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20 Antithrombotic Therapy
for Atrial Fibrillation and Cardioversion
Carmel M. Halley and Allan L. Klein
Co n t e n t s
Introduction
Risk Of Thromboembolism In Atrial Fibrillation
Management Options
New Antithrombotic Therapy For Atrial Fibrillation
Anticoagulation In Patients With Atrial Fibrillation In Clinical
Practice
References
Ab s t r A c t Thromboembolism, especially the cerebrovascular events, due to atrial fibrillation leads to
significant morbidity and mortality. A fundamental part of the management of any patient with atrial
fibrillation is stratification of this risk, and deciding upon suitable antithrombotic therapy. Currently, the
cornerstone of anticoagulation in high risk patients is the warfarin therapy. However, despite its efficacy,
warfarin has many practical limitations, and is known to be underused even when identified as the best
therapy. This has led to the search for a safe and effective alternative to warfarin which, if discovered,
would revolutionize anticoagulation in atrial fibrillation.
Key words: Atrial fibrillation • Thromboembolism • Stroke • Warfarin • Heparin • Cardioversion
INTRODUCTION
Atrial fibrillation is the most common cardiac arrhythmia, with an estimated prevalence of 2.3 million
people in North America and 4.5 million people in the European Union (1). Atrial fibrillation (AF) is
characterized by chaotic uncoordinated atrial activity, resulting in deterioration of mechanical function.
This predisposes to thrombus formation, especially in the left atrial appendage, due to a combination of
factors including blood stasis, endothelial dysfunction, and systemic hypercoagulability (2).
Thromboembolism due to AF leads to significant morbidity and mortality. Therefore, the stratification
of risk and anticoagulation therapies to reduce the risk are essential aspects of the clinical management
of all patients with AF, irrespective of other management strategies such as rate or rhythm control.
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI 10.1007/978-1-60327-235-3_20
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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RISK OF THROMBOEMBOLISM IN ATRIAL FIBRILLATION
The risk of stroke and thromboembolism is increased up to fivefold in non-valvular AF and up to
17-fold in valvular AF. The risk of embolic events does not depend on whether AF is paroxysmal or
permanent, or on the treatment strategy chosen
(3,4). Overall, AF is responsible for up to 25% of
all ischemic cerebrovascular events. Patients with AF who have suffered a stroke have a higher
mortality, greater disability, and longer hospital admissions compared to patients without AF
(5–9).
However, it should be noted that the pathogenesis of thromboembolism in AF is complex and not
solely related to embolism of thrombus generated in the left atrial appendage, with up to 25% of the
events resulting from intrinsic cerebrovascular disease, other cardiac source of embolism, and
atherosclerosis of the aorta (10,11).
Several clinical and echocardiographic characteristics have been identified that serve as predictors
of thromboembolic events in patients with AF. Clinical risk factors include a history of a prior embolic
event, hypertension, diabetes mellitus, old age, coronary artery disease, and heart failure
(1).
Echocardiographic risk factors, often more accurately identified with transesophageal echocardiogra-
phy (TEE) (12) (Fig. 1), include increased left atrial size, impaired left ventricular systolic function,
left atrial thrombus, spontaneous echocardiographic contrast (SEC), complex aortic atheroma, and
evidence of left atrial mechanical dysfunction. Reduced left atrial appendage emptying velocity
Fig. 1. Spectrum of left atrial appendage (LAA) thrombogenic milieu within the left atrium (LA) identified by trans-
esophageal echocardiography (TEE) with (a) severe spontaneous contrast (SEC) (b) sludge and (c) thrombus.
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Antithrombotic Therapy for Atrial Fibrillation and Cardioversion
(<20 cm/s) results from the loss of organized mechanical function in AF, and is associated with an
increased risk of thromboembolism
(13). In addition, the dynamic mechanical dysfunction that occurs
following cardioversion is also associated with an increased risk of thromboembolic events
(14). SEC
attributes the smoke-like swirling echocardiographic appearance to the presence of a low flow state
and red blood cell–protein interactions (rouleau formation)
(13). The presence of SEC has been asso-
ciated with an increased risk of thromboembolism. In one study of 302 patients undergoing TEE prior
to cardioversion or catheter ablation or as part of a clinical evaluation for cardiac source of embolism,
the presence of a viscid layered SEC or “sludge” in the left atrial appendage is an independent predic-
tor of all-cause mortality or thromboembolism (15). The incorporation of these risk factors into pre-
dictive risk models has become an integral component of clinical decision-making.
