675229

research-article2017
VMJ0010.1177/1358863X16675229Vascular MedicineCaron and Anand

CME Review Article

Vascular Medicine

Antithrombotic therapy in aortic 2017, Vol. 22(1) 57­–65

© The Author(s) 2017
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diseases: A narrative review sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1358863X16675229
vmj.sagepub.com

Francois Caron1,2 and Sonia S Anand1,2

CME Accreditation Statement

The University of Virginia School of Medicine designates this journal-based CME activity for a maximum of 1 AMA PRA Category
1 Credit™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Learners are expected to read this article along with any references and supporting material as appropriate, and complete the
online post-test questions with an 80% pass rate to receive credit. Post-test questions are accessed through the member portal
on the Society for Vascular Medicine (SVM) website (www.vascularmed.org). Please note that CME credits are only available to
members of the SVM. This activity expires two years after the publication date, on February 13, 2019.

Disclosures
The faculty, staff and planning committee of the University of Virginia Office of Continuing Medical Education have no financial
affiliations to disclose.
The CME planning committee of Vascular Medicine disclosed the following:
Heather Gornik: Astra Zeneca, research support; Summit Doppler Systems, Inc., intellectual property rights; FlexLife Health,
­intellectual property rights and stock/ownership (proceeds donated).
Aditya Sharma: National Institute of Health Sciences, research support; AstraZeneca, research support; Biomet Biologics,
research support; Portola Pharmaceuticals, research support; Pedra Technology, research support.
Valerie Clark: None.

Abstract
Aortic diseases are a heterogeneous group of disorders, including atherothrombotic conditions like aortic atheroma,
cholesterol embolization syndrome, aortic mural thrombus, thrombus within an aneurysm, and large vessel vasculitis. In
this review, we provide a summary of the current evidence regarding atherothrombotic diseases of the aorta, focusing on
therapeutic avenues. In patients with previous stroke, aortic arch atheroma is recognized as a strong predictor of recurrent
atheroembolism, and antiplatelet therapy alone is still associated with a high (11.1%) residual risk of recurrent stroke. In
secondary prevention, the use of dual antiplatelet therapy or moderate intensity anticoagulation with warfarin may lower the
risk of recurrent stroke at a cost of increased life-threatening bleeding. Thrombi adherent to the aortic wall are generally
associated with underlying atherosclerosis or aneurysmal disease. Primary aortic mural thrombus is a rare condition,
sometimes related with systemic prothrombotic or inflammatory diseases. Retrospective studies suggest that anticoagulation
is beneficial in patients with mobile mural thrombus. The pathogenesis and consequences of thrombus in an aortic aneurysm,
or in an endograft following endovascular aneurysm repair, have been studied, but the role of antiplatelet therapy in those
two conditions is still unclear and should be driven by general cardiovascular risk prevention. The benefit of anticoagulation
to reduce thrombus load is uncertain. Patients with large vessel vasculitis experience increased cardiovascular events
secondary to inflammation-driven atherothrombotic processes. Antiplatelet therapy is recommended as part of the therapy
for prevention of cardiovascular disease. Anticoagulation with warfarin has shown limited benefit in few retrospective studies.

Keywords
aneurysm, anticoagulants, aortic diseases, aspirin, atherosclerosis, review, thrombosis, vasculitis

Case report 1PopulationHealth Research Institute, Hamilton Health Sciences,

A 54-year-old male who was a former smoker, with a his-
tory of hypertension, stage 3 chronic kidney disease and
dyslipidemia, presented with complaints of progressive left
foot pain and discoloration over the past 1 week. On exami-
nation, his vital signs were stable and he was in sinus
rhythm. The popliteal and distal pulses and Doppler signals
were absent in the left extremity. There was marked
McMaster University, Hamilton, Ontario, Canada
2Department of Medicine and Clinical Epidemiology, McMaster
University, Hamilton, Ontario, Canada
Corresponding author:
Sonia Anand, McMaster University, Population Health Research
Institute, Hamilton, 237 Barton St East, Hamilton, ON L8L 2X2, Canada.
