Thromboembolism in Atrial Fibrillation

Jan Menke, MDa,*, Lars Lüthje, MDa, Andreas Kastrup, MDb, and Jörg Larsen, MDc

Thromboembolism is a severe complication in atrial fibrillation. This overview presents

thromboembolic disease as a single entity, ranging from stroke through mesenteric isch-
emia to acute limb ischemia. The PubMed, Embase, and Cochrane databases were system-
atically searched for the terms “atrial fibrillation” and “thromboembolism” in reports
published from January 1986 to September 2009. The information of 10 evidence-based
practice guideline documents and 61 further sources was systematically extracted. In atrial
fibrillation, the average annual stroke risk is increased by 2.3% (lethality 30%). The annual
incidence of acute mesenteric ischemia is 0.14% (lethality 70%), and that of acute limb
ischemia is 0.4% (lethality 16%). In total, approximately 80% of embolism-related deaths
are from stroke and 20% from other systemic thromboembolism. The ischemic symptoms
generally have an acute onset but may mimic other diseases, particularly in mesenteric
ischemia. Early diagnosis and treatment can limit or even prevent tissue infarction.
Guideline-recommended therapy with aspirin or warfarin reduces the thromboembolic
risk. Suitable patients may optimize their warfarin therapy by self-monitoring of the
international normalized ratio (INR). New oral and parenteral anticoagulants with more
stable pharmacokinetics are being developed. In conclusion, atrial fibrillation predisposes
to thromboembolism. If ischemic stroke or systemic thromboembolism occurs, early diag-
nosis and treatment can improve outcomes. The thromboembolic risks are reduced by
guideline-adherent antithrombotic therapy with warfarin or aspirin. Future directions may
include self-monitoring of the international normalized ratio and novel anti-
coagulants. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:502–510)

Nonvalvular atrial fibrillation (AF) is the most common
cardiac arrhythmia, with an overall prevalence of about
1%.1– 4 The prevalence increases with age and coexisting
cardiopulmonary disease.2,4 AF predisposes to thrombus
formation, especially in the left atrial appendage, with risk
for subsequent thromboembolism. Ischemic stroke is the
predominant complication, but extracerebral thromboembo-
lism also contributes to the elevated morbidity and mortality
in AF.1,2,5– 8 Early diagnosis within a few hours is crucial
for individual therapy and outcome. This overview pre-
sents thromboembolism in AF as a single entity, ranging
from stroke through mesenteric ischemia to acute limb
ischemia.
Methods
Identification of published research: The PubMed,
Embase, and Cochrane databases were searched for the
Medical Subject Headings “(atrial fibrillation) AND (throm-
boembolism OR embolism OR ischemia OR transient isch-
emic attack OR stroke)” and related terms in reports pub-
lished from January 1986 to September 2009, with a focus
on more recent publications. Further literature was identi-
fied from the reference lists of retrieved reports. This sys-
tematic term-driven literature search was intended to find
the most reports with direct linkages to the topic. Some
a the different organ manifestations. The evidence was syn-
University Hospital, Göttingen; bKliniken für Neurologie, Klinikum
Bremen, Bremen; and cEvangelisches Krankenhaus, Göttingen, Germany.
Manuscript received August 25, 2009; revised manuscript received and
accepted October 11, 2009.
*Corresponding author.
E-mail address: menke-j@t-online.de (J. Menke).
related issues were covered by additional specific literature
searches, for example, about the relevance of rehabilitation
after stroke.9 In total, 16,409 items were retrieved.
Selection of published research: We extracted theme-
specific information from 10 evidence-based practice guide-
line documents.2,5–7,10 –15 Structured summary data for most
of these guidelines are available from the National Guideline
Clearinghouse (http://www.guideline.gov). Of the 16,409 re-
trieved items, 16,169 were excluded by screening titles and
abstracts, and 104 items were excluded by reading the full
text. The remaining 136 reports were considered eligible,
including those with similar or overlapping contents. By
comparison, 71 references were selected by consensus with
the following rank order: practice guidelines (10 sources),
meta-analyses or reviews (21 sources), prospective studies
(18 sources), and retrospective studies (22 sources). The
literature selection was limited to English-language reports.