Several risk stratification schemes for anticoagulation in AF have evolved, incorporating data
from clinical trials and expert opinion (Table
1). However, a recent comparison of five different risk
stratification schemes had a comparable but limited ability to predict thromboembolism. Clearly,
better methods are needed to select patients for anticoagulation.
The role of other imaging modalities, including cardiac CT, continues to evolve. Despite being able
to distinguish severe left atrial appendage SEC or thrombus from lesser grades of SEC (16,17), a high
interobserver variability and modest diagnostic accuracy for detecting left atrial thrombus in patients
undergoing catheter ablation (18) have precluded the use of cardiac CT for the purpose of predicting
events following cardioversion.
The annual stroke rate in patients with AF ranges between 3 and 8% depending on the presence of
risk factors
(19). The lowest risk is in the so-called “lone” AF (defined as a patient younger than 60 years
with no clinical history or echocardiographic features of cardiopulmonary disease) at 0.5%/year
(20). In
patients with non-valvular AF, prior embolic event and age are the two most powerful predictors of risk.
The incremental relative risk, associated with prior embolic event, is estimated at approximately 3.0
(1,19,21). The annual risk of embolic events in AF is 1.5% in those younger than 60 years but increases
to 23.5% in octogenarians
(19). It should be emphasized that based on the available data, the type of AF
(paroxsysmal versus permanent) and the treatment strategy chosen (rate versus rhythm control) should
not be considered as major factors in the anticoagulant decision-making process (22–27).
MANAGEMENT OPTIONS
Oral anticoagulant therapy is the basis on which thromboembolism is prevented in patients with AF
with over 24 published trials in patients with non-valvular AF including 20,012 patients and an average
follow-up time of 1.6 years
(1,28). Alternative strategies such as surgical removal of the left atrial append-
age have not been proven to reduce thromboembolic risk (28). Ongoing clinical trials will examine the
long-term safety and efficacy of surgical ligation and percutaneous occluder devices of the left atrial
appendage
(29–32). Recently presented data from the Embolic Protection in Patients with Atrial
Fibrillation (PROTECT-AF) trial have demonstrated showed that device closure using the Watchman
device (Atritech, Plymouth, MN) was associated with a reduction in hemorrhagic stroke risk versus war-
farin and all cause stroke was non inferior to warfarin. Further data is awaited in this developing area.
Warfarin
Warfarin, a synthetic derivative of coumarin, inhibits the vitamin K g-carboxylation of coagulation
factors II, VII, IX, and X, resulting in the synthesis of inactive coagulation proteins of the prothrombin
complex (33). After rapid and complete absorption, it is almost completely bound to plasma albumin
with a half-life of 37 h. Clinically, there is a delay of 2–7 days in the onset of action. It is metabolized
in the liver, and therefore is subject to many (up to 80) drug and food interactions.
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Table 1
Risk stratification schemes for anticoagulation in atrial fibrillation
Scheme High risk Intermediate risk Low risk Management
ACC/AHA/ESC
guidelines 2006
Prior thromboembolism, mitral
stenosis, prosthetic heart valve
Age ³75 years,
Hypertension, heart
failure, EF <35% or
less, diabetes mellitus
Age 65–74 years,
coronary artery
disease, female
gender, thyrotoxicosis
(these are considered
less validated or
weaker risk factors)
No risk factor → Aspirin
One moderate risk
factor → Aspirin or Warfarin
Any high risk factor
or >1 moderate risk
factor → Warfarin
CHADS2 2001 Score 3–6
(Score 1 for each of the recent heart
failure, hypertension, diabetes;
score 2 for prior stroke or TIA)
Score 1–2 Score 0 Score 0 → Aspirin
Score 1–2 → Aspirin or Warfarin
Score 3–6 → Warfarin
Framingham 2003 14–31 points
(old age – max score <10, sex –
women
= 6, men = 0, hypertension
<4, diabetes = 6)
8–13 points 0–7 points Total score corresponds to
predicted 5-year stroke risk
ACCP 2004 Previous stroke or TIA or systemic
thromboembolism, age >75 years,
moderately or severely impaired
LV function with or without heart
failure, hypertension, diabetes
Age 65–75 without other
risk factors
Age <65 years with no
risk factors
Low risk → Aspirin
Moderate risk → Aspirin or
Warfarin
High risk → Warfarin
Atrial Fibrillation
Investigators
(AFI) 1994
Age >65 years, hypertension,
coronary artery disease or
diabetes
Age <65, no high risk
features
SPAF Investigators
trial 1995
Women >75 years, systolic blood
pressure >160 mmHg, left
ventricular dysfunction clinically
or on echocardiogram
Hypertension, no high
risk features
No history of
hypertension, no high
risk features
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Five large randomized trials (AFSAK 1, SPAF 1, BAATAF, CAFA and SPINAF) (34–38) have
evaluated warfarin compared with either placebo or control in the primary prevention of thromboem-
bolism in patients with non-valvular AF (Fig.