Email: anands@mcmaster.ca
58 Vascular Medicine 22(1)
Figure 1.  Supra- and infra-renal aortic mural thrombi (arrows).
(Image reproduced with permission from http://www.angiologist.
com/arterial-disease/mural-thrombus/.)
cyanosis of the left foot digits, with a capillary refill
increased over 5 seconds. The patient had no history of
intermittent claudication, connective tissue disease, throm-
botic disorder or myeloproliferative neoplasm. His medica-
tions were aspirin, ramipril and hydrochlorothiazide, and
rosuvastatin. An echocardiogram showed a normal ejection
fraction and no valvular disease or intracardiac thrombus. A
computed tomography (CT) angiogram revealed an acute
thrombosis of the popliteal artery and an adherent thrombus
in the supra- and infra-renal portions of the abdominal aorta
(arrows in Figure 1). What is the appropriate antithrom-
botic strategy in this patient?
Aortic atheroma
Aortic atherosclerosis involves mechanisms that are in
many ways similar to coronary atherosclerosis, but the
large diameter of the vessel and generous arterial blood
flow allows larger plaques to protrude into the arterial
lumen long before occluding it.1 Vulnerable plaques in the
aorta can remain clinically silent for long periods of time,
as demonstrated by post-mortem studies reporting 8% of
ruptured or ulcerated peri-renal aortic plaques in apparently
healthy organ donors, with increasing prevalence with age.2
Observational data from cardiac surgery, autopsy and
advanced imaging studies demonstrate the presence of
thrombi superimposed on complex or ulcerated aortic
plaques.3,4 This process is well described in patients
with coronary atherosclerosis who present with acute coro-
nary syndromes and undergo coronary angiography.5
Thromboembolism resulting from occlusion of distal arter-
ies by thrombotic material manifests clinically as ischemic
stroke, transient ischemic attack, renal or bowel infarction,
or acute limb ischemia.6,7
Atheromatous disease of the aorta is a relatively com-
mon finding in the general population. The Stroke
Prevention: Assessment of Risk in a Community (SPARC)
study8,9 was a cross-sectional analysis of transesophageal
echocardiography (TEE) in 581 participants over 45 years
of age, and showed a prevalence of simple (<4 mm of
maximal thickness) and complex (⩾4 mm of maximal
thickness) aortic plaques of 51.3% and 7.6%, respectively.
The APRIS study, a prospective cohort study, found a
similar prevalence of aortic arch plaques (62.2%) in 209
stroke-free subjects. The Framingham Offspring Heart
Study performed cardiac magnetic resonance imaging
(MRI) on 1763 participants, of which 200 had cardiovas-
cular disease (CVD). Aortic plaques were identified in
46% of CVD-free participants.10
Risk factors for aortic atherosclerosis include increas-
ing age (odds ratio (OR) 3.56 per 10-year increase; 95%
confidence interval (CI): 2.57–4.92), smoking (OR 2.18;
95% CI: 1.38–3.46), diabetes (OR 2.98; 95% CI: 1.58–
5.61), and hypertension (OR 1.18 per 10 mmHg increase
in out-of-bed systolic pressure; 95% CI: 1.01–1.38).8
Among CVD-free participants of the Framingham
Offspring cohort, the presence of hypertension increased
the risk of thoracic aortic plaques on cardiac MRI three-
fold.10 Increased concentrations of fibrinogen (OR 1.18;
95% CI: 0.96–1.12),11 homocysteine (OR 1.21; 95% CI:
1.05–1.41)12 and an elevated peripheral leukocyte count13
(adjusted OR 1.38; 95% CI: 1.05–1.79 per unit increase
in leukocyte count) have also been associated with aortic
atherosclerosis but may represent markers rather than
mediators of this disease process.
