Anticoagulation to prevent embolization in atrial fibrillation

Warren J Manning, MD
J Philip Kistler, MD
Robert G Hart, MD

UpToDate performs a continuous review of over 375 journals and other resources.
Updates are added as important new information is published. The literature review for
version 15.3 is current through August 2007; this topic was last changed on June 28,
2007. The next version of UpToDate (16.1) will be released in March 2008.

INTRODUCTION — Systemic embolization from atrial thrombi can occur with any form
of atrial fibrillation (AF), spontaneously or in association with cardioversion. As a
result, anticoagulation is considered in most of these patients. This decision is best
made with an appreciation of the risk of embolic events, the results of controlled trials,
and the risk of bleeding [1,2].

The following is a review of the issues surrounding anticoagulation for the prevention
of embolic events in patients with AF. The role of anticoagulation in relation to
restoration of sinus rhythm is discussed separately. (See "Anticoagulation prior to and
after restoration of sinus rhythm in atrial fibrillation").

INCIDENCE OF EMBOLISM — Atrial fibrillation occurs in 2 to 4 percent of the population

aged 60 years and older [3-5]. The prevalence of AF increases with age, affecting more
than 10 percent of people older than age 80 years (show figure 1) [3,6]. AF is thought
to be responsible for approximately one-sixth of all ischemic strokes in people over age
60 years [7].

The incidence of stroke associated with AF increases with age [7,8]. This was illustrated
in a study that evaluated 27,202 men and women, ages 50 to 89, with a hospital
diagnosis of AF and without a prior diagnosis of stroke [8]. The stroke rate (percent
per patient per year) was:

• 1.3 in those aged 50 to 59 years

• 2.2 in those aged 60 to 69 years
• 4.2 for those aged 70 to 79 years
• 5.1 for those aged 80 to 89 years

Compared with the general population, AF increased the risk of stroke in men (relative
risk 2.4) and women (relative risk 3.0).

Most embolic events are ischemic strokes; in one review, peripheral embolization
accounted for only 6.3 percent of events [9]. AF is associated with more severe strokes
and "longer" transient ischemic attacks than emboli from carotid disease, presumably
due to embolization of larger particles in AF [10,11]. This relationship was illustrated in
a report comparing ischemic brain events in patients with AF and those with carotid
disease in two major trials; the ratio of hemispheric events to retinal events was 25:1
with AF compared to 2:1 with carotid disease [10].

In addition to causing clinical stroke with major deficits, AF is also associated with
silent cerebral infarctions and transient ischemic attacks (TIAs) [12-14]. The frequency
of silent cerebral infarction was evaluated in a report of 516 patients with
 nonrheumatic AF in the SPINAF trial; CT scanning was performed initially and, in the
absence of neurologic symptoms, at the end of follow-up [12]. One or more silent
cerebral infarctions were seen at presentation in 15 percent; the estimated rate of new
silent cerebral infarcts was about 1.3 percent per year at up to three years follow-up.

Patients with AF who suffer an ischemic stroke appear to have a worse outcome (more
disability, greater mortality) than those who have a stroke in the absence of AF [15-
17]. Why this occurs is not clear, but may be related to the embolus and infarct size or
other factors that involve the clotting cascade [18].

Type of AF — The incidence of embolism depends in part upon the type of AF. The
following classification of AF has been proposed by the ACC/AHA/European Society of
Cardiology (ESC) [19]:

• Paroxysmal (ie, self-terminating) AF in which the episodes of AF generally last less

than seven days, usually less than 24 hours, and may be recurrent.

• Persistent AF fails to self-terminate and lasts for longer than seven days. Persistent AF
may also be paroxysmal if it recurs after reversion. AF is considered recurrent when
the patient experiences two or more episodes.

• Permanent AF is considered to be present if the arrhythmia lasts for more than one
year and cardioversion either has not been attempted or has failed.

• "Lone" AF describes paroxysmal, persistent, or permanent AF in individuals without

structural heart disease.

Most clinical trials have been conducted in patients with persistent or permanent AF.
Although the incidence of embolization has been thought to be lower in patients with
paroxysmal AF, the SPAF and Boston trials found a similar risk (show figure 2) [20-22].
Furthermore, embolic events can occur in patients with acute AF for as little as 72
hours [22]. This is an important issue because, in patients with paroxysmal AF,
approximately 90 percent have recurrent episodes of AF [23], up to 90 percent of
episodes are not detected by the patient [24], and asymptomatic episodes lasting more
than 48 hours are not uncommon, occurring in 17 percent of patients in a report using
continuous monitoring [23].

Thrombi can form during these prolonged episodes, possibly leading to clinical
thromboembolism. As a result, high risk patients with paroxysmal AF should probably
be anticoagulated if the AF is present for a substantial portion of the time. (See
"Paroxysmal atrial fibrillation").

In comparison, most patients with lone AF, particularly those under age 65 years, are
at relatively low risk for embolization and may be adequately treated with aspirin. (See
"Lone and low-risk atrial fibrillation" and see "Risk stratification" below).

No randomized trials of oral anticoagulation have been performed in patients with AF

and rheumatic mitral valve disease or prosthetic (mechanical or bioprosthetic) heart
valves. These patients are at high risk for embolization and all should receive oral
anticoagulation.
Rhythm versus rate control — Both rate and rhythm control are acceptable approaches
to the management of AF, depending upon the specific clinical circumstances. The
AFFIRM and RACE trials demonstrated that embolic events occurred with equal
frequency regardless of whether a rate control or rhythm control strategy was pursued,
and occurred most often after warfarin had been stopped or when the International
Normalized Ratio (INR) was subtherapeutic [25,26]. (See "Rhythm control versus rate
control in atrial fibrillation").

Patients treated with rhythm control likely remain at risk for embolization even when in
sinus rhythm for two main reasons: recurrent episodes of AF are common and
asymptomatic in up to 90 percent [23,24]; and some patients have other reasons for
thromboembolic risk such as complex aortic plaque or left ventricular systolic
dysfunction. (See "Indications for anticoagulation in heart failure" and see "Embolism from
aortic plaque: Thromboembolism").

These findings indicate that most patients with AF, regardless of whether a rate control
or rhythm control strategy is chosen, should be chronically anticoagulated with warfarin
or a comparable agent, with a target INR as described below. One exception is the use
of aspirin in patients deemed to be at low risk for embolization (see "Summary of risk
models" below).

MECHANISM OF THROMBOEMBOLISM IN NONVALVULAR AF — The mechanisms leading

to an increased risk of stroke, thrombus, and embolism in AF are multiple, complex,
and closely interact with each other. They are discussed in detail elsewhere and will be
only briefly summarized here. (See "Mechanisms of thrombogenesis in atrial fibrillation").

Blood stasis, especially in the left atrial appendage (LAA), along with activation of the
hemostatic system in AF, meet two criteria of Virchow's triad for thrombus formation.
The last feature of this triad, endocardial injury, may be a factor in thrombus
formation, but its role in AF has been less well defined.

