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Correspondence to: Gregory W. Albers, MD, Stanford Stroke Center, Building B, Suite 325, 701 Welch Rd, Palo Alto, CA 94304-1705; e-mail: albers{at}leland.stanford.edu
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Introduction |
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 TOP Introduction 1. Efficacy of Long-term...2. Anticoagulation for Elective...2.1. AF2.2. Atrial Flutter and...Recommendations 1. Efficacy of...2. Anticoagulation for Elective...References |
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The rate of ischemic stroke among patients with AF included in clinical trials of primary prevention and not treated with antithrombotic therapy averages about 5%/yr, with wide, clinically important variation among subpopulations of AF patients.6 7 8 9 AF becomes an increasingly important cause of stroke with advancing age. In the Framingham Heart Study,2 the attributable risk of stroke in AF patients rose from 1.5% in the 50- to 59-year age group to 23.5% in the 80- to 89-year age group. In patients > 80 years old, AF was the only cardiovascular condition associated with an increased risk of stroke.2
This chapter deals primarily with stroke prevention when AF is not associated with rheumatic mitral valve disease or prosthetic heart valves. These specific conditions are discussed in the chapters on valvular heart disease and prosthetic heart valves.
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1. Efficacy of Long-term Antithrombotic Therapy in AF |
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TOPIntroduction1. Efficacy of Long-term...2. Anticoagulation for Elective...2.1. AF2.2. Atrial Flutter and...Recommendations 1. Efficacy of...2. Anticoagulation for Elective...References |
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Aspirin vs Placebo or Control:
Five studies compared aspirin
with control: four studies7
11
12
14
15
16
were
placebo-controlled, and one study23
had a nontreatment
control. The dose of aspirin varied between 325
mg/d16
and 125 mg every second day.23
OAC vs Aspirin:
Five studies7
13
15
22
25
compared OAC with aspirin. In SPAF-2,22
patients who had
been randomized to aspirin or warfarin in the SPAF-1
study16
continued with their assigned treatment. Patients
originally assigned to placebo and 419 new patients were randomized to
warfarin or aspirin. Randomization was stratified according to the
patient’s age (< 75 years; 
75 years).
OAC vs Low-Dose OAC and Aspirin:
In the SPAF-3 high-risk
study,8
AF patients who had at least one of four
thromboembolic risk factors (congestive heart failure or left
ventricular [LV] fractional shortening 
25%, history of a
previous thromboembolism, systolic BP > 160 mm Hg at study entry, or
female gender > 75 years old) were randomized to either a combination
of low-intensity, fixed-dose warfarin (INR 1.2 to 1.5; daily dose of
warfarin 3 mg) plus aspirin (325 mg/d), or to adjusted-dose
warfarin (target INR 2.0 to 3.0). The AFASAK-2
study13
randomized patients to warfarin, 1.25 mg/d, and
aspirin, 300 mg/d, or to adjusted-dose warfarin (target INR 2.0 to
3.0).
OAC vs Low-Dose Anticoagulation:
Three
studies13
24
25
have compared adjusted-dose
anticoagulation with lower doses of OAC: warfarin, 1.25 mg/d, in two
studies,13
24
and warfarin (target INR 1.1 to 1.6) in the
third study.25
Other Antiplatelet Agents:
The Studio Italiano
Fibrillazione Atriale (SIFA) study10
randomized AF
patients with a recent nondisabling stroke or transient ischemic attack
(TIA) to therapy for 1 year with either indobufen (a reversible
inhibitor of cyclooxygenase), 200 mg bid, or warfarin (INR 2.0 to 3.5)
within 15 days of the qualifying ischemic event. In the second European
Stroke Prevention Study (ESPS-2),11
12
patients with a TIA
or stroke within the previous 3 months were randomized to one of four
treatments: (1) placebo; (2) aspirin, 25 mg/d bid; (3) extended-release
dipyridamole, 200 mg/d bid; or (4) aspirin, 25 mg/d bid, and
extended-release dipyridamole, 200 mg/d bid.
Aspirin Therapy in Low-Risk Patients:
Finally, in the SPAF-3
low-risk study,9
AF patients considered to be at low risk
of stroke, based on the absence of any of the four risk factors in the
SPAF-3 high-risk study8
(see above), were administered
aspirin only, 325 mg/d, and followed in a nonrandomized, longitudinal,
cohort study. This nonrandomized study does not provide data regarding
the efficacy of aspirin for stroke prevention, but it is useful in
determining the risk of stroke in selected patients with AF who are
treated with aspirin.
Outcome Events
The primary outcome events in each study are listed in Table 1 .
The data reported herein are the results of the intention-to-treat
analyses, although it is not clear if the data in the study by Posada
and Barriales23
were analyzed according to the
intent-to-treat principle. All studies considered stroke a primary
event, and some studies also included other vascular events as primary
events. The definition of major bleeding varied slightly among studies.