Aortic atherosclerosis has been associated with CVD
in studies using various methods for diagnosis. In the
SPARC study,8,9 the presence of aortic atherosclerosis
was associated with coronary artery disease (adjusted
OR 2.99; 95% CI: 1.47–6.10; p=0.003), but the associa-
tion with ischemic stroke and transient ischemic attack
was not significant after adjustment. In the APRIS
study,6 the presence of aortic plaques was not associated
with incident myocardial infarction and ischemic stroke.
In the Framingham Offspring Heart Study,10 aortic
plaque prevalence on cardiac MRI was significantly
higher in patients with known CVD and this difference
was more marked for thoracic plaques (relative risk (RR)
2.9; p<0.0001).
Aortic arch disease, due to its proximity with the cere-
bral vessels, has a stronger association with cerebrovascu-
lar disease. In an autopsy study of 500 patients with stroke
or other neurologic diseases, Amarenco and colleagues
reported a strong correlation between the presence of aortic
arch plaques and stroke (26% vs 5%; age-adjusted OR 4.0;
95% CI: 2.1–7.8).14 Ulcerated plaques were found more
frequently in patients with cryptogenic stroke (61% vs
22%). A similar study with TEE found atherosclerotic
plaques with a width of over 4 mm in 14.4% of patients
Caron and Anand 59
admitted for stroke, 28.2% of patients with cryptogenic
stroke, but only in 2% of the controls (OR 9.1; 95% CI:
3.3–27.5; p<0.001).7 In a prospective study of 331 consecu-
tive stroke patients aged 60 or above, the French Study
Group15 found a fourfold increase for stroke recurrence in
patients with aortic plaques of ⩾4 mm in thickness. The
annual incidence of stroke recurrence in that group was
11.9%, despite the fact that more than 70% were treated
with antiplatelet or anticoagulant therapy.
The natural evolution of aortic atheroma over time is
variable, dynamic, and dependent on concomitant dis-
eases (i.e. diabetes), medication use (i.e. statin use), and
risk factors (i.e. smoking, hypertension). In TEE retro-
spective studies, most atheroma remain stable at 1 year,
20–40% progress in size, and regression is observed in
about 10%.16,17 In a prospective MRI study, aortic plaques
regressed by 15% after 6 months of simvastatin 80 mg in
atherosclerotic patients.18 In patients with stroke or tran-
sient ischemic attack, the progression of atheroma is
associated with an increased risk of death or cardiovascu-
lar event (adjusted hazard ratio (HR) 5.8; 95% CI: 2.3–
14.5; p=0.0002).19
Diagnosis of aortic atheroma.  Despite its convenience and
technical progress with harmonic imaging, transthoracic
echocardiography (TTE) has a low sensitivity when com-
pared with other techniques.20,21 In the absence of a gold
standard, calculation of sensitivity can hardly be done, but
when considering TEE as the reference, we approximate
the sensitivity of TTE to be around 62%.21 TEE was tradi-
tionally the most frequently used imaging modality for
imaging of the aortic arch.20–22 A study of pathological cor-
relation23 showed a sensitivity of 91% and a specificity of
90% for identification of thrombus and an agreement of
93% for complex aortic plaque. TEE informs on mobility,
ulceration and composition of the plaque with good reli-
ability (kappa: 0.58–0.87) and has very good inter- and
intra-observer reliability for plaque thickness (intraclass
correlation coefficient: 0.85–0.97).24 Its limitations are the
necessity of conscious sedation and the invasive nature of
the test for patients. Furthermore, a small proportion of the
aortic arch adjacent to the innominate artery is masked by
the tracheal air column, resulting in approximately 2% of
missed atheroma.25
Non-enhanced CT has an 87% sensitivity when com-
pared with TEE, and can identify plaques in the innominate
artery missed by TEE.26 However, it has limited ability to
identify heavily calcified plaques and should be comple-
mented with a TEE or contrast-enhanced CT.