Stasis in the LAA — For patients with nonvalvular AF, the vast majority of thrombi are
located within or involve the LAA. The fibrillating LAA is a cul-de-sac that creates an
appropriate milieu for blood stasis and thrombus formation. On transesophageal
echocardiography (TEE), stasis of blood occurs more prominently in the LAA [27]; this
may be due to its shape and the presence of trabeculations [28]. One of the most
important determinants of stasis in the LAA is the degree of LAA peak outflow velocity
as detected by TEE [29]; LAA peak flow velocity less than 20 cm/sec is an independent
risk factor for thrombus formation and future thromboembolism [30,31]. (See
"Echocardiographic evaluation of the atria and appendages").

Spontaneous echo contrast — One of the initial events occurring in a fibrillating left
atrium (LA) is increased erythrocyte aggregation caused by low shear rate due to
altered LAA flow dynamics and uncoordinated LA systole [32-34]. The resultant smoke-
like echoes swirling slowly in the LA are referred to as spontaneous echo contrast
(SEC), an echo phenomenon, or "smoke". (See "Role of echocardiography in atrial
fibrillation").

SEC is a strong risk factor for and may be the preceding stage to thrombus
formation show echocardiogram 1 show echocardiogram 2 [30,31,35]. Its occurrence is
independently related to the hematocrit and fibrinogen concentrations and may be
associated with a hypercoagulable state (see below) [32,36].
 SEC is detected in one-half to two-thirds of patients with AF [31]. Once it occurs, SEC
is a stable phenomenon that cannot be resolved by either warfarin or aspirin therapy
[35,37]. However, anticoagulation can reduce subsequent thrombus formation and
thromboembolic events.

The LAA peak outflow velocity can be estimated by TEE and SEC semiquantitatively
graded as marked or dense if present throughout the entire cardiac cycle, or faint
when intermittent [31]. The risk of thromboembolism increases as these parameters
worsen [31,38]. This was illustrated in a study of 128 patients with nonvalvular AF and
dense SEC, all of whom were anticoagulated (mean INR 2.3) [38]. Serial TEE, cranial
MRI, and clinical examinations were performed over a period of 12 months. The
following findings were noted:

• Clinically apparent cerebral embolization occurred in 2 percent, death in 7 percent, and

silent embolization in 15 percent; in comparison, the 143 controls with faint SEC had a
4 percent rate of silent embolization

• The patients with an event had significantly lower left atrial appendage velocity and
were more likely to have denser SEC and to have had a prior thromboembolic event

Hypercoagulable state — A hypercoagulable state characterized by a change in

molecular markers of the hemostatic system occurs in some patients with AF. Markers
of both thrombotic and fibrinolytic pathways are significantly increased in these
individuals. (See "Mechanisms of thrombogenesis in atrial fibrillation").

• Fibrinopeptide A is liberated when fibrinogen is converted to fibrin by thrombin. The

plasma fibrinopeptide A concentration is increased in patients in AF and the level
correlates with the degree of SEC [36,39].

• The thrombin-antithrombin III complex, a marker of thrombin generation, and D-

dimers, released as a substrate of fibrin by activity of plasmin, are significantly
elevated in patients with AF compared with those in sinus rhythm [40-43].

RISK STRATIFICATION — The absolute embolic risk varies among patients. As a result,
an estimation of risk stratification is essential for making decisions about treatment in
order to maximize benefit and minimize bleeding; warfarin reduces stroke risk by about
two to three times with respect to aspirin, but increases the major bleeding rate by
about 1.5 times (see below). Risk stratification in patients with AF can be performed
using both clinical and echocardiographic parameters [1].

Clinical parameters from randomized trials — Five randomized stroke prevention trials
in patients with AF (BAATAF [20], Veteran Affairs SPINAF [44], AFASAK [45], CAFA
[46], and SPAF [21]) used their own risk stratification schemes. However, the end
point events in the control groups did not allow for risk stratification with high degrees
of confidence. The two largest trials with the greatest number of patient-years of
warfarin treatment, BAATAF and SPINAF, documented diabetes, hypertension, and
previous stroke as clinical risk factors, and left ventricular (LV) systolic dysfunction as
echocardiographic risk factors [20,44].

The five prevention trials (the Atrial Fibrillation Investigators, or AFI) systematically
pooled their data in an attempt to develop a stronger risk stratification scheme [47].
The following independent risk factors for embolism in AF were identified:
• Age >65 years
• History of stroke or transient ischemic attack (TIA)
• Diabetes mellitus
• History of systemic hypertension

Patients with none of these risk factors (15 percent of the group) comprised a low-risk
group with an annual stroke risk less than 1 percent without warfarin.

The risk stratification scheme in SPAF differed slightly, identifying the following clinical
high-risk factors for embolism in AF [48,49]:

• Women >75 years

• History of stroke or TIA
• Impaired LV systolic function (clinical heart failure [HF] in the last three months or
fractional shortening less than 25 percent on transthoracic echocardiography)
• Systolic blood pressure 160 mmHg

Clinical parameters from community cohorts — Although the results of clinical trials
constitute the basis for the use of anticoagulation in patients with AF, several questions
have been raised concerning the applicability of the major trials to routine medical
practice:

• Only a small proportion of subjects screened were randomized. In the SPAF-I trial, as
an example, 17,046 patients with AF were screened but only 1330 (8 percent) were
entered into the study [21].

• Patients included in the trials were motivated and given intensive monitoring,
suggesting that these selected patients were given "packages of care" rather than
simply antithrombotic therapy [50,51].

• The trials had relatively short-term follow-up, averaging two to three years; despite
this, the number of patients withdrawn from warfarin was high, ranging from 10
percent in BAATAF [20] to 38 percent in AFASAK [45].

• Very little information is available on patients who were withdrawn from therapy; these
patients are likely to represent a sizable number in clinical practice.

A systematic review of patients with AF who were anticoagulated in actual clinical

practice found stroke and bleeding rates that were similar to those found in
randomized trials, suggesting that clinical trials can reasonably be used to guide
clinical practice [52]. However, the clinical characteristics of trial participants may
influence the risk models developed from those trials. Participants in clinical trials are
younger, more likely to be men, and typically have fewer comorbidities than those in
the community with AF [53].

The impact of these limitations was assessed in a validation study comparing the
performance of the AFI and SPAF risk models in a population of 1733 Medicare
beneficiaries with nonrheumatic AF who were not prescribed warfarin at hospital
discharge [53]. During one year of follow-up, 94 patients were readmitted for a stroke
or a TIA (4.4 percent per year).
 The correlation between the predictive model and patient outcomes was assessed
using the c statistic, with a result of 0.5 representing chance correlation and 1.0 being
perfect correlation. The c statistics for the AFI and SPAF models were 0.68 and 0.74,
respectively. A better c statistic (0.82) was attained using the following score (which
the authors dubbed "CHADS2") derived from the AFI and SPAF models (show table 1):

• Congestive heart failure (HF, any history) — 1 point

• Hypertension (prior history) — 1 point
• Age 75 years — 1 point
• Diabetes mellitus — 1 point
• Secondary prevention in patients with ischemic stroke, TIA, or, most would add, a
systemic embolic event — 2 points

Using this model, patients with a score of 0 had an adjusted rate of ischemic stroke or
peripheral embolization of 1.9 percent per year, while those with the maximum score
(6) had an adjusted stroke rate of 18.2 percent per year. The CHADS2 score was
subsequently validated in a much larger, community-based, clinical practice cohort
(show table 1) [9]. Furthermore, in an analysis of patient data from six multicenter
trials, the CHADS2 score was also more effective at risk stratification than four other
models with which it was compared [54].