In general, bleeding was classified as major if transfusion was
required, if the patient was hospitalized, or if the bleeding occurred
in a critical anatomic location (eg, intracranial,
perispinal). The criteria used by the BAATAF
investigators17
were different: intracranial bleeding,
fatal bleeding, or bleeding leading to transfusion of 4 U of blood
within 48 h.
Primary Results
The primary results of the studies are summarized in Tables 3 , 4
.
OAC vs Control:
In all randomized studies comparing
adjusted-dose warfarin anticoagulation with placebo or control, there
was a decrease in the rate of primary outcome events in adjusted-dose
anticoagulation-treated patients compared with control patients, which
reached or exceeded conventional statistical significance in all
studies except the CAFA study.18
The CAFA
study18
was stopped early because of the results of the
other trials (Table 3)
. Pooling the results of all of these
trials except the EAFT7
in an intention-to-treat
analysis revealed an annual stroke rate of 4.5% for the control
patients and 1.4% for the adjusted-dose warfarin patients (relative
risk reduction [RRR] = 68%; 95% confidence interval [CI], 50 to
79%; number needed to treat for 1 year [NNT] = 32).6
The percentage of strokes that were classified as moderate, severe, or
fatal ranged between 43% and 64%. Anticoagulation was effective for
preventing strokes of all severities; there was no evidence that the
strokes occurring in anticoagulated patients were more severe. In the
EAFT,7
which enrolled only patients with a TIA or stroke
within the previous 3 months, the RRR was virtually identical,
although the absolute risk of stroke was higher; the annual rate of
stroke in control patients was 12% vs 4% in anticoagulated patients
(RRR = 66%; 95% CI, 43 to 80%; p < 0.001; NNT = 13).
There was no significant increase in major bleeding events in adjusted-dose anticoagulation-treated patients in these randomized trials (Table 4) . In five of the studies (the EAFT7 was excluded), anticoagulation lowered the death rate by 33% (95% CI, 9 to 51%) and lowered the combined outcome of stroke, systemic embolism, and death by 48% (95% CI, 34 to 60%).6
Aspirin vs Placebo or Control:
The evidence supporting the
superiority of aspirin to placebo is less robust than the evidence for
warfarin. In the AFASAK-1 study,15
the EAFT,7
the ESPS-2,11
and the study by Posada and
Barriales,23
the relative reduction in the stroke rate was
generally small and not statistically significant. In contrast, the
SPAF-116
showed a statistically significant RRR of 42%.
In the SPAF-1,16
the efficacy of aspirin was apparent in
only one of the two component subtrials. When the data from the
AFASAK-1 study,15
the EAFT,7
and the
SPAF-116
were combined in an individual-patient analysis,
aspirin therapy was associated with a 21% reduction in the risk of
ischemic stroke (annual stroke rate, 8.1% in control patients and
6.3% in aspirin-treated patients; p = 0.05; 95% CI, 0 to
38%).26
One meta-analysis27
combining all
four published trials as well as a small unpublished study found a
virtually identical 22% reduction in the risk of stroke. A second
meta-analysis28
concluded the aspirin results were
heterogeneous, resulting in a substantially broader CI: RRR = 24%
(range, - 33% to + 66%).
Adjusted-Dose Anticoagulation vs Aspirin:
In the AFASAK-1
study15
and the EAFT,7
adjusted-dose OAC
decreased the risk of primary events by 48% and 40%, respectively,
compared with aspirin, 300 mg/d (both results were statistically
significant). The results of the SPAF-2 study22
were
reported separately for patients 75 years of age (mean age, 65
years) and for patients > 75 years (mean age, 80 years; Table 3
). In
the younger group, adjusted-dose warfarin therapy decreased the rate of
stroke by 33%, compared with a 27% reduction in the older patients
(both differences were not statistically significant). However, in
SPAF-2,22
many of the strokes occurred in individuals who
had discontinued treatment with OACs. The AFASAK-2 study13
was stopped about midway through the planned enrollment; therefore, it
did not have substantial power to detect a difference between the two
drugs. In the AFASAK-2 study,13
the annual risk of primary
events was increased slightly in adjusted-dose warfarin-treated
patients compared with those receiving aspirin (3.4% vs 2.7%),
although the difference was not statistically significant. The study by
Hellemons et al25
reported a 19% RRR of stroke with OAC,
which was not statistically significant. Finally, the SPAF-3 high-risk
study8
found a marked superiority of adjusted-dose
warfarin (INR 2.0 to 3.0) over low-dose warfarin plus aspirin (see next
paragraph). Over all, these results suggest that the RRR associated
with adjusted-dose warfarin is considerably greater than that provided
by aspirin. A recent meta-analysis27
of these five studies
reported a 36% RRR (95% CI, 14 to 52%) of all stroke with
adjusted-dose OAC compared with aspirin, and a 46% reduction (95% CI,
27 to 60%) in the risk of ischemic stroke. The difference between the
two analyses was largely due to the increased rate of intracranial
hemorrhage in the SPAF-2 study.22
Of note, the target INR
range (2.0 to 4.5) in the SPAF-2 study22
extended
above currently recommended intensities.