Contrast-enhanced CT and magnetic resonance angiog-
raphy (MRA) provide the most detailed information about
plaque distribution, morphology and composition.27 MRA
has a 100% sensitivity to detect plaques visualized on TEE28
and has an 80% agreement with TEE for plaque characteri-
zation. Technological advances in the precision of CT angi-
ograms and MRAs and their ability to image the innominate
artery make them the modality of choice for imaging of the
aorta and its branches. One common limitation to those two
techniques is their inability to identify a mobile thrombus,
which the TEE can identify very reliably.
Primary prevention.  Given that aortic atheroma is modestly
prevalent in the general population, it is a frequent fortu-
itous finding on imaging tests. Aortic atherosclerosis is cor-
related with CVD in retrospective studies, but whether it is
an independent predictor remains unconfirmed. Recent
guidelines29–33 make no recommendation on how to prevent
CVD in patients with aortic atheroma on imaging. They do,
however, unanimously recommend the use of aspirin in
patients with asymptomatic peripheral artery disease, as
defined by an ankle–brachial index lower than 0.90. Alto-
gether, while the presence of aortic plaques in an asymp-
tomatic patient should not mandate antiplatelet therapy on
its own, it should lower the threshold to initiate it for the
primary prevention of cardiovascular events. Dual anti-
platelet therapy is not recommended in primary prevention
of cardiovascular events, as it is associated with an
increased risk of bleeding without reducing cardiovascular
events in patients with peripheral artery disease34 and cere-
brovascular disease.35 Furthermore, anticoagulation with
warfarin together with antiplatelet therapy is not recom-
mended in primary prevention, as it has been shown to
increase the rate of bleeding with no benefit in ischemic
events when compared with aspirin in patients with periph-
eral artery disease.36
Secondary prevention.  In patients with a previous history
of stroke with thoracic aortic plaques, the results from the
French Study Group suggest a high residual risk of recur-
rence in patients on single antiplatelet therapy.15 The Pat-
ent Foramen Ovale in Cryptogenic Stroke Study (PICSS)37
randomized 516 patients with ischemic stroke to warfarin
or aspirin and followed them over 2 years, evaluating
them at baseline with TEE for aortic plaques. Large
plaques were associated with an increased risk of recur-
rent ischemic stroke or death (HR 2.12; 95% CI: 1.04–
4.32), but event rates were similar in the warfarin and
aspirin groups (16.4% vs 15.8%; p=0.43). Thus, the selec-
tion of antithrombotic therapy in secondary prevention
should be made according to current stroke guidelines,
irrespective of the presence of aortic plaques.38 Thus,
based on the present evidence, short-term dual antiplatelet
therapy is a reasonable option after an acute atheroem-
bolic event for patients at low bleeding risk in whom full
dose anticoagulation with warfarin is not indicated.
Cholesterol embolization syndrome
Atheroembolism, also known as cholesterol crystal embo-
lism, refers to embolization of cholesterol crystals from a
large proximal artery to smaller distal arteries, causing end-
organ damage. The most frequent etiology of cholesterol
embolization syndrome (CES) is instrumentation of the
aorta (i.e. intra-aortic balloon pump, catheter intervention),
which breaks the plaque and releases the cholesterol
emboli.39 The incidence of clinically apparent atheroembo-
lism is less than 1% in patients with documented aortic ath-
erosclerosis and less than 2% in patients undergoing cardiac
catheterization.40 Clinical manifestations of CES are acute
progressive renal failure, gastrointestinal symptoms from
mesenteric infarctions, ‘blue toe’ syndrome and livedo
60 Vascular Medicine 22(1)
Figure 2.  Diagnostic algorithm for acute limb ischemia of thromboembolic origin. (HIT, heparin-induced thrombocytopenia;
APLS, antiphospholipid syndrome; TEE, transesophageal echocardiogram; CTA, computerized tomography-angiogram; aLow level of
evidence.)
reticularis.41 Crystals can be documented in retinal vessels
(Hollenhorst plaques) and contribute to the diagnosis.