Another risk model based upon a community cohort was developed from data from the
Framingham Heart Study. The analysis identified 705 participants with new onset AF
who were not treated with warfarin at baseline [55]. Risk scores for stroke and for
stroke or death were developed with censoring when warfarin was initiated (show figure
3A-3B). During four years of follow-up, 83 patients had a stroke (2.9 percent per year)
and 382 had a stroke or died (13.4 percent per year). Risk factors for stroke on
multivariate analysis included (show figure 4) [56]:

• Increasing age
• Female gender
• Higher systolic blood pressure
• Diabetes mellitus
• Prior stroke or TIA

Echocardiographic parameters — Echocardiographic parameters have also been

studied in an attempt to identify patients with AF who are at high risk of
thromboembolism [30,31,57,58]. Transthoracic echocardiography (TTE) provides
detailed information about cardiac anatomy and function, while TEE is a moderately
invasive imaging technique that provides superior visualization of posterior structures,
such as the LA and LAA. (See "Role of echocardiography in atrial fibrillation").

Transthoracic echocardiography — TTE is particularly useful for determining LA size,

mitral valve function, and LV function. Pooled analysis from the three trials that
incorporated echocardiography into their risk stratification scheme (BAATAF, SPINAF,
and SPAF) found that LV systolic dysfunction diagnosed by TTE was a risk factor for
stroke in patients with AF [58]. In this analysis of 1066 patients, the relative risk of
stroke was 2.5 for those with moderate to severe LV dysfunction compared to patients
with mildly abnormal or normal LV function (show figure 5).

Among 163 patients categorized as low risk based upon clinical features, 10 had
moderate to severe LV dysfunction and a 9.3 percent per year risk of stroke. By
 comparison, 728 of the 847 patients at high risk for stroke based upon clinical criteria
but normal or mildly abnormal LV function on TTE had a lower stroke rate of 4.4
percent per year.

LA diameter was not a predictor of stroke in the pooled analysis, possibly because of
the confounding impact of mitral regurgitation [58]. In contrast, the SPAF investigators
found that an LA anteroposterior diameter >2.5 cm/m2 was an independent predictor
of thromboembolism in addition to global LV dysfunction [57]. The association was
weaker when LA diameter was not corrected for body surface area, although it was still
significant.

In the SPAF trial, TTE helped identify a very low-risk group (stroke incidence less than
1 percent) who had no echocardiographic or clinical risk factors; this group accounted
for 26 percent of all patients [57]. However, as in the pooled analysis, TTE often
changed the risk group based upon clinical criteria. Among patients placed in a low-risk
group (stroke incidence 2.5 percent per year) clinically, 38 percent were judged to be
at high risk (stroke incidence greater than 5 percent per year) when TTE was
performed.

Transesophageal echocardiography — TEE is used in patients with AF primarily to

evaluate LAA anatomy, identifying those who are free of thrombi and are therefore
candidates for early cardioversion. (See "Anticoagulation prior to and after restoration of
sinus rhythm in atrial fibrillation").

The presence of thrombus in the LA or LAA also provides useful information for risk
stratification. The ability of TTE to detect or exclude LA or LAA thrombi is limited
compared with TEE. TEE also can identify other LA abnormalities that are associated
with increased risk, including SEC, and complex aortic plaque [30,31]. In addition,
estimates of LA and LAA blood flow velocity can be made, providing a more
quantifiable measure of stasis.

The presence of clinical risk factors is associated with an increased likelihood of

echocardiographic risk factors (show figure 6) [30]. However, these risk factors are
dissociated in some patients, raising the possibility that TEE can be used for risk
stratification. The potential utility of this approach was illustrated in the SPAF III TEE
substudy of 382 clinically or TTE high-risk patients, defined as one or more of the
following: women >75 years of age, hypertension, previous thromboembolism, or
recent HF, or those who had fractional shortening of less than 25 percent on an M-
mode echocardiogram [31]. The patients were treated with either adjusted-dose
warfarin (goal INR 2.0 to 3.0) or low-intensity warfarin (goal INR, 1.2 to 1.5) plus
aspirin (325 mg/day).

The risk of thromboembolism increased with one or both of the following findings:

• Any LA abnormality, including reduced LAA emptying flow, dense spontaneous echo
contrast, or thrombus

• A complex aortic plaque (mobile, ulcerated, pedunculated, or >4 mm thick) (see

"Embolism from aortic plaque: Thromboembolism")
 Among the 178 patients treated with the relatively ineffective regimen of low-dose
warfarin plus aspirin (see "Low-dose warfarin plus aspirin" below), the following rates of
thromboembolism were noted according to TEE findings:

• Left atrial abnormality — 7.8 percent per year

• Complex aortic plaque — 12.0 percent per year
• Both — 20.5 percent per year
• Neither — 1.3 percent per year

The last group, which comprised 37 percent of patients, demonstrated that some
patients who are classified as high risk based upon clinical and TTE criteria may
actually be at low risk when TEE features are considered. However, one cannot be
confident based upon these data that these patients are actually at low risk. Because
of the relatively small number of patients, the 95 percent confidence interval in these
groups was quite wide, including 0.2 to 9.5 percent per year in the low-risk group.
Adjusted-dose warfarin reduced the risk of stroke compared with combined therapy by
about 75 percent in patients with high-risk TEE features.

Routine TEE is not currently recommended in patients with AF purely for risk
stratification. If TEE is obtained, the results can be used to identify patients who may
derive particular benefit from warfarin therapy (see below). As previously mentioned, it
may also be useful in some patients prior to elective cardioversion. (See "Anticoagulation
prior to and after restoration of sinus rhythm in atrial fibrillation").

Summary of risk models — A number of clinical risk models have been devised in an
attempt to predict the thromboembolic risk and the likelihood of benefit from therapy
with warfarin or aspirin [1]. Two of these models, CHADS2 and SPAF have been most
widely validated in a cohort of patients separate from those used to derive the model
[54].

As mentioned in the preceding section, TEE measures of stasis of atrial flow, atrial
thrombus, and complex aortic plaque are predictors of stroke risk [30,31]. However,
these abnormalities are more likely to be present in patients with clinical risk factors
(show figure 6) [30]. Although some of these TEE abnormalities appear to be
independent predictors of risk, their predictive value has not been defined when
considered in multivariate models that include clinical predictors.

The major risk models include:

• The CHADS2 score, which was based upon independent clinical predictors from SPAF
and AFI and then tested and validated (show table 1) [9,53]

• The Stroke Prevention in Atrial Fibrillation (SPAF) investigators (show table 2) [48]

• The seventh American College of Chest Physicians (ACCP) Consensus Conference (show
table 3) [59]

• The 2006 guidelines from the American College of Cardiology, the American Heart
Association, and the European Society of Cardiology (ACC/AHA/ESC) (show table 4) [19]

• The pooled analysis from the Atrial Fibrillation Investigators (AFI) (show figure 7) [60]
• The community-based risk model from the Framingham Heart Study [55,56]

These models agreed on the following high risk features:

• A prior embolic event

• Hypertension
• Older age

Other features were regarded as high risk in some, but not all, of the models:

• Left ventricular dysfunction or HF — All of the models except that from the
Framingham Heart Study

• Diabetes — All of the models except SPAF

• Coronary artery disease — The ACC/AHA/ESC guidelines

• Thyrotoxicosis — The ACC/AHA/ESC guidelines

• Female gender — The Framingham Study and, for women over the age of 75 years,
SPAF and the ACC/AHA/ESC guidelines

The different models varied on the age at which risk was increased independent of
other risk factors: women >75 years in SPAF [48], age 75 years as high risk and 65
to 75 years as moderate risk in the ACCP Consensus Conference [59], and age 75
years in the ACC/AHA/ESC guidelines and CHADS2 [19,53]. As noted above, there
appears to be an equivalent risk in patients with chronic and paroxysmal AF (show
figure 2) [20-22].