Ninety-two percent (65 of 71) of the included references were
electronically available in the Portable Document Format
(Adobe Systems, Inc., Mountain View, California). One text-
book was added to the references.1
Evidence synthesis: This overview presents thrombo-
embolism in AF in a systematic order from its atrial origin
to the peripheral end points, including incidence, symptoms,
laboratory and imaging findings, therapy, and outcomes of
thesized by expert consensus, a standard method that is also
applied for constructing parts of the guidelines (http://www.
guideline.gov). Numerical meta-analytic methods for pri-
mary sources could not be applied for this overview, be-
cause the guidelines are not primary sources and because of

0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. www.AJConline.org
doi:10.1016/j.amjcard.2009.10.018
 Review/Thromboembolism in Atrial Fibrillation
Table 1
Key summary points
● In atrial fibrillation, thromboembolism generally has acute ischemic
symptoms but may mimic other diseases, particularly in acute
mesenteric ischemia.
● In atrial fibrillation, about 80% of embolism-related deaths are from
ischemic stroke, and about 20% are from other systemic
thromboembolism.
● Early diagnosis and treatment can limit or even prevent tissue
infarction.
● Guideline-adherent therapy with aspirin and warfarin reduces the
thromboembolic risk.
● Future therapy may include self-monitoring of the international
normalized ratio and novel oral or parenteral anticoagulants with more
stable pharmacokinetics.
the diversity of included sources (guidelines, reviews, etc.).
After reading the full text, the published evidence was
extracted from the Portable Document Format documents
using the search function of Adobe Reader version 9
(Adobe Systems, Inc.) to assess the retrieved electronic
literature as systematically as possible. For example, search-
ing for “mesenteric ischemia” or “intestinal ischemia” and
related terms yielded 301 text passages in the electronic
documents. The 6 additional printed articles and textbook were
similarly hand-searched. The retrieved published evidence was
weighed with the same rank order as during the literature
selection (evidence-based guidelines⬎meta-analyses or
reviews⬎prospective studies⬎retrospective studies). The
current levels of evidence are extensively documented in the
cited guidelines. This overview does not present the pathogen-
esis and treatment strategies of AF. The main results of this
overview are summarized by key points (Table 1).
Results
AF: The pathogenesis and treatment strategies of AF,
such as rate and rhythm control, are covered by other guide-
lines and publications.1,2,16 –18 These treatment strategies, as
well as the prevention of AF itself, can contribute to an
overall reduction in the risk for thromboembolism. How-
ever, thromboembolism may occur even with optimal AF
treatment.2,16
Left atrial thrombus formation: During episodes of
AF, cardiac blood flow is reduced, especially in the left
atrial appendage, which is the major site of thrombus for-
mation.2,19,20 Such thrombus formation is thought to be
triggered by Virchow’s triad of stasis, endothelial dysfunc-
tion, and a hypercoagulable state.2,21 Thrombus sizes range
from few millimeters to about 4 cm.19 Left atrial thrombi
are found in about 5% to 14% of patients, if AF lasts ⬎2
days.19 Atrial thrombi are usually diagnosed by transesoph-
ageal echocardiography.20,22 Alternative methods are car-
diac magnetic resonance imaging and computed tomogra-
phy.22 The main differential diagnosis of a left atrial
thrombus is atrial myxoma.1 However, both entities may
occur simultaneously when a thrombus is attached to a
myxoma. Atrial thrombi may be dissolved by endogenous
thrombolysis. Anticoagulation with warfarin helped to re-
solve about 75% of atrial thrombi within a month of treat-
ment in the Assessment of Cardioversion Using Trans-
503
esophageal Echocardiography (ACUTE) trial.19 If atrial
thrombi do not resolve, they may become detached and
embolize in the peripheral arterial system.20