Adjusted-Dose Anticoagulation vs Low-Dose Anticoagulation Plus
Aspirin:
The SPAF-3 high-risk study8
was terminated
early at the suggestion of the External Safety Monitoring Committee
because of a substantially increased rate of primary outcome events in
patients receiving combination therapy with fixed-dose, low-intensity
warfarin (INR 1.2 to 1.5; maximum daily dose, 3 mg) plus aspirin, 325
mg/d (7.9%/yr) compared with those receiving adjusted-dose warfarin
with a target INR of 2.0 to 3.0 (1.9%/yr). The absolute difference in
stroke rate of 6%/yr translates into a NNT of 17. The high stroke rate
in the combination therapy arm of this trial8
suggests
that the low-intensity anticoagulation selected for this study was
ineffective in these high-risk AF patients. In addition, no evidence of
a synergistic effect of the low-dose warfarin/aspirin combination could
be detected. No significant differences in the rates of major
hemorrhage were detected between the two groups (Table 4) .
The smaller AFASAK-2 study13 of moderate-risk patients (excluded were patients < 60 years old with lone AF and those with a history of stroke or TIA in the past 6 months or BPs > 180/100 mm Hg) was stopped prematurely following the publication of the SPAF-3 data.8 Analysis of their data demonstrated no differences, with an annual rate of primary events of 3.4% in patients receiving adjusted-dose warfarin (INR 2.0 to 3.0) compared with 3.2% in patients receiving aspirin, 300 mg, with fixed-dose warfarin, 1.25 mg/d.13
Adjusted-Dose OAC vs Low-Dose Anticoagulation:
In the
studies13
24
comparing adjusted-dose warfarin with
warfarin, 1.25 mg/d, the risk of stroke was reduced by 13% and 42% in
the adjusted-dose anticoagulation groups, respectively, both not
statistically significant. In another recent study,25
the
risk of stroke was slightly lower in patients randomized to a target
INR of 1.1 to 1.6, compared with OAC with a target INR of 2.5 to 3.5
(RRR = 14%), although this difference is likely due to chance.
Combining the results from all three trials in a
meta-analysis27
yielded an RRR of 38% (95% CI, 20 to
68%) in favor of adjusted-dose OAC, which was not statistically
significant.
OAC vs Other Antiplatelet Agents:
In the one randomized trial10
comparing adjusted-dose
warfarin with indobufen, there was no significant difference in the
incidence of primary events (stroke, myocardial infarction [MI],
pulmonary embolism, or vascular death) between the two groups (12% in
indobufen group vs 10% in warfarin group; p = 0.47). There were four
major GI hemorrhages in the warfarin group compared with none in the
indobufen group. The frequency of major bleeding episodes was 0.9% in
the warfarin group and 0% in the indobufen group. Indobufen is not
currently available in North America. However, the SIFA
study10
results suggest that additional studies of this
agent may be warranted.
For a discussion of when to begin anticoagulation after a stroke in AF patients, please refer to the chapter on "Antithrombotic and Thrombolytic Therapy for Ischemic Stroke."
Risk of Intracranial Hemorrhage
Intracranial hemorrhage is the most feared complication of
anticoagulant therapy because it is frequently fatal or permanently
disabling. Observational studies29
30
from large
anticoagulation clinics demonstrate that the risk of intracranial
hemorrhage rises dramatically at INR values > 4.0 to 5.0. Overall,
the initial randomized trials comparing anticoagulation with control or
placebo for AF were reassuring about the rate of intracranial
hemorrhage (Table 4)
. However, a substantially higher rate of
intracranial hemorrhage was observed in the SPAF-2
study.22
In particular, seven intracranial hemorrhages
were observed among patients > 75 years old, for an annualized rate
of 1.8%, compared with 0.8% in patients receiving aspirin. In
contrast, taken together, the earlier primary prevention trials
observed a rate of intracranial hemorrhage of only 0.3%/yr among
patients > 75 years old, one sixth of that seen in the SPAF-2
study.31
In the secondary prevention EAFT
study,7
32
the average age at entry was 71 years and no
intracranial hemorrhages were reported, although a CT scan was not done
in all patients with symptoms of stroke. In the high-risk arm of
SPAF-38
(mean age, 71 years; mean INR, 2.4; target INR,
2.0 to 3.0), the rate of intracranial hemorrhage was 0.5%/yr compared
to a rate of 0.9%/yr in the aspirin plus low-dose warfarin arm. The
AFASAK-2 study14
recently reported two intracranial
hemorrhages in the INR 2.0 to 3.0 arm for an annual rate of 0.6%,
compared to 0 to 0.3%/yr rates in the three other treatment arms.
The reasons for the unusually high intracranial hemorrhage rate in the SPAF-2 trial33 in patients > 75 years old as compared with the other studies are not entirely clear, although the patients were older than in any other AF trial, and the target anticoagulation intensity was high (INR 2.0 to 4.5). The importance of high INR levels in increasing the risk of intracranial hemorrhage was further reinforced by the SPIRIT trial,34 a non-AF secondary stroke prevention trial that used an INR target intensity of 3.0 to 4.5. In the SPIRIT trial,34 the annual rate of intracranial hemorrhage was > 3% among patients treated with anticoagulants. This rate was strongly related to INR values, particularly INR > 4.0.
