectively). The study results were confirmed after adjusting for TTR.

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Carotid ultrasonography and secondary outcome events

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Carotid atherosclerosis was associated with death (HR 1.99, 95% CI 1.12-3.51) and with all
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composite outcomes including this event (Table 2); in particular, the presence of carotid

atherosclerosis is associated with an increase of 73% in the risk for ischemic stroke or TIA or death
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after adjusting for CHA2DS2VASc and TTR (HR 1.73, 95% CI 1.07-2.79) (Figure).
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A higher incidence of death was observed in patients with carotid stenosis (6.1% vs. 3.8% per
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patient-year; HR 1.66, 95% CI 0.83-3.32). Carotid stenosis was associated with IHD and with all

composite study outcomes that included this event; however, these associations missed statistical
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significance after adjusting for CHA2DS2VASc and TTR (Table 2).

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No change in the results was observed after adjusting for the use of statins or antiplatelet agents.
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Discussion

We found that the prevalence of carotid atherosclerosis and carotid stenosis is relatively high in

patients with AF on anticoagulant treatment. In these patients, both these findings are associated

with a not significant increase in ischemic stroke or TIA. Carotid atherosclerosis is an independent

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predictor of death and of several combined cardiovascular event-based endpoints including death.

Carotid stenosis is an independent predictor of ischemic heart disease (IHD).

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In 2010, the CHA2DS2VASc score was introduced in clinical practice as it was claimed to be more

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effective than the original CHADS2 score for stroke-risk stratification in patients with non-valvular

AF (8). Ischemic heart disease, aortic plaques, peripheral artery diseases and not carotid plaques

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are included in the definition of vascular diseases in the CHA2DS2VASc score.
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Carotid atherosclerosis was associated with an about 2-fold increase in the risk for death in AF
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patients on anticoagulant treatment. A similar association was found between carotid

atherosclerosis and death or death plus ischemic stroke or TIA; these associations were confirmed
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after adjusting for CHA2DS2VASc and TTR. These findings suggests that the presence of carotid
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atherosclerosis rather than the severity of the stenosis could be a marker of increased
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cardiovascular risk. In this view, our findings are consistent with those from the ARIC study in

which an association was found between the presence of carotid plaque (regardless of the degree
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of obstruction) and ischemic events (23) and with those of a recent Italian study (24).
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Carotid stenosis is an independent risk factor for ischemic stroke in the general population (13-14).

The reported incidence of ipsilateral stroke or death in patients with asymptomatic carotid

stenosis of 60% or higher managed by medical therapy is 11% at 2 years (25). Limited data are

currently available on the prevalence of carotid stenosis in patients with AF. In a recent analysis of

724 patients included in the Atherosclerosis Risk in Communities (ARIC) study who developed AF

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within 5 years and with no history of stroke, the prevalence of carotid plaques was 38% (23). In

our cohort of ambulatory AF patients, we found a 65% prevalence of carotid plaques. This higher

prevalence can be explained by the higher prevalence of cardiovascular comorbidities in our study

population as compared to that of the ARIC study. Moreover, the prevalence of carotid

atherosclerosis increases with age; our patients were about 10 years older than those included in

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the ARIC study. The 7.7% prevalence of carotid stenosis observed in our study is lower than the 20

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to 25% prevalence reported in two different studies in ischemic stroke patients with AF (16, 26).

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In patients with AF, an association was claimed between carotid atherosclerosis and the risk of

ischemic stroke (23-24, 27). Carotid plaque was associated with an increased risk for stroke in the

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subgroup of patients from the ARIC study who developed AF (HR 1.56, 95% CI 1.00-2.45 after
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adjusting for CHA2DS2VASc) (23). In patients with AF admitted for an ischemic cerebral event

occurring during anticoagulation within the therapeutic range, high-grade stenosis of the
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extracranial carotid or vertebral arteries was claimed to be an independent predictor for stroke
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(OR 3.0; 95% CI 1.13–8.41, p = 0.028) (16). In a subgroup of patients form the retrospective
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FibStroke registry, carotid stenosis as assessed by computed tomography or angiography was

associated with recurrent ischemic stroke (27). These studies differed concerning their
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experimental design (population study, prospective cohort, case-control), study populations

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(primary prevention mainly at low risk vs. secondary prevention) and criteria for the assessment of
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atherosclerosis. Moreover, in one of these studies, only about 60% of patients were on anticoagulant

treatment and no data on TTR was reported (24). Thus, the association between carotid stenosis and

outcomes found in that study could be influenced by suboptimal antithrombotic therapy. The FibStroke

registry included all consecutive patients with diagnosed AF (about 4% with concomitant heart valve

prosthesis) who suffered a stroke or intracranial bleeding during the study period (27). In our study, the

use of anticoagulant treatment in all the study patients and the more common use of statins and
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antiplatelets in patients with carotid atherosclerosis as compared with patients without it could

have accounted for a reduced risk for stroke or TIA. In this view, the apparent reduction of the

association between carotid atherosclerosis and outcomes after adjusting for TTR could suggest

that a good quality of anticoagulation may protect against ischemic outcomes also in patients with

carotid atherosclerosis.