Thromboembolism: Thromboembolism most frequently
occurs during episodes of actual AF or within the first 10
days after electrical, pharmacologic, or spontaneous conver-
sion to sinus rhythm.2 Most events manifest in the brain,
which is particularly vulnerable to ischemia, but thrombo-
embolism in other organ systems also contributes to overall
morbidity and mortality.8,23–25
Ischemic stroke and transient ischemic attacks: DEF-
INITION: AF is associated with a high risk for cerebral
thromboembolism.1,5,15 Clinically, 2 courses of subsequent
focal cerebral ischemia are differentiated: in transient isch-
emic attacks, the neurologic deficit lasts on average no more
than 12 minutes and is by definition completely reversible
in ⬍24 hours.1 In ischemic stroke, the focal neurologic
deficit persists because of irreversible ischemia followed by
cerebral infarction. For differential diagnosis, 3 types of
focal cerebral ischemia can be differentiated: (1) local ar-
terial thrombosis that often causes small lacunar infarcts;1
(2) the embolic occlusion of a main cerebral artery or its
branches, which may cause partial or total infarction of the
depending vascular territory (Figure 1);1 and (3) nonocclu-
sive watershed ischemia at the boundary between 2 adjacent
vascular territories, which occurs during states of global
cerebral hypoperfusion (Figure 1).1 Cardiogenic thrombo-
embolism frequently causes territorial infarction but may
also result in clinically occult lacunar lesions.1
EPIDEMIOLOGY: In AF, the annual stroke incidence in-
creases with age from about 1.3% in 50- to 59-year-old
patients to 5.1% in octogenarians.23 On average, the throm-
boembolism-related extra stroke risk is about 2.3% per
year.23,26 With a 1-year lethality of about 30%, the associ-
ated extra mortality is about 0.7% per year.27 AF alone is
associated with a three- to fourfold increase in stroke inci-
dence, when statistically adjusting for other risk factors.5
The coincidence of AF and further factors increases the
individual stroke risk accordingly.28 Several scores have
been proposed to assess individual stroke risk.29 Current
guidelines recommend the CHADS2 score, which is com-
piled by assigning 1 point each for congestive heart failure,
hypertension, age ⱖ75 years, and diabetes mellitus and by
assigning 2 points for any history of stroke or transient
ischemic attack.5,28 Additional known risk factors are smok-
ing, hyperlipidemia, carotid artery stenosis, and other car-
diovascular factors.1,2,5
CLINICAL SYMPTOMS: The diagnosis of transient isch-
emic attack and ischemic stroke is based predominately on
clinical findings.1,30 The leading symptom is the acute onset
of a painless, focal neurologic deficit. The extent of neuro-
logic dysfunction is determined largely by the cerebral area
affected and only in part by the size of the infarct. Transient
ischemic attacks and stroke are linked with circumscribed
symptoms. Classic supratentorial stroke symptoms include
contralateral hemiparesis, homonymous hemianopsia, apha-
sia in stroke of the dominant hemisphere, and anosognosia
in stroke of the nondominant hemisphere.1 Cerebellar stroke
mainly causes ipsilateral ataxia.1 Brainstem ischemia usu-
504 The American Journal of Cardiology (www.AJConline.org)

Figure 1. Image gallery of unenhanced cranial computed tomography in patients with stroke. (A) Hyperdense artery sign (arrow) in ischemic stroke of the
right middle cerebral artery territory in a 71-year-old man with acute left-sided hemiparesis. (B) Follow-up computed tomography 3 hours later shows
hypodense cerebral edema with loss of gray matter–white matter distinction (arrow). (C) Chronic cerebral infarction with cystic change of demyelination and
gliosis (arrow) at 8 months. (D) Watershed infarction with bilateral hypodense areas at the boundaries between the middle and posterior cerebral artery
territories (arrows). (E) Acute hypertensive cerebral hemorrhage (arrow) in an 82-year-old woman with left-sided hemiparesis. (F) Secondary hemorrhagic
transformation (arrow) in ischemic stroke of the basal ganglia.