Optimal Level of Anticoagulation for AF
Only limited data are available directly comparing different
intensities of OAC in patients with AF.8
However, the
results of the randomized trials and of observational studies of
clinical practice provide fairly consistent evidence about the optimal
level of anticoagulation for AF. The initial set of randomized trials
of OAC vs control employed a range of target intensities, both
prothrombin time ratio-based and INR-based. The BAATAF
study17
and the SPINAF study19
used the
lowest target intensity, prothrombin time ratio 1.2 to 1.5,
corresponding roughly to an INR range of 1.5 to 2.7. Anticoagulation
appeared just as effective at preventing strokes in these trials as in
the others using a higher target intensity. A target INR of 1.2 to 1.5
was ineffective in the high-risk SPAF-3 trial,8
even when
combined with aspirin, 325 mg/d. There were too few patients in the
AFASAK-2 study14
to reliably determine the efficacy of
low-dose warfarin (1.25 mg/d) or low-dose warfarin combined with
aspirin (325 mg/d) compared with warfarin (INR 2.0 to 3.0; annual event
rates of 3.9%, 3.2%, and 3.4%, respectively). To our knowledge, no
trials have compared target intensities between an INR of 1.5 to 2.0
with an INR between 2.0 and 3.0 in a randomized fashion. One
trial25
compared an INR range of 1.1 to 1.6 with an INR
range of 2.5 to 3.5. No difference in efficacy was detected; however,
the low event rates in this study limit the power to detect a
difference. The EAFT32
found a decrease in efficacy below
an INR of 2.0, but the trial could not assess gradations in INR
< 2.0. A case-control study35
based in a large
anticoagulation unit found that INR levels > 2.0 added little
efficacy, while the risk of stroke increased at INR levels < 2.0. For
example, the odds of stroke doubled at an INR of 1.7 and tripled at an
INR of 1.5 compared to an INR of 2.0, and increased even more
dramatically if the INR was < 1.5. A second hospital-based
case-control study36
also found a sharp increase in risk
of stroke among AF patients with INR values < 2.0.
The optimal level of anticoagulation in AF is that level that preserves efficacy in preventing ischemic strokes while minimally increasing the risk of major hemorrhage, especially intracranial hemorrhage. In two studies,29 30 the risk of intracranial hemorrhage was fairly low at INR values < 4.0 but was sharply higher at greater INR levels. Several studies29 33 37 38 39 have shown that the risk of bleeding while receiving oral anticoagulants increased among older patients. The risk of ischemic stroke is low down to INR values of 2.0. Since randomized trials have successfully used INR targets of 2.0 to 3.0, this target range seems an appropriate standard. There is currently no evidence about whether this range should be changed for the very elderly (patients > 75 years old), who have both a higher risk of stroke and bleeding while receiving oral anticoagulants than younger patients.29 33 37 38 39 Suggested opinions from the literature for anticoagulation of very elderly patients include aiming for a target INR of 2.5 (range, 2.0 to 3.0) with especially close monitoring35 (which is consistent with our recommendation) or a target INR of 2.0 (range, 1.6 to 2.5).40 41
Risk Stratification in Patients With AF
Numerous studies have demonstrated that OAC is very effective in
decreasing the risk of stroke in patients with AF and that it is
considerably more effective than daily aspirin. It is also clear that
OAC is associated with a higher frequency of hemorrhage and is more
inconvenient than aspirin. Each individual AF patient’s risk of stroke
and hemorrhage must be considered when making the decision about the
best antithrombotic preventive therapy.
The risk of stroke among AF patients not receiving anticoagulants has been studied in subjects participating in several of the randomized trials of antithrombotic therapy.6 42 43 44 45 The Atrial Fibrillation Investigators (AFI) group6 analyzed the data from the pooled control groups of the first five primary prevention trials and found the following independent risk factors for stroke in AF: prior stroke or TIA (relative risk [RR] = 2.5), age (RR = 1.6/decade), history of hypertension (RR = 1.6), and diagnosis of diabetes mellitus (RR = 1.7). In addition, patients < 80 years of age whose only stroke risk factor was coronary artery disease (previous MI or angina) had stroke rates of 4.6%/yr if not receiving anticoagulants. In essence, patients > 65 years old and/or those with any of these risk factors faced a substantial annual risk of stroke. This risk was lowered to about 1.5%/yr with adjusted-dose anticoagulant therapy. A subsequent AFI analysis43 of echocardiograms done in three of the original trials found that moderate-to-severe LV dysfunction was an additional strong risk factor (RR = 2.5). Left atrial diameter was not related to risk of stroke in AF.