Patients with CES have a poor prognosis, with a mortality
rate of 17% to 75%, depending on the absence or presence
of end-stage renal failure, respectively. This high mortality
probably reflects the high baseline risk of the population
who undergo aortic instrumentation.
CES has been reported in association with the use of
anticoagulants such as warfarin.42 However, in contempo-
rary cohorts of patients with aortic plaques, it remains a
very rare event. In three studies including more than 1000
patients,15,43,44 CES occurred in four patients on warfarin
and three patients off warfarin. For that reason, we would
not suggest to hold warfarin in patients with CES and a
clear indication for anticoagulation.
While there is no evidence to use antiplatelet agents to
prevent CES, they are recommended for prevention of car-
diovascular events in patients with known peripheral artery
disease.
Primary aortic mural thrombus
Thrombotic material adherent to the aortic wall is associ-
ated with atherosclerosis or aortic aneurysms in the vast
majority of cases.45,46 Primary aortic mural thrombus occurs
in the absence of the aforementioned conditions, has been
reported in case series,47–50 and is associated in the majority
of cases with systemic conditions like heparin-induced
thrombocytopenia,51,52 antiphospholipid syndrome,53,54
underlying malignancy,55–57 chemotherapy,58,59 myelopro-
liferative neoplasms,46 or thrombophilias.56,60,61
In a retrospective study of 88 patients with acute limb
ischemia, 19 were found to have an underlying aortic mural
thrombus.47 The most frequent sites of thrombus in this
series were the distal aortic arch and descending thoracic
aorta, abdominal aorta and ascending aorta, found in 74%,
14% and 12% of cases, respectively. The patients did not
exhibit the risk factors typically associated with atheroscle-
rotic disease: only 5.3% were smokers and none of the 19
patients had any other comorbidity. Aorta mural thrombi
are also occasionally identified during the investigation of
peripheral arterial embolism. In a large retrospective
cohort,62 the source of acute lower limb ischemia was
embolic in 40% of cases, of which 78% were of cardiac
origin and non-cardiac or unknown embolic sources
accounted for the remaining 22%. In a series of 556 con-
secutive patients undergoing TEE, Karalis and colleagues63
found an aortic thrombus in 7% of the patients. Pedunculated
and highly mobile thrombi were associated with a higher
risk of embolic events (73%) than were layered and immo-
bile thrombi (12%). With the advent of imaging techniques
allowing visualization of the aorta, we estimate that 10% of
non-cardiac emboli originate from the aorta, half from
aneurysmal disease and half from atherothrombosis.64–66
The management of aortic mural thrombi relies largely
upon experience and mechanistic understanding of the dis-
ease, as evidence is limited to case reports. While some
authors suggest that anticoagulation alone is a reasonable
Caron and Anand 61
solution that leads to complete resolution of the mural
thrombus,67,68 other studies report a high risk of recurrence
and suggest a surgical approach in young patients with a
mobile thrombus located in the aorta.45 An analysis of 200
published cases up to 2014 compared surgical manage-
ment with anticoagulation.46 One in four patients initially
anticoagulated required a secondary aortic procedure for
persistent thrombus or recurrent peripheral arterial emboli-
zation, whereas only 4.5% of patients in the primary sur-
gery group required a second procedure. Factors associated
with a higher risk of recurrent embolization were location
of the thrombus in the ascending aorta (OR 12.7; 95% CI:
2.3–38.8) or aortic arch (OR 18.3; 95% CI: 2.6–376.7),
stroke as a presenting symptom (OR 11.8; 95% CI: 3.3–
49.5) and atherosclerotic aortic wall (OR 2.5; 95% CI:
1.0–6.4). Figure 2 suggests a diagnostic and therapeutic
algorithm for patients with acute limb ischemia and aortic
mural thrombus. The duration of antithrombotic treatment
in patients treated with an anticoagulation-only approach
should be guided by the evolution of the thrombus on
repeated imaging and a consideration of the patient’s
bleeding risks. Complete resolution of the thrombus in a
patient without an ongoing prothrombotic condition makes
it a reasonable option to discontinue anticoagulation,
depending on the patient’s clinical risk factors and severity
of presenting thrombosis, and considering the patient’s
values and preferences.