ally has crossed peripheral symptoms due to the simulta-
neous involvement of cranial nerve nuclei and nerve tracts.1
IMAGING: The major task of unenhanced computed to-
mography or any other initial imaging is to rule out intra-
cranial hemorrhage rather than to prove the clinical diagno-
sis of stroke.1,10,15,31 About 2 hours after the onset of stroke
symptoms, early signs may be shown on unenhanced com-
puted tomography, but these signs have no clear prognostic
value.10 For example, a hyperdense middle cerebral artery
indicates occlusion by a locally formed thrombus or embo-
lus impaction (Figure 1).10 Slight parenchymal hypodensity
indicates increased water content in affected brain matter
due to developing cytotoxic edema (Figure 1). Within the
affected territory, diffusion-perfusion-weighted magnetic
resonance imaging frequently demonstrates a nonviable in-
farct core and a surrounding penumbra of potentially viable
but hypoperfused tissue-at-risk.1,10,32 Contrast-enhanced
computed tomographic perfusion techniques are performed
for the same purpose.10 Changes during the temporal course
of stroke are usually examined using unenhanced computed
tomography. This allows the assessment of complications
such as critically space-occupying edema and hemorrhagic
transformation of an infarct (Figure 1).6 The latter may
range from asymptomatic petechial bleeding to focal sec-
ondary hemorrhage with mass effect, occasionally necessi-
tating neurosurgical intervention.6
DIFFERENTIAL DIAGNOSIS: Most stroke patients have
ischemic insults, but about 15% have primary intracranial
hemorrhages (Figure 1).1,6,11,31 These stroke entities may be
clinically indistinguishable, necessitating the routine use of
imaging to rule out a hemorrhagic origin.1,6,33 Further dif-
ferential diagnoses of stroke include complicated migraine,
transient paresis after seizure, and intracranial neoplasms that
may bleed or excite profound perifocal edema.1,33 Epidemio-
logic data indicate that strokes in patients with AF are
frequently caused by cardioembolism.1,5 However, because
of co-morbidities, these patients also encounter stroke due
to coexisting diseases, such as carotid artery disease or
arterial hypertension.1,5
THERAPY: Public education programs aim to increase
public awareness of stroke symptoms to decrease referral
time to stroke units.30 Guidelines provide general recom-
mendations for stroke therapy.6,15 Individualized therapeu-
tic decisions are based on a patient’s clinical findings and
co-morbidities.6,33 Supportive therapy aims at limiting ce-
rebral infarction. This includes the prevention of fever,
hyperglycemia, and malignant hypertension.1 Specific ther-
apy with systemic intravenous thrombolysis using recom-
binant tissue plasminogen activator (rtPA) is given to se-
lected patients with strokes lasting ⬍3 hours.1,6,31,33
Different studies have investigated further diversifications
of stroke treatments, including thrombolysis for stroke du-
ration beyond the 3-hour time window, the imaging-based
selection of patients who are more likely to benefit from
thrombolysis, and the local intra-arterial administration of
thrombolytic agents.1,6
OUTCOME: In AF, about 30% of patients with strokes
die within 1 year.1,27 From 15% to 30% of stroke survivors
 Review/Thromboembolism in Atrial Fibrillation 505

Figure 2. Image gallery of computed tomography and magnetic resonance imaging in extracerebral systemic thromboembolism. (A) Thromboembolic splenic
infarction a with wedge-shaped hypodense perfusion defect (arrow) on contrast-enhanced computed tomography. (B) Subtotal embolic narrowing of the
proximal superior mesenteric artery (arrows), which was successfully treated by local transcatheter thrombolysis with recombinant tissue plasminogen
activator. (C) Computed tomographic angiography shows occlusion of the ileocecal branch of the superior mesenteric artery (arrow) and distended small
bowel loops with thickened walls in an 83-year-old woman with AF and acute mesenteric ischemia. During laparotomy, the distal ileum was partially resected
and the patient survived. (D) Magnetic resonance angiography shows occlusion of the distal brachial artery (arrow) with delayed filling of the radial and ulnar
arteries (arrows) in a 48-year-old man with acute left forearm ischemia. (E) Acute bilateral lower-limb thromboembolism in a 75-year-old woman with AF
and occlusion of both common femoral arteries. Except for filling of short segments of the proximal superficial femoral arteries (arrows), both legs were
completely ischemic. The patient died the next day. (F) Acute thromboembolism of the right popliteal artery in a 56-year-old man with chronic obstructive
pulmonary disease and coexisting AF.