The AFI analyses6
included data from the untreated control
group of the SPAF-1 study.16
The SPAF Investigators
recently published44
an analysis of risk factors for
stroke among the 2,012 patients allocated to the aspirin arms of the
SPAF-1, SPAF-2, and SPAF-3 randomized trials (in SPAF-3, aspirin was
combined with very-low-intensity anticoagulation) and the SPAF-3
aspirin cohort study. Six features were found to be significant
independent risk factors: prior stroke or TIA (RR = 2.9), age
(RR = 1.8/decade), history of hypertension (RR = 2.0), systolic BP
> 160 mm Hg (RR = 2.3), female gender (RR = 1.6), and alcohol
consumption of 14 drinks/wk (RR = 0.4, ie, protective).
When patients with a prior stroke or TIA were excluded from the
analysis, female gender was no longer significant, but the other
features remained significant. Diabetes was a univariate risk factor
(RR = 1.6) that dropped out of the multivariable model. The SPAF
analysis provided an additional provocative finding. Among women in the
SPAF-3 studies,8
hormone replacement therapy was found to
be a powerful independent correlate of stroke risk (RR = 3.2). On the
basis of these analyses, the SPAF Investigators44
proposed
stratifying patients with AF into categories of high, moderate, and low
risk of stroke. Overall, high-risk patients faced a > 7%/yr risk of
stroke; moderate-risk patients, 2.5%/yr; and low-risk patients, about
1%/yr. The features qualifying for these three risk strata are as
follows: (1) high risk (any of the following: prior stroke or TIA,
women > 75 years old with a history of hypertension; or systolic BP
> 160 mm Hg at any age); (2) moderate risk (history of hypertension
and age 75 years, or diabetes); (3) low risk (no high-risk or
moderate-risk features). Patients with multiple risk factors appear to
be at substantially higher stroke risk than those with a single risk
factor.44
45
It is clear that the AFI and SPAF risk stratification schemes are
largely consistent with each other. Prior stroke or TIA, older age,
hypertension, and diabetes are considered by both analyses to be risk
factors for stroke in AF. Unlike the AFI analysis, the SPAF scheme
emphasizes the impact of age in women and separates the effect of
hypertension into an effect associated with the diagnosis itself and an
effect due to elevated systolic BP at examination. There is, as well, a
difference in the observed absolute risks of stroke. For patients
without a history of stroke or TIA, the annual risk of stroke in the
AFI data was 4.0% vs 2.7% in the SPAF data. This difference may be
the result of differences in patient populations, chance, or a
therapeutic benefit of aspirin among the SPAF patients. Such small
differences can affect the decision to use anticoagulants in apparently
lower-risk patients. The different impact of age in the AFI and SPAF
risk schema probably affects the greatest percentage of AF patients. In
particular, the AFI scheme would view all patients 65 years old as
at high risk for stroke, including those without any other risk factor
for stroke. By contrast, the SPAF scheme would view women with AF
75 years old and men of any age, without other risk factors, as at
low risk of stroke. The resulting uncertainty about the risk faced by
AF patients aged 65 to 75 years and men of any age without other risk
factors applies to roughly 20% of the entire population with
AF.46
A recurrent clinical concern is whether patients with paroxysmal, or intermittent, AF (PAF) face the same risk of stroke as those with sustained AF. Periods of sinus rhythm should lessen stroke risk, yet transitions from AF to sinus rhythm may acutely heighten risk in a manner similar to the increase in risk caused by cardioversion (see below). Retrospective studies47 48 suggest that PAF is associated with a lower risk of stroke than chronic AF. These epidemiologic data suggest that PAF has an intermediate risk of stroke between constant AF and sinus rhythm. However, when associated stroke risk factors are controlled for, clinical trial data suggest that PAF confers an RR of stroke similar to constant AF.6 49 Patients with PAF tend to be younger and have a lower incidence of associated cardiovascular disorders than those with constant AF; therefore, their absolute stroke rate is lower. The RRR provided by warfarin appears to be similar for patients with both PAF and constant AF. This conclusion, however, is limited by the relatively small number of patients (about 12% in the first five randomized trials6 ) with PAF participating in the trials. Analyses of PAF are complicated by the fact that PAF patients differ greatly in the frequency and length of AF episodes. Studies of PAF are also limited by significant differences in patient awareness of their episodes of AF. The risk-benefit ratio for anticoagulation therapy in patients with PAF therefore remains imprecise. In patients with very infrequent and brief episodes of AF, the benefits of warfarin therapy may be offset by inconvenience and bleeding risks. In patients with frequent or prolonged paroxysms of AF, particularly those with stroke risk factors, warfarin therapy should be strongly considered.
The risk of stroke in patients with atrial flutter may be higher than previously assumed, as suggested in a retrospective analysis50 of 100 patients with atrial flutter. This assumption is also supported by the results of a study51 that evaluated the risk of thromboembolism in 191 consecutive unselected patients referred for treatment of atrial flutter, and documented an embolic event rate of 7% during 26 months of follow-up. These studies differ from earlier reports52 that found no risk of stroke or thromboembolism related to atrial flutter. To our knowledge, the role of anticoagulation therapy for patients with atrial flutter has not been evaluated in clinical trials; however, because these patients have a significant risk of developing AF, it may be reasonable to use similar antithrombotic therapies for stroke prevention.