It is not clear if patients with hypertension who are adequately treated have the same
risk as those with sustained hypertension. Thus, any patient with either a history of or
current sustained hypertension is considered to be at high risk.

A systematic review calculated the number of patients in various stroke risk categories
who would need to be treated with aspirin or warfarin to prevent a single stroke (show
table 5) [61]. Similar data have come from a validation study of the CHADS2 score
(show table 1) [9,53].

We believe that the CHADS2 score is currently the best validated and most clinically
useful model for risk stratification of patients with AF (show table 1). Its main
advantage compared to other risk models is that it was tested in a trial cohort from the
National Registry of Atrial Fibrillation, and then validated in a large clinical practice
case series [9,53]. Furthermore, in an analysis of patient data from six multicenter
trials, the CHADS2 score was also more effective at risk stratification than four other
models with which it was compared [54].

It has been estimated that approximately one-third of patients with AF (range 14 to 45

percent in different reports) are at low risk for stroke (less than 1 percent per year)
and can be treated with aspirin [62].
CHRONIC THERAPY — Treatment with warfarin or aspirin is indicated in many patients
with chronic AF for prevention of stroke and other thromboembolic events. The use of
these drugs is based upon clinical features of the patients and risk assessment;
recommendations for the choice of therapy have been published by the ACCP and
ACC/AHA/ESC (show table 3 and show table 4) [19,59]. The following discussion will
emphasize the efficacy and side effects of warfarin and aspirin in the medical
management of patients with AF.

Clinical trials [20,21,44-47,63] and meta-analyses [64-66] demonstrate similar results.

Among patients with AF at high risk of thromboembolic events, both warfarin and aspirin
significantly reduce the incidence of stroke, but warfarin is approximately three times
as effective.

Issues related to patients who have already had an embolic event are described below
(see "Stroke in the setting of AF" below).

A separate issue, for which little published data are available, is the role of
anticoagulation in patients who have undergone radiofrequency catheter ablation to
prevent recurrent AF. A recommended approach is presented elsewhere. (See
"Radiofrequency catheter ablation to prevent recurrent atrial fibrillation").

Warfarin — The five studies cited above addressed the issue of prevention of clinical
stroke in patients with AF. Together these trials randomly assigned more than 4000
patients to aspirin, warfarin, or placebo, and demonstrated that anticoagulation with
adjusted-dose warfarin significantly reduced stroke risk in patients with AF when
compared with aspirin [21,45] or placebo (show figure 8) [20,21,44-46]. Overall,
adjusted-dose warfarin reduces the risk of stroke by 62 to 69 percent (show table 6)
with an absolute annual reduction of 2.7 to 3.1 percent [47,64,67]. Thus, treating 100
patients with warfarin will prevent almost three strokes per year. However, the highest
risk patients still had a 1.7 percent annual incidence of stroke with warfarin therapy.
For comparison, the stroke incidence among 70-year olds without AF averages about 1
percent per year.

Embolic events occurring during adequate anticoagulation are more likely in patients
with dense spontaneous echo contrast and low left atrial appendage velocity [38]. In
addition, the INR is often subtherapeutic, even with careful monitoring, and
subtherapeutic values are associated with increased embolic risk [68]. (See
"Spontaneous echo contrast" above and see "Underutilization and underanticoagulation" below).

Warfarin was more effective in women than in men (84 and 60 percent risk reduction,
respectively), and was beneficial in all age groups, including those over the age of 75
years (show figure 7) [47,60]. In addition, warfarin provided benefit even in patients
who developed a stroke while taking warfarin; the death rate was reduced by 33
percent compared with those who had a stroke and were not taking warfarin.

The most compelling two of these trials were identical in design, both using the
BAATAF protocol [20,44]. They showed the highest risk reduction with warfarin
treatment (86 percent in BAATAF, 79 percent in SPINAF, with 95 percent confidence
intervals of 0.51 to 0.96 and 0.52 to 0.90, respectively).

These figures underestimate the benefit of therapeutic warfarin. In all five prevention
studies, only 27 patients assigned to warfarin developed a stroke; of these, 13 were
subtherapeutic with an INR <1.5 at the time of the embolic event and eight were not
taking warfarin when they had the embolic event. (See "Underutilization and
underanticoagulation" below).

Alternatives to chronic warfarin — Although conventional-dose warfarin reduces the

risk of embolization in AF, its use is made more difficult by the requirement for
frequent INR monitoring as well as the need to avoid dietary and medication
interactions. For these reasons, a number of alternatives have been studied, including
aspirin, low-dose warfarin plus aspirin, clopidogrel plus aspirin, and ximelagatran.
Warfarin has been superior to any alternative therapy in patients at high-risk of stroke,
while aspirin therapy is considered a reasonable option in patients at low
thromboembolic risk.

Aspirin — Several trials have evaluated the role of aspirin for the prevention of
thromboembolism in AF with conflicting results [21,45,47,63]. In the AFASAK trial,
aspirin (75 mg/day) was associated with a nonsignificant 18 percent reduction in
stroke [45]. In contrast, the SPAF-I study, which used a higher dose of aspirin (325
mg/day), found a statistically significant 44 percent reduction in stroke [21]. However,
the benefit of aspirin was mainly in reducing the rate of minor strokes, which
accounted for 50 percent of all strokes in this study; only 20 to 30 percent of strokes
were minor in other trials. In patients over the age of 75 years, the risk of intracranial
hemorrhage with aspirin was much lower than with warfarin; in this age group, the
benefit of warfarin in reducing embolic stroke was largely offset by the increased
incidence of hemorrhagic stroke [69].

A meta-analysis of six trials comparing aspirin with placebo found that aspirin reduced
the incidence of clinical stroke or TIA by 22 percent (95% CI 2-38 percent); the
absolute risk reduction for prevention was 1.5 percent per year [64]. Similar findings,
an almost significant 32 percent reduction in stroke risk (odds ratio 0.68, 95% CI
0.46-1.02), were noted in a meta-analysis performed by the American Academy of
Family Physicians and the American College of Physicians (show table 6) [67].

However, as with warfarin, the efficacy of aspirin varies with risk. In a pooled analysis,
aspirin was of particular benefit in patients between the ages of 65 and 75 years who
had no other risk factors (eg, hypertension, diabetes mellitus, previous TIA or stroke,
poor LV function) [60]. In this group, the risk of stroke was 4.3 percent per year with
no therapy, 1.1 percent per year with warfarin, and 1.4 percent per year with aspirin
(show figure 7).