remain permanently disabled.5,30 Cardioembolic strokes
are, on average, more disabling and carry higher mortality
than noncardioembolic strokes.2,34 In patients with strokes
who require mechanical ventilation, prognoses are gen-
erally poor, but a small number survive without severe
disability.35 There is evidence that stroke survivors benefit
from rehabilitation.9
Splenic thromboembolic infarction: Splenic thrombo-
embolic infarction is a rare finding in AF.36,37 Because of an
unspecific or even quiescent presentation, only 10% of
splenic infarctions are clinically suspected. Symptoms and
laboratory findings may include left upper abdominal pain,
fever, and leukocytosis.36 Contrast-enhanced computed to-
mography shows splenic hypodensity during the venous
equilibrium phase. Classically, this hypodense lesion is
wedge-shaped, indicating its segmental vascular origin
(Figure 2). Other causes of splenic infarction include hema-
tologic disorders, thromboembolism from other cardioarte-
rial sources, and endocarditis with septic embolism and
splenic inflammation. Rarely, splenic infarction progresses
to massive subcapsular hemorrhage or splenic abscess, ne-
cessitating laparotomy and splenectomy.36 However, the
usual course of splenic infarction is asymptomatic or with
gradual resolution of pain without clinical sequelae.36
Acute renal thromboembolism: In AF, a low incidence
of about 0.01% is reported for renal thromboembolism, but
the condition may be underdiagnosed.24,37,38 Most patients
present with acute flank pain or generalized abdominal pain,
sometimes associated with fever and vomiting.37,39 The
clinical findings are frequently unspecific. Therefore, the
standard differential diagnosis encompasses other causes of
acute abdominal pain, including urolithiasis, pyelonephritis,
and acute mesenteric ischemia.37 Typical laboratory find-
ings of renal ischemia are an elevated serum lactate dehy-
drogenase (LDH) level ⬎400 U/dl and leukocytosis.37 Mi-
crohematuria and proteinuria are present in about 50% of
patients.37 Renal function is frequently impaired, with se-
rum creatinine levels increasing to ⬎2 mg/dl during the
course of the disease. Catheter angiography is the gold
standard of imaging in renal artery stenosis and occlusion,
with sensitivity reported as high as 100%.37 Renal scintig-
raphy has similarly high sensitivity for diagnosing renal
ischemia.37 Computed tomography has intermediate sensi-
tivity of about 80% for the detection of thromboembolic
arterial occlusion, whereas ultrasound has low sensitivity.37
Conservative therapy includes anticoagulation with hepa-
rin.37,39 Systemic or local transcatheter thrombolysis has
been performed with variable effect and carries a risk for
506 The American Journal of Cardiology (www.AJConline.org)
hemorrhage.37,39 In a retrospective study of 44 patients,
about 25% had persistent latent or apparent renal failure,
with serum creatinine levels ⬎2 mg/dl, while renal func-
tion normalized in 60%. Eleven percent of patients died
because of further complications.37
Acute thromboembolic mesenteric ischemia: DEFINI-
TION: Embolic obstruction of the superior mesenteric artery
or its branches can cause acute ischemia of the small intes-
tine and proximal colon.1,7,40 The embolus often lodges just
proximal to the origin of the middle colic artery, so that the
jejunum remains perfused.1 Embolic occlusion of the infe-
rior mesenteric artery may cause ischemic colitis of the
distal colon if the normal collateral arterial supply through
the arc of Riolan and via anorectal arteries is insufficient.1
EPIDEMIOLOGY: In AF, acute thromboembolic mesen-
teric ischemia has a low incidence of about 0.14%/year.24
However, the condition has a high lethality of approxi-
mately 70%.1,7,24,40 – 42 This causes an additional mortality
of about 0.1% annually.
CLINICAL SYMPTOMS: Patients with acute intestinal
ischemia present with severe nonremitting abdominal pain
that is initially out of proportion to the findings on physical
examination.1,7 This is often followed by an interval of
several hours with only a few symptoms. Finally, bowel
necrosis and perforation lead to peritonitis and shock.
LABORATORY AND IMAGING FINDINGS: Laboratory
evaluation often shows mild leukocytosis and metabolic
acidosis, with lactic acidosis in the initial stage.7,40 – 43 As
the illness progresses to bowel necrosis and perforation, labo-
ratory markers of inflammation increase. Abdominal x-rays
may initially be normal or show dilated loops of intestine with
air-fluid levels, indicating the onset of paralytic ileus.7 To
consider differential diagnoses in acute abdominal pain of
unknown origin, contrast-enhanced computed tomogra-
phy is the diagnostic modality of choice. In acute throm-
boembolic mesenteric ischemia, high-resolution com-
puted tomographic angiography can show the site of
arterial occlusion (Figure 2).1,44,45 With time, there is wall
thickening of the affected ischemic bowel segments.7,44 The
progression of intestinal ischemia to necrosis is indicated by