AF develops in 10 to 15% of patients with thyrotoxicosis and is most
common in patients 60 years of age, presumably reflecting an
age-related reduction in the threshold for developing
AF.47
The prevalence of thyrotoxicosis in patients with AF
is 2 to 5%.47
Some studies53
54
55
56
57
have
reported a high frequency of stroke and systemic embolism in patients
with thyrotoxic AF, although one study58
did not find a
statistically significant difference when AF patients were compared to
age- and sex-matched patients with normal sinus rhythm. Some of these
studies have methodologic problems, which complicate interpretation of
the results.47
Accordingly, available studies do not
confirm that thyrotoxic AF is a more potent risk factor for stroke than
other causes of AF. Since the incidence of thromboembolic events in
patients with thyrotoxic AF appears to be similar to other etiologies
of AF,47
antithrombotic therapies should probably be
chosen based on associated risk factors (see "Recommendations"
section).
Left atrial size can be adequately assessed by transthoracic
echocardiography, but other abnormalities of the left atrium can be
seen via transesophageal echocardiography (TEE). While this
modestly invasive approach is commonly used as an adjunct to elective
cardioversion, it has also been applied to studies of outpatients with
chronic AF.59
60
Spontaneous echo contrast (a marker
of stasis) and frank thrombi in the left atrium appear to confer a
twofold to fourfold increase in risk of subsequent stroke. The vast
majority (> 90%) of these thrombi involve or are confined to the
left atrial appendage. Patients with TEE-detected aortic plaques with
complex features (mobile, pedunculated, ulcerated, or 4 mm in
diameter) had extremely high stroke rates in the SPAF-3
study.8
At present, there is no clear evidence that TEE
findings add independently to risk stratification when clinical and
transthoracic echocardiographic risk factors are considered.
Finally, studies have shown that AF patients with prosthetic heart valves (both mechanical and tissue valves) or rheumatic mitral valve disease are at high risk of stroke (see the chapters on valvular heart disease and prosthetic valves) and should be treated with adjusted-dose warfarin.
The purpose of risk classification schemes is to identify subgroups of patients with different risks of stroke: those in whom the risk of stroke is so high that warfarin is clearly indicated unless their risk of bleeding is very high, and those in whom the risk of stroke is sufficiently low that warfarin need not be used. Although there are groups of patients who clearly fall into these categories, there are also patients for whom the choice of warfarin vs aspirin is more difficult. Patients with AF who have at least one of the following risk factors are at high risk of stroke and should be offered OAC unless their risk of bleeding is high: previous stroke or TIA or systemic embolism, age > 75 years old, history of hypertension, prosthetic heart valve (mechanical or tissue valve), or rheumatic mitral valvular disease. Patients with poor LV systolic function also appear to be at high risk. The risk factor status is less secure in those age 65 to 75 years, in those with diabetes mellitus, and in those with coronary artery disease in the absence of LV dysfunction. However, we recommend anticoagulation if more than one of these "less severe" risk factors are present. Patients without cardiovascular disease or risk factors who are < 65 years old are at such low risk of stroke that they should be treated with aspirin alone. For patients who do not meet the high-risk or low-risk criteria, the absolute benefit of warfarin therapy is likely to be small. Treatment decisions should be individualized and consideration given to patient preferences and risk factors for bleeding.
Anticoagulation is a potentially risky therapy that imposes a variety of lifestyle constraints on patients. As a result, patient education and involvement in the anticoagulation decision is important. Many AF patients have a great fear of suffering a stroke and wish to take warfarin for a relatively small decrease in the risk of stroke,61 while others who are at relatively low risk for stroke will want to avoid the burdens and risks of anticoagulation and opt for aspirin.62 63 64 The safe use of anticoagulants depends on patient cooperation and a monitoring system that can achieve INR targets on a regular basis. The AFASAK-2 study13 demonstrates that anticoagulation at an INR of 2.0 to 3.0 can be quite safe even for elderly patients, and the study by Palareti et al38 demonstrates that low hemorrhage rates can be duplicated in clinical practice outside of trials, particularly if anticoagulation clinics are involved.
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10 days after cardioversion, the majority of these adverse
events occur during the first 72 h after cardioversion and are
presumed to be the result of thrombi present within the left atrium at
the time of cardioversion.71
New thrombus may develop
after DC cardioversion and highlights the importance of periconversion
anticoagulation (see below). The duration of anticoagulation before
cardioversion is not clearly defined, as the majority of these studies
were retrospective analyses, but specific recommendations of 3 to 4
weeks of prophylactic adjusted-dose warfarin therapy before and after
have been made by many investigators.72
73
In the
recommendations that follow, clinical observations and the data from
several of these studies are utilized. The vast majority of data on cardioversion-related thromboembolism are based on electrical cardioversion. There are limited clinical data that have examined the issue of embolization after pharmacologic or spontaneous cardioversion of AF to sinus rhythm. Goldman74 reported that embolism occurred in 1.5% of 400 patients treated with quinidine for reversion of AF to sinus rhythm. This was similar to the 1.2% incidence of embolization that Lown68 reported in 450 electrical cardioversions in patients not receiving anticoagulants. Therefore, it seems prudent to administer anticoagulants to individuals undergoing pharmacologic cardioversion in a similar manner to those undergoing electrical cardioversion.