Although there is modest benefit from aspirin, randomized trials have shown that it is
consistently and substantially less effective than warfarin (except in low-risk patients)
[63-65]. The magnitude of the difference was illustrated in an individual patient meta-
analysis of prevention trials in patients with nonvalvular AF (76 percent primary
prevention) [65]. Patients treated with warfarin were significantly less likely to
experience an ischemic stroke (2.0 versus 4.3 per 100 patient-years, hazard ratio
0.55, 95% CI 0.45-0.71); the benefit was similar in patients with chronic and
paroxysmal AF. It was concluded that treating 100 patients with warfarin rather than
aspirin for one year would prevent 2.3 ischemic strokes. As mentioned above,
however, the benefit varies by patient subgroup (show figure 7) [60].

The use of aspirin for secondary prevention of cardiovascular disease in patients treated
with warfarin for AF is discussed below. (See "Concurrent therapy with aspirin" below).
Low-dose warfarin plus aspirin — In contrast to adjusted-dose warfarin, low-dose
warfarin (1.25 mg/day or goal INR between 1.2 and 1.5) in combination with aspirin
(300 to 325 mg/day) should not be used to reduce stroke risk in patients with AF (show
table 6) [49,67,70]. In the SPAF-III trial of 1044 patients with AF who were at high risk
for embolism (women age >75 years, systolic blood pressure >160 mmHg, poor left
ventricular function, or prior thromboembolic event), low-dose warfarin plus aspirin
was associated with significantly higher morbidity and mortality than adjusted-dose
warfarin (show figure 9 and show figure 10) [49].

The potential benefit of a low-dose coumarin derivative, acenocoumarol, in combination

with the antiplatelet agent, triflusal, was evaluated in the NASPEAF trial [71]. In this
analysis of 1209 patients at intermediate to high risk of embolism (including 311 with
mitral stenosis), acenocoumarol (target INR 1.25 to 2.00) plus triflusal 600 mg per day
reduced both embolic events and bleeding compared with acenocoumarol alone (target
INR 2.0 to 3.0). However, although the target INR in the combined group was 1.25 to
2, the median INR in this group during the trial was 2.0. Thus, it is premature to
recommend combination therapy with an anticoagulant plus antiplatelet therapy on the
basis of these findings with a small patient sample and an antiplatelet agent with
limited general use that is not available in North America.

Aspirin plus clopidogrel — The safety and efficacy of dual antiplatelet therapy was
compared to oral anticoagulation in the ACTIVE W trial [72]. In this trial, 6706 patients
with AF and at least one risk factor for stroke (average CHADS2 score 2.0; show table
1) were randomly assigned to oral anticoagulation (target INR 2.0 to 3.0) or the
combination of clopidogrel 75 mg per day and aspirin 75 to 100 mg per day. The
primary end point was the rate of stroke, systemic embolus, MI, or vascular death.

The trial was stopped early at a mean follow-up of 1.3 years because patients treated
with combined antiplatelet therapy had significant increases in both the primary end
point (5.6 versus 3.9 percent per year with oral anticoagulants) and the rate of
bleeding (15.4 versus 13.2 percent per year). Thus, dual antiplatelet therapy should
not be considered an alternative to warfarin therapy in high risk patients with AF.

Ximelagatran — Ximelagatran is one of several investigational, orally administered

direct thrombin inhibitors that inhibits the conversion of fibrinogen to fibrin by
thrombin. It has consistent pharmacokinetics, which can eliminate the need for
anticoagulation monitoring. (See "New anticoagulants", section on Direct thrombin
inhibitors).

Noninferiority of ximelagatran to warfarin was demonstrated in two large randomized

trials of patients with AF and at least one additional risk factor for stroke: SPORTIF III,
which was open-label, and SPORTIF V, which was blinded [73,74]. However, because of
concerns about hepatotoxicity, ximelagatran has been removed from the market by
the manufacturer.

In SPORTIF V, liver enzyme elevation (serum ALT >3 times the upper limit of normal)
occurred significantly more often with ximelagatran (6 versus 0.8 percent), usually
within the first six months. Although serum ALT tended to decline over time whether or
not ximelagatran was continued, there was one documented and one suggestive case
of fatal liver disease.
Risk of bleeding — The major concern with the use of warfarin is the risk of bleeding.
Intracranial bleeding is the most serious potential consequence of warfarin therapy.
The risk factors for this complication are discussed separately. (See "Risk of intracerebral
hemorrhage in patients treated with warfarin").

Both the risk of any bleeding and of major bleeding appears to be significantly higher
with adjusted-dose warfarin compared with aspirin. In the individual patient meta-
analysis of six prevention trials cited above, the absolute rate increase of major
bleeding with warfarin compared with aspirin was 0.9 events per 100 patient-years
(2.2 versus 1.3 events per 100 patient-years) [65]. Major bleeding included
intracranial bleeds and other bleeds that required hospitalization, transfusion, or
surgery. The risk of bleeding rises dramatically at an INR above 4.5 to 5.0 (show figure
11) [75].

Another meta-analysis of six randomized trials evaluated the risk of intracranial

hemorrhage with oral anticoagulants alone or with aspirin [76]. Combination therapy
was associated with a significant increase in risk (relative risk 2.4, 95% CI 1.2-4.8)
[76].

The increased risk of bleeding is particularly relevant to the elderly in whom frailty,
poor mobility, forgetfulness or poor compliance, the use of concomitant medications
that can result in drug interactions, and frequent falls may supersede the
thromboprotective benefits from warfarin.

The bleeding risk in the elderly was evaluated in a review of over 10,000 Medicare
recipients (mean age 77 years) who were treated with warfarin for AF [77]. At 180
days, the rate of major bleeding was 2.0 percent in patients treated only with warfarin
and 2.8 percent in those treated with warfarin plus aspirin. Combination therapy was
associated with a three-fold increase in the risk of intracranial hemorrhage (0.9 versus
0.3 percent, odds ratio 2.95).

Issues related to anticoagulation in the elderly are discussed separately. (See

"Anticoagulation in the elderly").

Risk models — In an attempt to estimate the probability of major bleeding in patients

on chronic warfarin therapy, a number of risk models have been developed. These are
discussed in depth separately. (See "Therapeutic use of warfarin", section on Bleeding).

Hyperthyroidism — The role of warfarin is less well defined in patients in whom the
underlying disease can be corrected, as in hyperthyroidism. (See "Causes of atrial
fibrillation" and see "Cardiovascular effects of hyperthyroidism", section on Cardiac
arrhythmias).

The 2006 ACC/AHA/ESC guidelines recommended oral anticoagulation with warfarin or

other vitamin K antagonist to a goal INR of 2.0 to 3.0 [19]. This recommendation was
made even though it was noted that it remains controversial whether AF in
hyperthyroidism is associated with increased thromboembolic risk compared to AF in
other settings. Once the patient is euthyroid, the recommendations for antithrombotic
prophylaxis if AF persists are similar to those in patients without hyperthyroidism. (See
"Patient selection" below).
The 2004 Seventh ACCP Conference reached a somewhat different conclusion [59]. AF
in hyperthyroidism was considered to have a similar thromboembolic risk as other
causes of AF. As a result, antithrombotic therapy should be based upon the presence of
validated stroke risk factors. (See "Patient selection" below).

Lower than normal warfarin doses are usually required, since hyperthyroidism is
associated with increased clearance of vitamin K-dependent clotting factors [78].