intestinal pneumatosis, perforation, and peritonitis.7,44 If non-
invasive computed tomographic angiography does not estab-
lish the diagnosis, invasive catheter angiography can show the
mesenteric occlusion with the highest image resolution.7
Alternatively, explorative laparotomy is performed.1,7,40 – 42
DIFFERENTIAL DIAGNOSIS: Acute abdomen due to acute
mesenteric thromboembolism has several differential diag-
noses, including rupture of an aortic aneurysm, abdominal
inflammatory diseases, and diabetic ketoacidosis with pseu-
doperitonitis.1,46 Most similar is the preexisting atheroscle-
rosis of the superior mesenteric artery with superimposed
acute local thrombosis.1,42,46 A further vascular differential
diagnosis is nonocclusive mesenteric ischemia due to blood
flow redistribution away from the bowel towards vital or-
gans. This may occur with low cardiac output states, shock,
catecholamines, or the administration of other vasocon-
stricting drugs.1,7,45 A further vascular differential diagnosis
is mesenteric or portal venous thrombosis, which can be
imaged by biphasic contrast-enhanced computed tomogra-
phy with scanning in the arterial and venous perfusion
phases.1,42,45,46
THERAPY: Selected patients with superior mesenteric
thromboembolism without signs of bowel necrosis can be
treated by local transcatheter thrombolysis, balloon angio-
plasty, and, occasionally, stenting.7 Patients treated in this
way may still require laparotomy, which is the therapeutic
gold standard in embolic mesenteric ischemia. It consists of
embolectomy, eventually bypass grafting, and the resection
of nonviable bowel.7,40,41 When appropriate, a second-look
laparotomy is performed 24 to 48 hours after revasculariza-
tion to reevaluate intestinal viability.1,7,40
OUTCOME: If acute occlusive mesenteric ischemia is
diagnosed and treated within the first 6 hours, bowel resec-
tion can often be avoided, and the general prognosis is
good.43 Treatment thereafter frequently requires the resec-
tion of necrotic bowel loops, and lethality increases pro-
gressively with time.43 Frequently, acute occlusive mesen-
teric ischemia remains unrecognized initially, so that
specific treatment is delayed for ⱖ24 hours. This results in
a high overall lethality of about 70%.1,7,24,40,41 Survivors
treated by small bowel resection may have short bowel
syndrome.1
Acute thromboembolic limb ischemia: DEFINITION:
In acute thromboembolic limb ischemia, the affected artery
is suddenly occluded by an embolus from a cardiac or other
upstream source.1,7 Arterial emboli typically lodge at
branch points in the arterial tree, where the arterial lumen
diminishes.1 Occasionally, a large embolus is stopped at the
aortic bifurcation, forming a saddle embolus that extends
into both iliac arteries.47 Thrombus fragments may then
cause bilateral acute leg ischemia, which has particularly
high lethality (Figure 2).7,47 However, more commonly,
acute thromboembolism affects only 1 extremity.
EPIDEMIOLOGY: Patients with AF have an additional
incidence of aortoiliac and lower-extremity arterial throm-
boembolism of about 0.4%/year.24 The upper limbs are less
frequently affected than the lower limbs. The associated
lethality at 12 months is about 16%,7,48,49 resulting in an
estimated extra annual mortality of about 0.06%.7,24
CLINICAL SYMPTOMS: Acute limb ischemia is charac-
terized by an acute onset of pain, paralysis, paresthesia,
pulselessness, and paleness.7 Because of superficial collat-
erals, reduction of skin temperature usually begins a limb
segment below the level of the arterial occlusion.7 The
severity of symptoms varies considerably among patients,
depending on the extent of arterial occlusion as well as the
volume of collateral perfusion.7
LABORATORY AND IMAGING FINDINGS: Acute limb
ischemia has no specific laboratory findings. Duplex sonog-
raphy helps to confirm the clinical diagnosis and often
demonstrates the level of the occlusion.7 However, catheter-
based digital subtraction angiography is the gold standard
for the imaging of peripheral arterial disease, including
acute limb ischemia.7 Digital subtraction angiography has
the highest image quality of all angiographic techniques but
may have complications due to its invasive nature.7 Nonin-
vasive imaging alternatives are computed tomography and
magnetic resonance angiography.7 Generally, computed to-
mographic angiography can depict pelvic and leg arteries
 Review/Thromboembolism in Atrial Fibrillation
Table 2
Antithrombotic therapy for patients with atrial fibrillation*
Risk Category (ACC/AHA/ESC 2006) CHADS2 Score† (AHA/ASA 2006)
No risk factors
One moderate-risk factor
ⱖ2 moderate-risk factors or any high-risk factor
Less validated or weaker risk factors
Coronary artery disease
Thyrotoxicosis
Age 65–74 years
Female gender
* Based on the ACC/AHA/ESC 2006 guidelines for patients with atrial fibrillation2 (Table 13) and the AHA/ASA 2006 guidelines for the primary
prevention of ischemic stroke5 (Table 8).