2) (39). The European Atrial Fibrillation Trial compared
phenprocoumon or acenocoumarol (other synthetic derivatives of coumarin with the same action
mechanism but with different half-life compared to warfarin) and placebo in the secondary prevention
of stroke among patients with non-valvular AF
(40). In a meta-analysis of these six trials, adjusted-
dose warfarin reduced the relative risk of stroke (both ischemic and hemorrhagic) by 61% (95% CI
47–71%) compared to placebo
(41). When only ischemic strokes are considered, treatment with
adjusted-dose warfarin was associated with a 65% (95% CI 52–74) relative risk reduction, and was
equally effective in preventing disabling and non-disabling strokes
(41). The absolute risk reduction
for all strokes is far greater for secondary stroke prevention (8.4% per year; number needed to
treat for 1 year to prevent one stroke, 12) than for primary stroke prevention (2.7% per year;
number needed to treat for 1 year to prevent one stroke, 37
(41)). In addition, adjusted-dose warfarin
significantly reduced the all-cause mortality compared to placebo (RR 0.69, 95% CI 0.53–0.89;
p = 0.005) (42).
The main risk associated with warfarin therapy is major bleeding. Patient age and intensity of
anticoagulation are the most powerful predictors of major bleeding (43–46). Other factors, besides
intensity of anticoagulation, associated with an increased risk of bleeding include hypertension
(systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg), alcoholism or liver
disease, poor drug adherence, presence of bleeding lesions (e.g., peptic ulcer disease, intracranial
hemorrhage, bleeding diatheses), and concomitant use of non-steroidal antiinflammatory drugs or
specific antibiotics.
The optimum intensity of anticoagulation balances the prevention of ischemic stroke with the risk
of hemorrhagic complications (45). Patients with an INR of 1.7 have twice the odds of stroke (95%
CI 1.6–2.4), and those with an INR of 1.5 have 3.3 times the odds of stroke (95% CI 2.4–4.6 times)
compared with those achieving an INR of 2.0 (47). An INR above 3.0 increases the risk of major
bleeding threefold (OR 3.21, 95% CI 1.24–8.28)
(48,49). Therefore, the optimum target intensity in
protection against ischemic stroke is probably achieved at an INR range 2.0–3.0
(1).
Clinical practice differs from the carefully selected and closely monitored population of clinical
trials. Warfarin, with an unpredictable dose–response relationship, delayed the onset and offset of
action and significant drug–drug and drug–food interactions requires careful monitoring with blood
tests and dose adjustments. However, even with careful monitoring, initiation of warfarin dosing is
associated with highly variable responses between individuals, possibly related to genetic variation.
Variants of two genes, CYP2C9 and VKORC1, account for 30–50% of the variability in warfarin
dosing. Recent data suggest that initial variability in the INR response to warfarin is more strongly
associated with VKORC1 than with CYP2C9 (50). Although the routine use of warfarin genotyping
is not recommended at this time, in certain situations, CYP2C9 and VKORC1 testing may be useful
and warranted in determining the cause of unusual therapeutic responses to warfarin therapy (51).
These factors may help to explain the under-utilization of warfarin for anticoagulation in AF in
clinical practice. A number of observational studies have confirmed that under half of all patients
eligible for warfarin for AF, actually receive it (52). Even among patients who have been prescribed
warfarin for AF, therapeutic anticoagulation is achieved in only about 30–50% of the time (53,54).