Nonpharmacologic options — Approximately 20 percent of patients with AF in whom

warfarin is indicated have a relative or absolute contraindication to warfarin (eg,
systemic or intracranial bleeding, noncompliance with therapy, pregnancy) [51]. (See
"Therapeutic use of warfarin" and see "Risk of intracerebral hemorrhage in patients treated with
warfarin").

In the past, cardioversion to sinus rhythm with maintenance of sinus rhythm using
antiarrhythmic drugs had been considered an appropriate option for such patients,
because it was presumed that embolic risk would be reduced. However, in the AFFIRM
and RACE trials comparing rhythm and rate control, embolization occurred with equal
frequency whether a rhythm control or rate control strategy was adopted [25,26]. In
both groups, embolization primarily occurred after warfarin had been stopped or when
the INR was subtherapeutic. As a result, rhythm control (at least by pharmacologic
means) cannot be used as an alternative to anticoagulation to prevent embolization in
AF. (See "Rhythm versus rate control" above and see "Rhythm control versus rate control in
atrial fibrillation").

As noted above, some patients have other reasons for embolic risk such as complex
aortic plaque or left ventricular systolic dysfunction. The risk from such factors would
not be reduced by the following nonpharmacologic approaches. (See "Embolism from
aortic plaque: Thromboembolism" and see "Indications for anticoagulation in heart failure").

Prevention of AF — Nonpharmacologic strategies to prevent recurrent AF might reduce

the risk of embolic stroke. Approaches that may be considered include the surgical
atrial isolation/maze procedure in patients undergoing cardiac surgery for some other
reason and pulmonary vein isolation by radiofrequency catheter ablation. However,
there are only limited data confirming a reduction in embolic risk with these
procedures and their use should be considered only in selected patients and only by
experienced operators. (See "Radiofrequency catheter ablation to prevent recurrent atrial
fibrillation", see "The role of pacemakers in the prevention of atrial fibrillation", and see
"Surgical approaches to prevent recurrent atrial fibrillation").

LAA ligation, amputation, or occlusion — Interventional techniques to prevent

thrombus formation in the LAA have been attempted. The rationale for this approach is
that the vast majority of emboli in nonvalvular AF arise within or involve the LAA. (See
"Stasis in the LAA" above).

These approaches include surgical ligation or amputation of the LAA, which is only
performed in patients who are undergoing cardiac surgery for other indications, and
percutaneous LAA occlusion. Ligation of the LAA at the time of mitral valve surgery has
now become routine in many centers with expertise in this technique; it is also a
routine part of the maze procedure. The 2006 American College of
Cardiology/American Heart Association (ACC/AHA) guidelines on the management of
valvular heart disease recommended amputation of the LAA at the time of mitral valve
surgery to reduce the likelihood of postoperative thromboembolic events [79,80].

The data evaluating the efficacy of these procedures is presented separately. (See "Left
atrial appendage amputation, ligation, or occlusion in patients with atrial fibrillation").

STROKE IN THE SETTING OF AF — Some patients with AF develop an ischemic stroke

despite appropriate prophylaxis, while the presenting manifestation of AF is a stroke in
others. The general evaluation and management of the patient with stroke are
presented elsewhere; the following discussion addresses these issues in the specific
setting of the patient with AF. (See "Overview of the evaluation of stroke" and see
"Fibrinolytic (thrombolytic) therapy for acute ischemic stroke" and see "Antithrombotic
treatment of acute ischemic stroke").

Risk of recurrent embolism — As noted above, all patients who have had a prior
embolic event already have the most potent clinical high-risk factor for subsequent
stroke (see "Risk stratification" above). A risk of up to 12 percent per year for untreated
patients in the first two to three years after a stroke has been reported [81,82]. The
risk of recurrent stroke in the first few weeks after the initial event is 3 to 5 percent
based upon large numbers of patients observed in the control arms of randomized
trials [83,84].

Evaluation — Patients with AF who have suffered an ischemic stroke are likely to have
had a cardioembolic event. On the other hand, AF is common in the elderly, who often
have disease in other organ systems including the vascular system and are therefore
at risk for other types of stroke. Thus, the presence of AF in a stroke victim does not
always mean that there is a causal relationship [85]. As a result, all patients with a
stroke, even in the setting of AF, need a thorough evaluation to determine the etiology
of the stroke since the treatment of different types of stroke varies. (See "Overview of
the evaluation of stroke").

Echocardiography — Echocardiographic evaluation is usually recommended, primarily

to investigate the underlying mechanism of AF. Because chronic anticoagulation with
warfarin is recommended in all eligible patients, echocardiography often will not have a
significant impact on management decisions. (See "Role of echocardiography in atrial
fibrillation" and see "Causes of atrial fibrillation").

Pathophysiologically, the final common event for embolism in AF is usually the

formation of LA or LAA thrombus with subsequent embolization. However,
thromboembolism of aortic atheroma can also occur. (See "Embolism from aortic plaque:
Thromboembolism").

Residual thrombus is rarely seen on TTE and can be detected by TEE in 45 percent of
patients presenting with an acute embolic event in the setting of new onset AF [31,86].
Even when not seen on TEE, an intracardiac thrombus is presumed to have been
present in all patients with AF who have had a recent thromboembolic event. This
hypothesis is based in part upon the observations that microscopic thrombus can be
identified in most patients with chronic sustained AF at autopsy [87] and that patients
with a recent thromboembolism and newly recognized AF are significantly more likely
to have spontaneous echo contrast than similar patients without a thromboembolic
event (87 versus 48 percent) [86].
 Diagnostic evaluation by TEE to search for an intraatrial thrombus is not essential since
the absence of a thrombus will not alter the clinical management. However, TEE may
be reasonable if cardioversion is desired. (See "Role of echocardiography in atrial
fibrillation"). Unless contraindicated, all stroke, peripheral embolism, and transient
ischemic attack patients with AF are given warfarin therapy for prevention of recurrent
embolic events (see "Patient selection" below).

Acute antithrombotic therapy — In patients with AF who suffer an ischemic stroke,

acute antithrombotic therapy may be warranted both to reduce disability and to reduce
the risk of early recurrent stroke, which as noted above is 3 to 5 percent in the first
two weeks [83,84]. These benefits must be balanced against the risk of intracranial
bleeding with any given therapy.

Thrombolysis — Thrombolytic therapy administered within three hours of the onset of

symptoms in patients with acute ischemic stroke reduces disability, but at the expense
of an increase in deaths within the first seven to 10 days and an increase in the risk of
intracranial hemorrhage [88,89]. The general approach to thrombolytic therapy in
ischemic stroke is discussed separately. (See "Fibrinolytic (thrombolytic) therapy for acute
ischemic stroke" and see "Clinical trials of intravenous fibrinolytic (thrombolytic) agents in the
treatment of acute ischemic stroke").

Specific data on the effectiveness of thrombolytic therapy in ischemic stroke are

limited for patients with AF, although such patients account for 20 to 30 percent of
those participating in clinical trials [89,90]. The NINDS trial, the largest and best study
of thrombolytic therapy in acute ischemic stroke, included 115 patients with AF (18
percent). No subgroup analysis of these patients has been reported, although there
was no evidence of a treatment interaction between a history of AF and benefit from
alteplase. The large size and worse prognosis of AF-associated acute ischemic stroke
accentuates both the risks and the benefits of thrombolysis [90].

Based upon the above observations, most experts endorse the use of alteplase for
patients with AF and acute ischemic stroke if given within three hours of stroke onset.