Aortic aneurysm-related thrombus
Abdominal aortic aneurysms (AAAs) are frequently lined
with a layer of intraluminal thrombus.69 This thrombus has
mixed effects on the evolution of the aneurysms. In studies
using CT-generated three-dimensional reconstructions on
the aorta,69 it appeared that the presence of thrombus
reduced wall stress by up to 38%, thus potentially reducing
the risk of rupture. The thrombus was also associated with
further progression of the aneurysm by enhancing the pro-
teolytic process within the aortic wall.70
Whether antiplatelet therapy affects the rate of growth or
rupture of aneurysms is a matter of debate. In a meta-
analysis of individual data from 4137 patients included in
six studies,71 the use of antiplatelet agents was not associ-
ated with a significant difference in the rate of growth of
AAAs after multivariable adjustment (–0.123 mm/year,
standard error 0.106, p=0.24). Furthermore, a Danish case–
control study72 compared 4010 patients with a ruptured
AAA with patients with an unruptured AAA, and found no
difference in the risk of rupture between patients taking
aspirin and those who did not (adjusted OR 0.97; 95% CI:
0.86–1.08). However, the case fatality rate was higher in
patients on aspirin (adjusted RR 1.16; 95% CI: 1.06–1.27).
Endovascular aneurysm repair (EVAR) is gaining in
popularity for the management of AAAs in higher-risk
patients. Mural thrombus develops as a result of rheologic
factors and properties of the device, but whether the pres-
ence of thrombus leads to thrombotic consequences is
uncertain. In a retrospective cohort of 414 post-EVAR
patients, 68 developed thrombus over a median follow-up
of 3.4 years, and were compared with a control group of
patients without thrombus.73 The incidence of peripheral
thromboembolic events did not differ between the group
with thrombus and the group without thrombus (4.4% vs
3.5%, p=0.70). A majority of patients in both groups
received antiplatelet therapy (91.2% vs 85.4%), and a
minority received oral anticoagulation (10.3% vs 15.4%).
Oral anticoagulation at time of implantation was not associ-
ated with the rate of thrombus accumulation in the endo-
graft (HR 0.63; 95% CI: 0.27–1.46). These results do not
support intensification of antithrombotic therapy in patients
with mural thrombus within an aortic endograft.
In patients with AAA and post-EVAR, general cardio-
vascular risk prevention should be the main driver of anti-
platelet therapy prescription. The high prevalence of
atherosclerosis in other vascular beds warrants single anti-
platelet therapy for patients without contraindications.