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We found a not significant 40% increase in the risk of stroke or TIA in AF patients at moderate to

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high risk for stroke (according to CHADS2 and/or CHA2DS2VASc scores) on anticoagulant treatment

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and carotid stenosis of at least 50%. The non-high prevalence of this high-grade carotid stenosis

and the low rate of stroke observed in our study (35 events overall) could have reduced the

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potential to show a significant association between carotid stenosis and ischemic stroke.
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Moreover, the optimization of cardiovascular prevention (statins or antiplatelets) could have

contributed to reduce the risk of stroke or TIA in AF patients with carotid atherosclerosis and/or
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stenosis.
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In our study, carotid stenosis was associated with an incidence of IHD. Although this association is
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biologically plausible and is consistent with previous findings, it disappeared after adjusting for
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other predictors (28-29).

Our study has several limitations and some strengths. Firstly, study patients were recruited among
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those referred to the anticoagulation clinics of the study centers and were mainly ambulatory AF
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patients able to undergo carotid ultrasonography. Thus, our study population could be not

representative of the overall spectrum of AF population. However, the low proportion of patients

with low CHA2DS2VASc score excludes the selection of a low-risk population. Secondly, during the

study period, 30 ischemic stroke or TIA occurred. Although the annual incidence of events is

consistent with currently expected rates during anticoagulant treatment, the number of events is

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lower than expected and does not allow adjustment for all identifiable confounders (e.g. the use

of statins or antiplatelet agents). Thirdly, we report the incidence of study outcome events as

assessed by local investigators without central adjudication. This methodology is currently

accepted in several contemporary studies provided the use of validated and internationally

recognized definitions of events. For the purpose of this study, we used the definition of stroke or

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systemic embolism reported in international guidelines (20).

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The strengths of our study are the prospective design, the duration of follow-up and the sample

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size. As documented by the incidence of stroke or systemic embolism observed in the study, our

population probably was receiving the optimal medical treatment (anticoagulation, statins,

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antiplatelet agents, treatment for hypertension, etc) for the prevention of cardiovascular events.
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The inclusion in a study focused on cardiovascular events and the follow-up at centers dedicated

to cardiovascular diseases could have further improved the standard of care.

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In conclusion, the presence of carotid atherosclerosis is associated with a modest increase in the
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risk for stroke or systemic embolism in AF patients on anticoagulant treatment.The finding of the
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the increased risk for IHD in patients with carotid stenosis deserves attention although it is unclear
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whether it justifies an upgrading in antithrombotic treatment such as associating antiplatelet to

anticoagulant treatment.
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Conflict of Interest

None of the authors has conflict of interest to disclose for the present study.

Financial support

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Dr Giorgia Manina received a Research Grant for this study by the Società Italiana di Medicina

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Interna on October 2012.

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Author contributions

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Cecilia Becattini, Giorgia Manina and Giancarlo Agnelli contributed to the conception of the study

design, starting procedures, analysis and interpretation of the results, writing the preliminary draft
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of the manuscript.
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Francesco Dentali, Giuseppe Camporese, Agnese Sembolini, Elena Rancan, Chiara Tonello, Seena
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Padayattil contributed in recruiting patients, performing study procedures, interpretation of the

results, critical revision of study manuscript.

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Table 1 Main features of the overall study population and of the subgroups of patients with or without carotid atherosclerosis and with or

without carotid stenosis

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Carotid atherosclerosis ICA stenosis
All
Patients
patients
Present Absent Adjusted OR Present Absent Adjusted OR

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features p-
N = 587 p- value
N= 380 N= 207 (CI 95%) N = 45 N = 542 value (CI 95%)

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Age years, mean ±SD 74.5±9 76±8 72±10 <0.001 1.05 (1.02-1.07) 78±8 74±9 0.008 1.05 (1.01-1.1)

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243 159 (41.8) 84 (40.6) Ns --
Female sex, n (%) 19 (43.2) 224 (41.3) Ns --

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(41.4)

443 293 (77.3) 150 (72.8) Ns --

Hypertension, n (%) 37 (84.1) 406 (74.8) Ns --

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(75.5)

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101 90 (23.7) 27 (13.0) 0.002 1.9 (1.2-3.1)
Diabetes, n (%) 12 (27.3) 89 (16.4) Ns --
(17.2)

Chronic heart failure,

n (%)
109
(18.5)
76 (20.0) 33 (15.9)
TE Ns -- 11 (24.4) 98 (18.1) Ns
EP
130 96 (25.3) 34 (16.4) 0.14 --
Statin use, n (%) 15 (34.1) 115 (21.2) Ns --
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(22.1)
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Antiplatelets, n (%) 46 (7.8) 33 (8.7) 13 (6.3) Ns -- 6 (13.6) 40 (7.4) Ns --