The mechanism of benefit conveyed by the month of warfarin treatment prior to elective cardioversion had previously been ascribed to the promotion of thrombus organization and adherence to the atrial wall.74 More recently, serial TEE studies75 76 77 of those presenting with new-onset AF and atrial thrombi on initial TEE have demonstrated resolution of the atrial thrombi after 1 month of warfarin treatment in the majority of subjects. It thus appears that the month of warfarin treatment may also facilitate "silent" thrombus resolution.
The immediate postcardioversion period is associated with increased risk for thrombus formation. Utilizing TEE, further depression of atrial appendage velocities, more intense left atrial spontaneous echocardiographic contrast, and even new thrombus formation have been described after external DC, internal DC, and even spontaneous cardioversion.78 79 80 81 These data underscore the importance of therapeutic anticoagulation during the pericardioversion period. Following restoration of normal atrial electrical activity on the surface ECG, the mechanical contraction of the body of the left atrium may remain dysfunctional for as long as 2 to 4 weeks after cardioversion.82 83 84 For this reason, adjusted-dose anticoagulation should be continued for 1 month after cardioversion. In addition to prophylaxis against new thrombus formation during recovery of atrial mechanical activity, warfarin also serves as prophylaxis against thrombus formation should the patient revert to AF.
Therefore, for patients with AF, the following are recommended: (1) therapeutic warfarin (target INR 2.5; range, 2.0 to 3.0) anticoagulation should be given for 3 weeks before elective cardioversion; (2) anticoagulation should be continued for 4 weeks after successful cardioversion because it will decrease the likelihood that a fresh thrombus will form in the noncontractile left atrial appendage if the resumption of mechanical contraction is delayed, and it will decrease the formation of thrombus if AF recurs soon after successful cardioversion. For patients presenting with their first episode of AF, long-term anticoagulation beyond the first 4 weeks after cardioversion may be indicated if the patient has high clinical risk factors for stroke or is at high risk for recurrent AF (enlarged left atrium, significant LV dysfunction). If AF recurs, long-term (after 1 month) anticoagulation decisions should be based on the previously described clinical and echocardiographic criteria for chronic or paroxysmal AF.
Over the past decade, an alternative strategy has been suggested for cardioversion of patients with AF of > 2 days or of unknown duration. Among patients with AF, the vast majority (> 90%) of thrombi are located within, or involve, the left atrial appendage.75 76 81 84 85 While the detection of left atrial appendage thrombi is unreliable utilizing conventional transthoracic echocardiography, biplane and multiplane TEE have demonstrated very high accuracy86 87 and therefore offer the opportunity to perform early cardioversion for those in whom no atrial appendage thrombi are observed. Systemic anticoagulation with IV heparin and/or warfarin should still be employed at the time of TEE and cardioversion because of the concern that new thrombus may form during the pericardioversion or postcardioversion period. Data from several studies75 76 81 84 85 currently suggest rates of thromboembolism that are similar to those associated with standard therapy, with the advantages of an earlier recovery of atrial mechanical function, ease of anticoagulation management, elimination of the need for hospital readmission for elective cardioversion, and of cost-effectiveness if performed expeditiously and without a somewhat redundant transthoracic echocardiographic examination.88 Limitations of the TEE approach include patient discomfort, rare procedural complications, and limited availability at some centers.
Stroke has been described among patients who did not receive anticoagulation at the time of TEE or continued anticoagulation for a full month after cardioversion despite the absence of left atrial appendage thrombi on TEE.89 90 91 92 93 These adverse events may have occurred because the sensitivity of TEE for small atrial appendage thrombus is not 100%, development of new thrombus because of transient atrial dysfunction during the postcardioversion period, or other mechanisms. Because of uncertainty regarding the role of TEE in guiding anticoagulant therapy at the time of electrical cardioversion, a large (> 1,000 patients) randomized multicenter international study, Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE), comparing conventional vs the novel TEE approach is currently underway. The results of the ACUTE pilot study75 comparing TEE-guided cardioversion with standard management of cardioversion in AF patients have been reported. Sixty-two of 126 patients who had AF lasting > 48 h were randomly selected to receive TEE-guided cardioversion. TEE was performed in 56 patients, and atrial thrombi were found in 7 patients. Cardioversion was successful in 38 of 45 patients who had early cardioversion. There were no embolic events in the patients who were free of left atrial thrombus. There was one embolic event (1.6%) occurring 3 days after cardioversion in a patient randomized to the conventional management group. Though cardioversion occurred earlier in the TEE-guided group, there was no difference in the likelihood of sinus rhythm at 8 weeks after cardioversion.