Large vessel vasculitis
Giant cell arteritis (GCA) and Takayasu arteritis, the large
vessel vasculitides, are the most common non-infectious
causes of aortitis, although other rheumatic diseases have
been associated with aortic involvement, namely HLA-B27-
associated spondyloarthropathies, Cogan’s syndrome, rheu-
matoid arthritis, systemic lupus erythematosus, sarcoidosis
and anti-neutrophil cytoplasmic antibody (ANCA)-
associated vasculitides.74 In the last few years, recognition
of immunoglobulin (Ig)G4-related systemic disease has
brought a potential explanation for an important proportion
of aortitis and periaortitis cases formerly labeled as ‘isolated
aortitis’.41 While the clinical presentation is generally repre-
sentative, GCA and Takayasu’s share many aspects of their
pathogenesis. Vascular injury results from influx of leuko-
cytes and macrophages through the vasa vasorum into the
lumen intima. Inflammatory mechanisms involve tumor
necrosis factor (TNF)-alpha, interleukin (IL)-6, B-cell acti-
vating factor, and matrix metalloproteases, leading to angio-
genesis, myointimal proliferation and, eventually, stenosis
or occlusion of the lumen, and/or destruction of elastic fib-
ers resulting in aneurysm formation. Granuloma and multi-
nucleated giant cells, although generally attributed to GCA,
can be observed in both diseases.75,76 Clinical manifesta-
tions differ: occlusive or stenotic manifestations are encoun-
tered more commonly in patients with Takayasu aortitis,
whereas patients with GCA have a much higher likelihood
of developing aneurysmal disease.77 Despite the lower age
and baseline cardiovascular risk of patients with Takayasu
arteritis, intermittent ischemic symptoms are very common
(62% in the upper limb and 32% in the lower limb), and
cardiac manifestations occur in almost 40% of cases, mainly
driven by aortic regurgitation. In patients with GCA, a large
population-based retrospective study where 28% of patients
were taking aspirin, compared with 22% of controls, dem-
onstrated an increased risk of cardiovascular events includ-
ing myocardial infarction, stroke, peripheral artery disease,
aneurysm or aortic dissection (adjusted HR 2.1; 95% CI:
1.5–3.0).78
Aspirin for GCA.  The use of antithrombotic therapy for pri-
mary prevention of vascular events in GCA was addressed
62 Vascular Medicine 22(1)
Table 1.  Recommendations for antithrombotic medications in aortic atherothrombotic conditions.
Aortic arch atheroma
Primary prevention (no SAPT
previous ischemic event)
Secondary prevention DAPTa
(previous ischemic event) OACa
DOACb
SAPT, single antiplatelet therapy; OAC, oral anticoagulant; DAPT, double antiplatelet therapy; DOAC, direct oral anticoagulant.
aLow level of evidence; bongoing trials.
in a recent Cochrane review.79 While three retrospective
studies80–82 have found a correlation between low-dose
aspirin use and a reduced incidence of ischemic events, oth-
ers have not.83,84 In 175 consecutive patients with GCA, of
which 36 were on aspirin at the time of diagnosis and 41
were started on aspirin by the treating physician, aspirin
prevented cranial ischemic complications with an odds
ratio of 0.18 (95% CI: 0.04–0.84; p=0.03).80 Another retro-
spective case series of 143 patients with GCA recorded a
relative risk of ischemic complications of 16.2% in patients
on aspirin versus 48% in patients without aspirin.81 Two
later studies comparing patients already on antiplatelet
agents at the time of diagnosis with controls found no sta-
tistically significant difference in the incidence of ischemic
events.83,84 Finally, a recent Brazilian retrospective cohort
with a high proportion of aspirin-treated patients (71.1%)
suggested a strong preventive effect of aspirin against
relapses (OR 0.19; 95% CI: 0.04–0.80; p=0.024).82 Despite
this uncertainty about the preventive effect of aspirin on the
evolution of the inflammatory disease, low-dose aspirin is
advocated as part of the treatment in GCA,85,86 based on the
increased risk of CVD in that population.