Heparin — Treatment with heparin or low molecular weight heparin (LMWH) in patients
with acute stroke and AF does not appear to be beneficial [83,84,91,92].

The results of two randomized trials illustrate the important findings:

• The International Stroke Trial (IST) evaluated the use of heparin (12,500 or 5000 IU
subcutaneously twice daily), aspirin, both, or neither in 19,435 patients with ischemic
stroke [83]. Among 18,451 of these patients for whom cardiac rhythm data was
available, 3169 (17 percent) had AF [84]. In the AF patients, there was no difference
between the heparin and no heparin groups in the incidence of any stroke or death at
two weeks (11.7 versus 12.0 percent). Heparin therapy was associated with a
significant reduction in new ischemic stroke (2.3 versus 4.9 percent) and a significant
increase in hemorrhagic stroke (2.8 versus 0.4 percent).

• The Heparin in Acute Embolic Stroke Trial (HAEST) compared the LMWH dalteparin (100
IU/kg subcutaneously twice daily) with aspirin in 449 patients with acute ischemic
stroke and AF [91]. Treatment was started within 30 hours of stroke onset. The
primary end point of recurrent ischemic stroke during the first 14 days occurred with
 similar frequency in the dalteparin and aspirin arms (8.5 versus 7.5 percent). There
was also a similar rate of symptomatic cerebral hemorrhage (2.7 versus 1.8 percent).

In summary, IST found a reduction in ischemic stroke with heparin that was offset by
an increase in hemorrhagic stroke, while HAEST found no reduction in ischemic stroke
with LMWH. The reason for the difference in results with respect to ischemic stroke is
unclear. However, neither trial showed a benefit of anticoagulation on functional
outcome at three to six months [84,91].

It is possible that there are subsets of patients with AF and ischemic stroke who may
benefit from heparin:

• Patients with multiple prior embolic events and those with "residual" left atrial
appendage thrombi on TEE are at especially high risk for early recurrent emboli.

• Patients with a submaximal stroke in a major arterial territory, in whom imaging and
Doppler studies have shown that the embolus has not migrated or lysed, may be
subject to progressive neurologic injury.

Whether heparin might be of benefit in these settings has not been studied in clinical
trials. A decision about its use should be made on a case-by-case basis.

Aspirin — Two trials have evaluated the use of aspirin to reducing the rate of recurrent
stroke in patients with acute stroke and AF:

• In the IST, there was a trend toward a reduction in recurrent ischemic stroke with
aspirin (3.3 versus 4.5 percent) with no increase in hemorrhagic stroke (1.4 versus 1.1
percent) [84].

• In the Chinese Acute Stroke Trial (CAST), conducted in parallel with the IST, 21,106
patients with acute ischemic stroke were randomly assigned to aspirin or placebo [93].
Of the study patients, 1411 (7 percent) had AF. Among the patients with AF, there was
a modest trend toward a lower risk of recurrent stroke with aspirin (5.0 versus 5.3
percent) [90].

In a combined analysis of the patients with AF from both the CAST and IST trials (4580
patients), the same trend toward a reduction in the rate of ischemic stroke was seen
(3.8 versus 4.8 percent) [90,94]. There was no difference in the rate of hemorrhagic
stroke (1.68 versus 1.64 percent).

Recommendations — In the absence of definitive data, clinical practice regarding the

use of antithrombotic therapy in patients with AF and an acute stroke varies widely. A
careful assessment of the risk for recurrent thromboembolism and serious bleeding in
the individual patient is essential. Consensus guidelines from the ACCP recommended
that a CT or MRI should be obtained before commencing any antithrombotic agent to
confirm the absence of intracranial hemorrhage and to assess the size of any cerebral
infarction [95]. Among patients with AF, subsequent therapy is determined by the
radiologic findings:

• The presence of a current intracranial hemorrhage is an absolute contraindication to

immediate use of thrombolysis and a relative contraindication to anticoagulation.
 Patients with a previous ICH may be candidates for anticoagulation depending upon
their risk of recurrent ischemic stroke. (See "Anticoagulant and antiplatelet therapy in
patients with an acute or prior intracerebral hemorrhage" and see "Management of warfarin-
associated intracerebral hemorrhage", section on Resumption of anticoagulation).

• In patients presenting within three hours of clearly defined symptom onset who meet
specific eligibility guidelines, thrombolytic therapy with intravenous alteplase reduces
disability overall, although there is an increase in the risk of intracranial hemorrhage.
(See "Fibrinolytic (thrombolytic) therapy for acute ischemic stroke", section on
Recommendations).

• We do not recommend the routine use of unfractionated or low molecular weight

heparin in patients with AF presenting with an acute ischemic stroke. A possible
exception occurs in patients with a submaximal stroke in whom the embolic fragment
is still in the intracranial segment of the artery.

• Warfarin (goal INR 2.0 to 3.0) can be initiated as soon as the patient is medically and
neurologically stable with minimal risk in normotensive patients with no evidence of
intracranial hemorrhage and small infarct size (or no evidence of infarction) [90]. Some
experts routinely obtain a repeat CT scan before initiating warfarin therapy. (See
"Therapeutic use of warfarin").

Among patients with large infarcts, the initiation of warfarin therapy should be delayed
for two weeks because of the potential risk of hemorrhagic transformation. Although
there is no standard definition, many stroke neurologists would consider "large"
infarcts to be those that involve more than one-third of the middle cerebral artery
territory or more than one-half of the posterior cerebral artery territory, usually based
upon CT or MRI evidence. Infarct size can also be clinically defined, but clinical
evaluation can result in an underestimation of the true infarct volume due to "silent"
areas of association cortex. Clinical estimation of infarct size can be improved by using
validated scales that have been correlated with infarct volume and clinical outcome,
such as the National Institutes of Health Stroke Scale (NIHSS). As an example, one
study found that an NIHSS score >15 was associated with a median infarct volume of
55.8 cm3 and worse outcome than NIHSS scores of 1 to 7 (median volume of 7.9 cm3)
or 8 to 15 (median volume of 31.4 cm3) [96].

A similar delay is recommended in patients with poorly controlled hypertension.

• Patients may benefit from aspirin administered until warfarin is therapeutic. Based upon
the IST, an aspirin dose of 325 mg/day is recommended [84]. (See "Antithrombotic
treatment of acute ischemic stroke").

Long-term therapy — Warfarin is the most effective long-term antithrombotic therapy

for prevention of recurrent stroke in patients with AF and an ischemic stroke. Aspirin
alone offers inadequate long-term protection, with a stroke risk that averaged 10
percent per year in a pooled analysis of individual participants in six randomized trials
[65]. Treatment with adjusted-dose warfarin reduced this risk to 4 percent per year.

In an analysis from the European Atrial Fibrillation trial (EAFT) and SPAF III of 834
patients with prior nondisabling ischemic stroke at study entry, the long-term risk of
recurrent stroke was lower in patients with a prior TIA than in those with a completed
ischemic stroke [97]. However, the reduction in recurrent stroke risk with warfarin
therapy was comparable in both groups: 3 versus 7 percent per year with aspirin in
patients with a TIA and 4 versus 11 percent per year in those with a completed
ischemic stroke.