For AF of short duration (< 48 h), the usual clinical practice is to perform cardioversion without TEE or prolonged precardioversion anticoagulation. This practice was called into question when a study94 reported a 13% prevalence of atrial thrombi on TEE among patients with AF of < 72 h duration. Subsequently, however, data were reported from a study95 of 357 patients who had a symptomatic duration of AF for < 48 h. Two hundred fifty patients converted spontaneously, and 107 underwent pharmacologic or electrical cardioversion, all without screening TEE or a month of warfarin treatment prior to cardioversion. Clinical thromboembolism occurred in three subjects (< 1%), all of whom were elderly woman without a history of prior AF and with normal LV systolic function. Preliminary data from the Canadian AF Registry94 96 also suggest a very low incidence of adverse events if these patients undergo early cardioversion. Although safe in these studies, it may be prudent to perform TEE or delay cardioversion for 1 month for very high-risk patients (eg, patients with a history of prior stroke/thromboembolism or severe LV systolic dysfunction)
While patients with short-duration AF (< 48 h) may not require TEE or a month of prolonged warfarin treatment prior to cardioversion, it may be prudent to initiate heparin anticoagulation at presentation. Many of these patients will require anticoagulation after cardioversion, and the use of heparin will further decrease the likelihood of new thrombus formation during the pericardioversion period.
Anticoagulation for Emergency Cardioversion of AF Patients
Emergency cardioversion is performed to terminate atrial
tachyarrhythmias with a rapid ventricular response causing angina,
heart failure, hypotension, or syncope. In individuals with impaired
ventricular function, clinical deterioration may occur within minutes
or hours of the onset of the arrhythmia, and urgent electrical or
pharmacologic cardioversion is indicated. The role of anticoagulation
in these circumstances remains controversial, but heparin therapy at
the time of cardioversion may be useful to prevent thrombi from forming
due to further atrial appendage dysfunction after cardioversion.
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Risk Stratification
High-risk factors include prior stroke/TIA or systemic embolus,
history of hypertension, poor LV systolic function, age > 75 years,
rheumatic mitral valve disease, and prosthetic heart valve.
Moderate-risk factors (factors for stroke that have been identified in
AF patients in various studies but are not as strong or consistent as
the high-risk factors listed above) include age 65 to 75 years,
diabetes mellitus, and coronary artery disease with preserved LV
systolic function.
High-Risk Patients
1.1. We recommend the use of adjusted-dose warfarin
anticoagulation (target INR 2.5; range 2.0 to 3.0) rather than aspirin
in patients with AF at high risk for ischemic stroke because it
markedly decreases the risk of ischemic stroke in patients with AF
(grade 1A).
1.2. For high-risk patients, we recommend that clinicians offer aspirin therapy if adjusted-dose warfarin is contraindicated or declined by the patient and if there are no contraindications to aspirin (grade 1A).
1.3. We recommend that clinicians do not use aspirin plus low-fixed-dose warfarin therapy (grade 1A).
1.4. Although to our knowledge no randomized trials of OAC have been undertaken in AF patients with rheumatic mitral valve disease or prosthetic heart valves (mechanical or tissue valves), we recommend that clinicians use OAC in these patients (grade 1C+).
Low-Risk Patients
1.6. We recommend that patients with AF who are < 65 years with
no clinical or echocardiographic evidence of cardiovascular disease
should be treated with aspirin (grade 2C).
Moderate-Risk Patients
1.7. Some AF patients will have a risk of stroke that is between
that of the high-risk and low-risk groups mentioned. For these
patients, the absolute stroke RR of warfarin vs aspirin is likely to be
small. We recommend the use of either OAC or aspirin for patients with
one of these moderate risk factors (grade 1A in comparison to no
treatment).
1.8. Patients with more than one of these moderate-risk factors are at higher risk of stroke than are those with only one risk factor, and we recommend to treat these patients in the same manner as high-risk patients (see above; grade 2C).
The ultimate choice of therapy depends on many factors, including the clinician’s assessment of the magnitude of the patient’s risk (eg, whether the patient has single or multiple risk factors), the ability to provide high-quality monitoring of the intensity of OAC, the patient’s risk of bleeding with OAC, and patient preference.
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2.1.2. Alternatively, we recommend that AF patients undergo anticoagulation then undergo TEE, and have cardioversion performed without delay if no thrombi are seen (grade 1C). For these patients, adjusted-dose warfarin therapy should still be continued until normal sinus rhythm has been maintained for at least 4 weeks.
2.1.3. Although data are limited, the risk of embolism following cardioversion in patients who have been in AF for < 48 h appears to be low. However, we recommend the use of anticoagulation during the pericardioversion period (grade 2C).
2.2. Atrial Flutter and Supraventricular Tachycardia
2.2.1. We recommend that clinicians manage OAC at the time of
cardioversion in patients with atrial flutter in a manner similar to
that used for AF (grade 2C).
2.2.2. In the absence of prior thromboembolism, we do not recommend antithrombotic therapy for cardioversion of supraventricular tachycardia (grade 2C).
Treatment of potential precipitants of AF (ie, thyrotoxicosis, pneumonia, congestive heart failure) should be completed prior to attempting elective DC cardioversion.
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References |
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