†
The CHADS2 score is compiled by assigning 1 point each for Congestive heart failure, Hypertension, Age ⱖ75 years, and Diabetes mellitus and by
assigning 2 points for previous Stroke or TIA.
‡
If the patient has a prosthetic heart valve, the target INR should be ⬎2.5.
LVEF ⫽ left ventricular ejection fraction; TIA ⫽ transient ischemic attack.
with good image quality, although in the lower leg ex-
tensive atherosclerosis may hinder differentiation be-
tween contrast-enhanced residual lumen and calcified ob-
struction.7,50,51 Magnetic resonance angiography tends to
slightly overestimate arterial stenoses but shows occlusions
well and is not affected by vascular calcification (Figure 2).7
DIFFERENTIAL DIAGNOSIS: In patients with AF and co-
existing atherosclerosis, acute limb ischemia may be caused
either by systemic embolism or by local arterial thrombosis,
which may be difficult to distinguish.1,7 Further differential
diagnoses of acute limb ischemia include arterial occlusion
due to trauma and popliteal artery entrapment.1,7
THERAPY: Therapy for acute thromboembolic limb isch-
emia depends on individual findings. Interventional trans-
catheter approaches include local arterial thrombolysis with
fibrinolytic agents, thrombus aspiration, and the use of
thrombectomy devices.1,7,12 Patients with severe limb isch-
emia may require immediate surgical embolectomy or re-
vascularization to prevent limb necrosis, rhabdomyolysis,
and Tourniquet’s toxic reperfusion syndrome.1,7,12 If isch-
emia is irreversible, amputation is performed.7
OUTCOME: In the Rochester randomized prospective
trial, the limb loss rate at 12 months was about 18% with the
surgical and thrombolytic approaches.48 Lethality at 12
months was about 16% with thrombolysis and 42% for
surgical patients.48 The survival difference was attributable
primarily to more major in-hospital complications in the
surgical group.
Prevention of thromboembolism: GUIDELINES: In AF,
the treatment of thromboembolic complications generally
aims at limiting tissue infarction and restoring perfusion to
the tissue-at-risk.1,6,7,12 However, the major goal is to pre-
vent such thromboembolism.2,5 For this purpose, two cur-
rent guidelines recommend antithrombotic therapy with as-
pirin or warfarin after the assessment of individual risk
(Table 2).2,5 The American College of Cardiology, American
Heart Association, and European Society of Cardiology (ACC/
AHA/ESC) 2006 guidelines incorporate the CHADS2 score–
based recommendations from the American Heart Association
and American Stroke Association (AHA/ASA) 2006 guide-
507
Recommended Therapy
0 Aspirin (81–325 mg/d)
1 Aspirin (81–325 mg/d) or warfarin (INR 2–3, target 2.5)
ⱖ2 Warfarin (INR 2–3, target 2.5)‡
Moderate-risk factors High-risk factors
LVEF ⱕ35% Prosthetic heart valve‡
Congestive heart failure Mitral stenosis
Hypertension Previous systemic embolism
Age ⱖ75 years Previous TIA
Diabetes mellitus Previous Stroke
lines and add some cardiovascular risk factors (Table 2):2,5 (1)
patients with nonvalvular AF and low stroke risk should re-
ceive the antiplatelet drug aspirin, and (2) patients with ⱖ2
moderate-risk factors or with any high-risk factor should re-
ceive oral anticoagulation with the vitamin K antagonist war-
farin, unless contraindicated (Table 2).2,5,52 These recommen-
dations have also been incorporated in the American College
of Chest Physicians (ACCP) 2008 guidelines.13
ASPIRIN: Aspirin was found to reduce the stroke risk by
about 20%.5,28,53 According to the guidelines, AF patients
with low stroke risk should receive aspirin but do not benefit
sufficiently from warfarin to warrant its use for primary
stroke prevention.2,5 In the Clopidogrel for High Athero-
thrombotic Risk and Ischemic Stabilization, Management,
and Avoidance (CHARISMA) trial, a subgroup analysis of
a primary stroke-prevention population showed a signifi-
cantly increased mortality rate if dual-antiplatelet therapy
comprising aspirin and clopidogrel was used instead of
aspirin alone.54 This preliminary finding does not currently
support such dual-antiplatelet therapy for primary stroke
prevention and requires further prospective evaluation.15,54
Also, a combination of aspirin with warfarin is not generally
recommended, as stated in detail in chapter 8.1.4.2.4 of the
ACC/AHA/ESC 2006 guidelines for the management of
patients with AF.2