Aspirin
Aspirin offers a modest protection against stroke for patients with AF, but is inferior to warfarin in
this regard and should not be considered an adequate substitute in high-risk patients. A recent large
meta-analysis of 29 trials (n = 28,044, mean age 71 years, mean follow-up 1.5 years) concluded that
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Antithrombotic Drug Therapy in Cardiovascular Disease
Fig. 2. (a) Meta-analysis of ischemic stroke or systemic embolism for adjusted-dose warfarin compared with placebo,
aspirin, fixed low-dose warfarin (with or without aspirin), and ximelagatran in patients with non-valvular atrial
fibrillation (AFASAK Copenhagen atrial fibrillation, aspirin, and anticoagulation study, BAATAF Boston Area
Anticoagulation Trial for Atrial Fibrillation, CAFA Canadian Atrial Fibrillation Anticoagulation study, CI confidence
interval, EAFT European Atrial Fibrillation Trial, MWNAF Minidose Warfarin in Non-rheumatic Atrial Fibrillation,
PATAF Primary Prevention of Arterial Thromboembolism in Non-rheumatic Atrial Fibrillation, RR relative risk, SPAF
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Antithrombotic Therapy for Atrial Fibrillation and Cardioversion
compared with controls, adjusted-dose warfarin (six trials, n = 2,900) and antiplatelet agents (eight
trials, n
= 4,876) reduced stroke by 64% (95% CI 49–74) and 22% (95% CI 22–52), respectively (55).
Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (RR reduction
39% [95% CI 22–52%])
(55). However, there did not appear to be an increased hemorrhagic stroke
risk with warfarin as compared with aspirin
(55). The combination of antiplatelet therapy and low-
dose warfarin is not as effective as the adjusted-dose warfarin
(56,57).
Meta-analysis of six randomized clinical trials (n
= 3,119 participants) showed a stroke reduction
of 22% (CI 2–38%) with aspirin compared to placebo; absolute risk reductions were 1.5% per year
for primary prevention and 2.5% per year for secondary prevention
(39,41) (Fig. 2). This level of
stroke reduction is similar to the effect of antiplatelet treatment in patients without AF who are at high
risk for vascular disease
(58). Aspirin has been shown to be more effective for non-cardioembolic
strokes that tend to be less disabling
(41,59). Therefore, the greater the risk of disabling cardioembolic
stroke in a population of patients with AF, the lesser is the protection provided by aspirin
(59).
There is differing opinion regarding the optimum dose of aspirin in patients with AF. Based on the
Antithrombotic Trialists’ Collaboration, trials with a higher daily dose of aspirin did not result in
statistically different proportional reductions in vascular events – 19% with 500–1,500
mg/day, 26%
with 160–325
mg/day, and 32% with 75–150 mg/day compared with placebo (58). The current ACC/
AHA/ACC guidelines recommend aspirin use at 81–325
mg/day, while the current ACCP guidelines
recommend a dose of 75–325
mg/day (1,60).
Antiplatelet Therapy
Given the practical limitations associated with warfarin use and the proven effectiveness of combina-
tion antiplatelet therapy in cardiovascular disease, the ACTIVE W study was designed to test the effec-
tiveness and safety of dual antiplatelet therapy instead of warfarin in AF (61). In this study, 6,706 patients
with AF were randomly assigned aspirin and clopidogrel or warfarin. However, this study was discon-
tinued prematurely because of a lack of efficacy relative to warfarin. The ACTIVE A a randomized trial
of aspirin plus clopidogrel versus aspirin alone in patients with AF unwilling or incapable of using oral
anticoagulants, has found that the addition of clopidogrel to aspirin reduced the risk of stroke (2.4 % per
year in clopidrogrel group vs 3.3 % in placebo, RR 0.72; 95% CI, 0.62 to 0.83; P<0.001) and increased
the risk of major bleeding (2% per year occurred in 251 patients receiving clopidogrel (2.0% per year in
clopidrogrel group vs 1.3% per year in placebo, RR 1.57; 95% CI, 1.29 to 1.92; P<0.001).
Low Weight Molecular Heparins
Low weight molecular heparins (LWMHs) were discovered accidentally in the late 1970s, and are
prepared by depolymerization of unfractionated heparin (UFH) (62). LWMHs have many pharmaco-
logical and biological advantages over UFH and have replaced it in many clinical scenarios in cardiology.
These include predictable bioavailability and anticoagulant response, and fixed or weight-adjusted doses
in most clinical scenarios (63). Like UFH, LWMHs produce an anticoagulant effect by activating
antithrombin and accelerating the rate at which it inhibits factor Xa and thrombin (63).
Stroke Prevention in Atrial Fibrillation study, SPINAF Stroke Prevention in Non-rheumatic Atrial Fibrillation,
SPORTIF Stroke Prevention Using the Oral Thrombin Inhibitor in Patients with Non-valvular Atrial Fibrillation).