Hypercholesterolemia 162 99 (26.1) 44 (21.3) Ns -- 15 (34.1) 147 (27.1) Ns --

, n (%) (27.6)

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Previous stroke/TIA, n 80 (21.1) 19 (9.2) <0.001 2.2 (1.3-3.8)

99 (16.9) 14 (31.8) 85 (16.7) 0.01 2.0 (1.1-4.1)
(%)

Ischemic Heart 72 (18.9) 20 (9.7) 0.003 1.7 (1.0-3.0) <0.00

86 (14.7) 17 (38.6) 69 (12.7) 3.8 (2.0-7.3)
Disease, n (%) 1

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CHA2DS2VASc, 3.7±1.7 3.0±1.7 <0.001 -- <0.00

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3.5±1.7 4.6±1.7 3.4±1.7
mean ±SD 1

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Table 2 Association between carotid stenosis and study outcome events and between carotid atherosclerosis and study outcome events.

Carotid stenosis Carotid atherosclerosis

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Clinical Outcome HR 95% CI p-value HR 95% CI p-value

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Ischemic stroke or TIA 1.39 0.42-4.57 Ns 1.48 0.66-3.33 Ns

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Any stroke or TIA 1.02 0.31-3.30 Ns 1.38 0.69-2.76 Ns

IHD 2.93 1.00-8.63 0.05* 2.22 0.75-6.54 Ns

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Death univariate 1.66 0.83-3.32 Ns 2.36 1.36-4.13 0.003

Adjusted for CHA2DS2VASc 1.20 0.59-2.43 Ns 1.99 1.12-3.51 0.018

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Ischemic Stroke or TIA or death 1.40 0.73-2.69 Ns 1.88 1.17-3.02 0.009

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Adjusted for CHA2DS2VASc

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1.09 0.56-2.13 Ns 1.73 1.07-2.79 0.025

Ischemic stroke or TIA or IHD 2.16 1.02-4.56 0.04* 1.56 0.85-2.85 Ns

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Ischemic stroke/TIA or IHD or death 1.76 0.99-3.14 0.06* 1.96 1.24-3.07 0.04
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Adjusted for CHA2DS2VASc 1.41 0.78-2.55 Ns 1.77 1.12-2.80 0.015

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1.71 0.96-3.05 Ns 2.00 1.28-3.14 0.003

Any stroke/TIA or IHD or death
1.38 0.76-2.48 Ns 1.82 1.15-2.87 0.010

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Adjusted for CHA2DS2VASc

Major bleeding 0.61 0.08-4.56 Ns 1.85 0.68-5.02 Ns

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RI
*the correlation missed statistical significance after adjusting for age or CHA2DS2VASc and TTR

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Figure – Risk for ischemic stroke or TIA or death in patients with and without carotid

atherosclerosis

Patients with carotid atherosclerosis are represented as a dotted line and patients without carotid

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atherosclerosis are represented as a continuous line.

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CAROTID ATHEROSCLEROSIS AND THE RISK FOR ISCHEMIC STROKE IN PATIENTS WITH ATRIAL

FIBRILLATION ON ORAL ANTICOAGULANT TREATMENT

Cecilia Becattini 1, Francesco Dentali2, Giuseppe Camporese3, Agnese Sembolini1, Elena Rancan2,

Chiara Tonello3, Giorgia Manina1, Seena Padayattil 4, Giancarlo Agnelli1

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1
Internal and Cardiovascular Medicine-Stroke Unit, University of Perugia, Italy. 2Internal Medicine,

University of Insubria, Italy. 3Unit of Angiology, University Hospital of Padua, Italy. 4Cardiology

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Unit, University Hospital of Padua, Italy.

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Running head: Carotid atherosclerosis and atrial fibrillation
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Keywords Atrial fibrillation, carotid atherosclerosis, carotid stenosis, stroke, anticoagulants
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Word count for the abstract 248

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Word count for the main text 2564

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Total number of figures and tables: 2 Tables 1 figure

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Address for correspondence: Cecilia Becattini, M.D.

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Internal and Cardiovascular Medicine - Stroke Unit

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University of Perugia
cecilia.becattini@unipg.it
Phone 0039.075.5786424
Fax 0039.075.5782436
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Highlights

• In patients on anticoagulant treatment for atrial fibrillation (AF), carotid atherosclerosis is

highly prevalent.

• Carotid atherosclerosis is associated with an increased risk for death or ischemic stroke or

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transient ischemic attack (TIA) in AF patients on anticoagulant treatment, after adjusting

for CHA2DS2VASc and time in therapeutic range.

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• Carotid stenosis is associated with a not significant increase in the risk for ischemic stroke

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or transient ischemic attack (TIA) in AF patients on anticoagulant treatment

• The clinical benefit of a more intense antithrombotic treatment should be evaluated in

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patients with AF and carotid atherosclerosis.
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