WARFARIN: In AF patients with high stroke risk, the
Atrial Fibrillation Clopidogrel Trial With Irbesartan for
Prevention of Vascular Events (ACTIVE W) showed that
oral anticoagulation with warfarin is superior to the combi-
nation of clopidogrel plus aspirin for the prevention of
vascular events.55 In AF, warfarin reduces the risk for
thromboembolic stroke by ⬎50%.2,5,25,53,56 Warfarin also
halves the risk for systemic thromboembolism.56 Because of
multiple food and drug interactions, the anticoagulant effect
of warfarin may vary over time, necessitating dose adjust-
ments by monitoring the international normalized ratio
(INR) of antithrombin time. With some exceptions, the
recommended INR target range is 2.0 to 3.0.2,5 About 20%
to 30% of the moderate- to high-risk patients have absolute
or relative contraindications to warfarin.57,58 In the remain-
508 The American Journal of Cardiology (www.AJConline.org)
ing patients without contraindications, about 30% to 60%
do not take warfarin for various individual reasons, which
constitutes an underutilization.25,57–59 Among warfarin-
treated patients, only 60% have INRs within the target
range, while 25% to 30% have lower INRs (undertreatment)
and 10% to 15% have higher INRs (overtreatment), indi-
cating the well-recognized difficulties with dose-adjusted
warfarin.60 In selected patients, INR self-monitoring can
help to optimize the individual warfarin dosage, thus reducing
major thromboembolic and hemorrhagic events.61 Recommen-
dations for the implementation of patient self-testing and pa-
tient self-management of oral anticoagulation were published
in 2005.62 Further details about the anticoagulation manage-
ment with warfarin are provided in the American College of
Chest Physicians (ACCP) 2008 guidelines.14
BLEEDING COMPLICATIONS: Anticoagulation with war-
farin bears an extra risk for intracranial and major extracra-
nial bleeding.2,14,25,52,56 – 61,63,64 Although extracranial hem-
orrhage is often survived, warfarin-associated intracranial
hemorrhage carries a high lethality of about 50% and
causes residual neurologic deficits in many survivors.63
The reported incidence of major hemorrhage in warfarin-
treated patients varies considerably among different stud-
ies and patient groups, ranging from 0.1% to ⬎5% per
year.2,25,62,65– 67 In overtreated patients with INRs ⬎4, the
bleeding risk increases sharply without a further reduction
in the ischemic stroke risk.2 Nonwhite patients seem to be
more prone to warfarin-associated hemorrhage than white
patients.66 Furthermore, especially octogenarians are at high
risk for intracranial and other major hemorrhages when
starting anticoagulation.65 Elderly patients, who are prone
to fall, were found at increased risk for traumatic intra-
cranial bleeding while on anticoagulation.64 In contrast,
in AF patients with indications for anticoagulation, the
well-known high thromboembolic stroke risk is more than
halved by warfarin.2,5,63,67 Therefore, the positive effect of
dose-adjusted warfarin on morbidity and mortality gener-
ally exceeds its extra bleeding risk.25,52,63 However, in
some patients, this turns out differently, so that the risk
for warfarin-related intracranial hemorrhage remains a
concern to the responsible physician when prescribing
anticoagulation.59,64,65
THERAPY OPTIMIZATION: Adequate adjustment of
warfarin dosage through INR monitoring can reduce the
warfarin-associated bleeding risk.68 It is similarly impor-
tant to treat coexisting diseases such as hypertension,
which is a risk factor both for intracranial hemorrhage
and ischemic stroke.5 Hypertension belongs to the treat-
able risk factors, while several other risk factors, includ-
ing a history of previous stroke, are not modifiable (Table
2). New anticoagulants with more stable pharmacokinet-
ics are being developed and studied as alternatives to
warfarin.69 –71 They include parenteral and oral factor Xa
inhibitors, direct oral thrombin inhibitors, and oth-
ers.69 –71 For example, the novel direct oral thrombin
inhibitor dabigatran has successfully passed a large ran-
domized noninferiority trial in comparison to warfarin
(Randomized Evaluation of Long-Term Anticoagulation
Therapy [RE-LY]).72 So far, guideline-recommended
therapy with aspirin or with warfarin plus INR monitor-
ing helps to prevent thromboembolism in AF (Table 2).2,5
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