(b) Meta-analysis of trials comparing aspirin with placebo in reducing risk of thromboembolism in patients with atrial
fibrillation (ESPS European Stroke Prevention Study, LASAF Low-Dose Aspirin, Stroke, and Atrial Fibrillation pilot
study, UK-TIA United Kingdom Transient Ischemic Attack). Reproduced with permission from (39).
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There have been limited randomized controlled trials to assess the efficacy of LWMH for the pre-
vention of thromboembolism in AF. The Anticoagulation for Cardioversion using Enoxaparin (ACE)
trial demonstrated that enoxaparin was not inferior to heparin and phenprocoumon, an oral vitamin K
antagonist with a serum half-life longer than warfarin
(64). The ACUTE II randomized trial compared
the safety and efficacy of enoxaparin with UFH as antithrombotic bridging therapy in patients with
AF of >48
h duration undergoing TEE-guided cardioversion (65). No differences in safety outcomes
were observed between the two strategies; however, the enoxaparin group was associated with a
shorter hospital stay
(65). Further analysis with regard to resource uses and cost effectiveness dem-
onstrated that costs of initial and subsequent hospitalizations, outpatient procedures, and emergency
room visits were lower in the enoxaparin group as were average total costs
(66). Therefore, the use
of enoxaparin as a bridging therapy for patients with AF undergoing TEE-guided cardioversion can
be considered a cost-saving strategy with similar clinical outcomes and lower costs
(66).
NEW ANTITHROMBOTIC THERAPY FOR ATRIAL FIBRILLATION
Given the practical limitations, there has been much interest in finding agents that could replace
warfarin. In the search for an alternative, two key targets in the coagulation cascade have been identi-
fied – factor Xa and thrombin (factor IIa) (Table 2). If a safe and effective alternative is discovered,
it will revolutionize anticoagulation in AF.
Direct Thrombin Inhibitors
Direct thrombin inhibitors bind to thrombin (fibrin bound and fluid-phase) and block its interaction
with substrates
(67). Three parenteral direct thrombin inhibitors are licensed in the United States for
limited clinical indications – hirudin for the treatment of heparin-induced thrombocytopenia (HIT);
argatroban for the treatment of HIT and for patients with or at risk of HIT who are undergoing per-
cutaneous intervention; and bivalirudin as an alternative to UFH in patients undergoing percutaneous
intervention
(62).
Ximelagatran is the first orally active direct thrombin inhibitor and is a prodrug of the active site-
directed thrombin inhibitor, melagatran, which is eliminated via the kidneys (67). Ximelagatran has a
plasma half-life of 4–5
h and is administered orally twice daily without dosage adjustments or moni-
toring compared to warfarin
(67). The Stroke Prevention using an Oral Thrombin Inhibitor in AF
(SPORTIF) III and V trials randomized more than 7,000 patients with non-valvular AF to adjusted-
dose warfarin (INR 2–3) or fixed-dose ximelagatran (68,69). These trials concluded that ximelagatran
was not inferior to warfarin for the prevention of stroke and systemic embolic events. Rates of major
bleeding were similar in the two groups but minor bleeding was lower in the ximelagatran group. The
drug was not approved by the FDA and was removed from the European market due to hepatotoxicity,
an idiosyncratic event which led to the death of three patients in preclinical testing.
Dabigatran etexilate, a prodrug of dabigatran, is an orally active, specific, competitive and revers-
ible inhibitor of thrombin. A phase 3 trial (Randomized Evaluation of Long-term anticoagulant
therapY – the RELY trial) with 14,000 patients is currently underway using dabigatran administered
twice daily for the prevention of stroke or thromboembolism in patients with AF.
Factor Xa Inhibitors
Factor Xa inhibitors block factor Xa either directly by binding to the active site of factor Xa or
indirectly via antithrombin (67). These agents have not yet been systematically evaluated in patients
with AF and cannot be recommended as a therapeutic option at this point in time.