Animal studies suggested that high-dose aspirin can
inhibit interferon-gamma and block the inflammatory pro-
cess of GCA.87 However, the doses of aspirin used in most
patients in the above-mentioned studies are antiplatelet
doses and may not reach the appropriate concentration to
inhibit inflammation. On the other hand, thrombocytosis is
associated with a higher incidence of ocular complications
of GCA, suggesting a role for antiplatelet therapy.88
High doses of corticosteroids are the cornerstone of
therapy for GCA, but their association with aspirin may
raise concern over the risk of gastrointestinal bleeding. In
the general population (n=22,049), the association of high-
dose corticosteroids with low-dose aspirin increases the
risk of upper gastrointestinal bleeding (RR 4.43; 95% CI:
2.10–9.34).89 However, in a cohort of 143 patients with
GCA, there was no increase in bleeding in patients on con-
comitant aspirin and corticosteroids (3%) when compared
to patients on prednisone alone (8.8%, p>0.2).81
Aspirin for Takayasu’s arteritis.  Fundamental studies suggest
a theoretical benefit for antiplatelet agents in Takayasu’s
patients90–92 and there is a small amount of evidence from
retrospective studies to support it.93 In the evolution of their
disease, patients with Takayasu’s arteritis often undergo
percutaneous interventions to restore patency in occluded
vessels. The rate of restenosis following angioplasty in
Primary aortic mural thrombus Large vessel vasculitis
OACa SAPT
OACa SAPT
OACa
retrospective series varies between 48% and 78%.94–97
While there is no satisfying evidence for the use of anti-
platelet therapy after aortic angioplasty, experience from
other populations requiring arterial stents suggests that, at a
minimum, single-agent antiplatelet therapy is benefi-
cial.31,98,99 A retrospective review of 97 patients with
Takayasu’s arteritis suggested that patients on immunosup-
pressive therapy at the time of the intervention had an
increased rate of successful endovascular intervention
(85% vs 24%; p=0.001), but this may be biased by the fact
that patients off-therapy probably have a burned-out phase,
which reflects a heavier arterial burden and higher risk.94
Anticoagulants.  Few studies have assessed anticoagulant med-
ications in large vessel vasculitis. In a retrospective cohort
study of 143 patients with GCA by Lee and colleagues,81 war-
farin use had a protective effect against ischemic events with-
out increasing bleeding after adjustment for age, sex, and
previous cerebrovascular risk factors (OR 0.17; 95% CI:
0.03–0.92; p<0.04). This finding should be reproduced in ran-
domized studies before it is translated to practice.
Direct oral anticoagulants (DOACs)
Currently, no study has assessed the newer anticoagulants
in aortic arch atheroma, aortic thrombus or aortitis. Two
phase 3 randomized trials are currently assessing dabi-
gatran (RE-SPECT ESUS, NCT: 02239120) and rivaroxa-
ban (NAVIGATE ESUS, NCT: 02313909) in patients with
embolic stroke of undetermined source (ESUS). The results
of these large trials will help inform future treatment
choices in patients with aortic thrombosis.
Back to the patient
In the case of our patient, since the decreased renal function
is a relative contraindication to endovascular intervention,
anticoagulation with unfractionated heparin was started,
and the patient was bridged to warfarin with a target inter-
national normalized ratio (INR) between 2 and 3. The
ischemic symptoms in the leg improved promptly in the
first week of treatment. The patient was kept on warfarin
alone, and had no recurrence of limb ischemia at 1-year
follow-up. The duration of warfarin therapy in this case is
unknown, and until directed by future trials should be indi-
vidually tailored to the patient’s risk profile, presence of
persistent aortic thrombi on repeat imaging, and preference
for anticoagulants.
Caron and Anand 63
Conclusion
As the scientific knowledge of atherothrombosis advances,
the pathogenesis of aortic atherosclerosis still raises unre-
solved questions. We have summarized the data available for
antithrombotics in aortic diseases (Table 1). For three dec-
ades, TEE has allowed an in vivo description of aortic ath-
erosclerosis and identification of high-risk patients. The risk
of CVD should be assessed in asymptomatic patients with
aortic arch atheroma, and complex plaques should be consid-
ered to double the risk of cardiovascular events. Patients with
cryptogenic stroke in which a complex aortic arch atheroma
is identified remain at high risk of subsequent cerebrovascu-
lar events, despite single antiplatelet therapy. The presence
of an aortic thrombus superimposed on an atherosclerotic
plaque makes it a complex lesion, but does not immediately
mandate anticoagulation. However, patients with a thrombus
with a mobile component should be anticoagulated, and sur-
gery should be considered, depending on the patient’s surgi-
cal risk, and the location and size of the thrombus. Future
studies of DOACs compared to antiplatelet therapy will add
to the evidence base to guide clinicians regarding antithrom-
botic therapy in patients with aortic atherosclerosis.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
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