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Antithrombotic Therapy for Atrial Fibrillation and Cardioversion
Table 2
Possible alternatives to warfarin for anticoagulation in atrial fibrillation
Drug Pharmacological target Parenteral Oral Indications Ongoing trials
Direct thrombin
inhibitors
Bind to thrombin and
block its interaction
with substrates
Hirudin Treatment of HIT
Argatroban Treatment of HIT or for
patient with or at high risk
of HIT undergoing PCI
Bivalirudin Alternative to UFH in PCI
Ximelagatran Not approved by FDA Non-inferior to warfarin in
SPORTIF III and V but concerns
over effects on liver enzymes
Dabigatran Undergoing clinical trials RELY trial with 14,000 patients
ongoing for prevention of stroke/
thromboembolism in AF
Factor Xa
inhibitors
Direct inhibitors act by
binding to the active
site of Xa
Rivaroxaban Undergoing clinical trials Ongoing phase 3 non-inferiority
trial in patients with AF and high
risk of stroke
Apixaban Undergoing clinical trials Ongoing phase 3 non-inferiority
trial in patients with AF for
prevention of stroke and phase 3
superiority trial with aspirin
Indirect Factor Xa
inhibitors act via
antithrombin
Fondaparinux
(subcutaneous
injection)
Treatment of ACS and DVT
Idraparinux
(subcutaneous
injection)
Excess bleeding when evaluated for
stroke prevention in AF
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Direct Xa (Anti-Xa) Inhibitors
Direct inhibitors of factor Xa inactivate both free factor Xa and factor Xa incorporated within the
prothrombinase complex
(70). Rivaroxaban and apixaban are oral anti-Xa inhibitors with similar
properties except for the pathway of excretion – renal for rivaroxaban and biliary/fecal for apixaban.
The clinical development of rivaroxaban is more advanced than apixaban with phase 2 trials in
patients with deep vein thrombosis, providing proof of principle for efficacy and safety. Rivaroxaban
is being compared with warfarin in a phase 3 non-inferiority, randomized, controlled trial in patients
with AF at a high risk of stroke (previous ischemic stroke or at least two vascular risk factors)
(62).
Apixaban is being compared with warfarin for the prevention of stroke or thromboembolism in
patients with AF in a phase 3 non-inferiority trial, and is being compared with aspirin in patients with
AF not treated with warfarin in a phase 3 superiority trial
(62).
Indirect Factor Xa Inhibitors
Fondaparinux is the only commercially available agent in this class and has been extensively evalu-
ated in patients with acute coronary syndrome and deep vein thrombosis. It is administered once daily
by subcutaneous injection. Idraparinux is a longer acting subcutaneous agent which only requires
once weekly administration; however, when evaluated for prevention of stroke in patients with AF, it
caused excess bleeding and is no longer being developed for this indication
(62).
ANTICOAGULATION IN PATIENTS
WITH ATRIAL FIBRILLATION IN CLINICAL PRACTICE
Cardioversion
Up to 50% of patients with new onset of AF spontaneously convert back to sinus rhythm within
24
h (71). If this does not occur in the stable patient, pharmacological or electrical cardioversion can
be attempted. The guidelines of anticoagulation are the same irrespective of the approach undertaken-
-electrical or chemical. However, if the patient is hemodynamically unstable (hypotension, cardiac
failure, or ischemia related to arrhythmia) at the time of presentation, immediate cardioversion may
be required without further delay of achieving therapeutic anticoagulation, although heparin--either
intravenous or subcutaneous--should be initiated before cardioversion (1).
Cardioversion without anticoagulation has a risk of thromboembolism that can be as high as 5.6%
and usually occurs within the first week after the procedure (72). There is no significant difference in
this embolic risk between electrical and chemical cardioversions (72). TEE studies have demonstrated
that left atrial mechanical function declines or SEC increases after cardioversion reflecting transient left
atrial mechanical dysfunction or “stunning”
(14). It has also been demonstrated that transmitral atrial
wave does not return to normal until 3–4 weeks after cardioversion (73). These form the basis for the
current recommendations that regardless of the approach to anticoagulation pre-cardioversion and the
method of cardioversion, anticoagulation should be continued empirically for 4 weeks afterwards (1).
Generally, in stable patients without high risk features and with duration of AF <48 h, cardiover-
sion can be performed after the initiation of anticoagulation with heparin (1). In patients with AF
>48 h in duration or AF of uncertain duration, there are two approaches to pre-cardioversion antico-
agulation – either empirical anticoagulation for 3 weeks prior to cardioversion or a TEE-guided strat-
egy (1). With a TEE-guided strategy, TEE is used to exclude atrial thrombi and allow immediate
cardioversion with concomitant heparin (intravenous or subcutaneous). The ACUTE study was a
randomized multi-center clinical trial in which 1,222 patients with either AF persisting longer than
48 h or atrial flutter were randomized to a TEE-guided strategy or a conventional strategy (74). There
was no difference in the rate of stroke or thromboembolism between the two groups (0.81% vs. 0.5%,
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