Thus, oral anticoagulation with warfarin is recommended for warfarin eligible patients.
For medically stable patients with a small or moderate-sized infarct, warfarin can be
initiated soon after admission with minimal risk, while withholding anticoagulation for
two weeks is generally recommended for those with large infarctions or poorly
controlled hypertension. Patients who are not treated with heparin or warfarin earlier
are likely to benefit from aspirin until warfarin is begun [94]. (See "Antithrombotic
treatment of acute ischemic stroke").

In addition to warfarin therapy, control of hypertension is another important component

of the management of patients with AF who have had a stroke. Antihypertensive
therapy, preferably including an ACE inhibitor, reduces the risk of warfarin-associated
intracranial hemorrhage and may reduce the rate of recurrent stroke. (See "Management
of warfarin-associated intracerebral hemorrhage").

The latter benefit was suggested in a secondary analysis from the PROGRESS trial,
which demonstrated the benefit of blood pressure lowering (using perindopril and
indapamide) among both hypertensive and nonhypertensive patients who had a
previous stroke or TIA [98]. Among the subset of 476 patients with AF, perindopril-
based therapy was associated with a 34 percent reduction in the incidence of recurrent
stroke (13.6 versus 18.9 percent), a difference that was not statistically significant
because of the small number of recurrent events. (See "Treatment of hypertension
following a stroke", section on Long-term therapy).

Warfarin-associated ICH — The preceding discussion has addressed the issue of acute
ischemic stroke in the setting of AF. A separate issue, which is discussed separately, is
the management of patients with AF who develop a warfarin-associated intracranial
hemorrhage. (See "Management of warfarin-associated intracerebral hemorrhage").

INFORMATION FOR PATIENTS — Educational materials on this topic are available for
patients. (See "Patient information: Atrial fibrillation" and see "Patient information: Warfarin
(Coumadin®)"). We encourage you to print or e-mail this topic review, or to refer
patients to our public web site, www.patients.uptodate.com, which includes this and other
topics.

SUMMARY AND RECOMMENDATIONS — The following recommendations apply primarily

to patients with AF who have not suffered an embolic event, and to patients with AF
who have suffered an embolic event more than two weeks ago. Recommendations for
the prevention of secondary embolism in patients with an acute stroke are presented
above (see "Acute antithrombotic therapy" above).

AF increases the risk of stroke by approximately five-fold. Warfarin therapy reduces this
risk by almost 70 percent to a level similar to that seen in a population free of AF (show
table 6) [65,67]. A meta-analysis of six randomized, controlled trials that investigated
primary (76 percent) and secondary prevention in patients with AF (AFASAK 1, EAFT,
PATAF, SPAF-II, AFASAK 2, SPAF-III) found that compared with aspirin, patients
receiving oral anticoagulants were significantly less likely to experience any stroke or
cardiovascular events, but were more likely to experience major bleeding [65]. Taken
together, treating 100 AF patients for one year with oral anticoagulants rather than
aspirin would prevent 2.3 ischemic strokes (2.0 versus 4.3 percent) while causing 0.9
additional bleeding episodes. Overall, all-cause survival did not differ between aspirin
and warfarin groups, but appeared to improve for warfarin-treated patients three years
after therapy was started.

However, not all patients with AF are at equal risk of stroke. In a pooled analysis of
five prevention, placebo-controlled trials, the reduction in stroke risk with warfarin was
related to the patient age and the presence or absence of risk factors [60]. In the
absence of lone AF, the risk of stroke in untreated patients ranged from 4.3 to 12
percent per year and was reduced by warfarin to 1.1 to 4 percent per year (show figure
7). (See "Summary of risk models" above).

These benefits must be balanced against an increased risk of bleeding. In addition,

warfarin therapy imposes a variety of lifestyle constraints, including frequent blood test
monitoring and possibly dietary modification, and is associated with a number of drug
interactions.

The following recommendations refer to the use of warfarin and aspirin in the medical
management of patients with AF. A separate issue, for which little published
information is available, is the role of anticoagulation in patients who have undergone
radiofrequency catheter ablation to prevent recurrent AF. A recommended approach is
presented elsewhere. (See "Radiofrequency catheter ablation to prevent recurrent atrial
fibrillation").

Warfarin — Most embolic events in patients with AF are ischemic strokes; in one
review, peripheral embolization accounted for only 6.3 percent of events [9]. In
addition, AF is associated with more severe strokes and "longer" transient ischemic
attacks than emboli from carotid disease, presumably due to embolization of larger
particles in AF [10,11]. This relationship was illustrated in a report comparing ischemic
brain events in patients with AF and those with carotid disease in two major trials: the
ratio of hemispheric events to retinal events was 25:1 with AF compared to 2:1 with
carotid disease [10].

The following recommendations for warfarin therapy to prevent these events assume
that the patient is compliant and has no contraindications, such as alcoholism, an
underlying bleeding tendency, or recent trauma or surgery. (See "Therapeutic use of
warfarin").

Patient selection — Long-term anticoagulation with warfarin (INR 2.0 to 3.0) should be
considered as prevention for patients with chronic nonvalvular AF who have risk factors
for stroke as outlined above (see "Risk stratification" above). A summary of guidelines
from the ACCP [59], which are similar to recommendations from the ACC/AHA/ESC
[19], is shown in the following tables (show table 3 and show table 4). In addition, a
systematic review calculated the number of patients in various stroke risk categories
who would need to be treated with aspirin or warfarin to prevent a single stroke (show
table 5) [61].

However, in terms of risk stratification, we believe that the CHADS2 score is currently
the best validated and most clinically useful model to predict the risk of ischemic
stroke (defined as focal neurologic signs or symptoms persisting for more than 24
hours that cannot be explained by hemorrhage, trauma, or other factors) or peripheral
 embolization (which accounts for approximately 6 percent of events); transient
ischemic attacks are not included (show table 1) [9].

The main advantage of the CHADS2 score compared to other risk models is that it was
tested in a trial cohort from the National Registry of Atrial Fibrillation, and then
validated in a large clinical practice case series [9,53]. In addition, in an analysis of
patient data from six multicenter trials, the CHADS2 score was also more effective at
risk stratification than four other models with which it was compared [54]. (See
"Summary of risk models" above).

• Patients with a CHADS2 score of 0 are at low risk for ischemic stroke or peripheral
embolization (0.5 percent per year in the absence of warfarin) and can be managed
with aspirin.

• Patients with a CHADS2 score 3 are at high risk (5.3 to 6.9 percent per year) and
should, in the absence of a contraindication, be treated with warfarin.

• Patients with a CHADS2 score of 1 or 2 are at intermediate risk (1.5 to 2.5 percent per
year). One exception is that most experts would consider patients with a prior ischemic
stroke, transient ischemic attack, or systemic embolic event to be at high risk even if
they have no other risk factors and therefore a CHADS2 score of 2. Furthermore, the
great majority of these patients have some other risk factor and a CHADS2 score of at
least 3.

In patients with a CHADS2 score of 1 or 2 and no prior embolic event, the choice
between anticoagulation with warfarin and the use of aspirin will depend upon many
factors, including the clinician's assessment of risk, the ability to provide high-quality
monitoring of the intensity of oral anticoagulation, the patient's risk of bleeding with
oral anticoagulation, and patient preference.

Patient preference is an important issue in this setting, since the absolute reduction in
stroke risk required by the average patient with AF to favor warfarin therapy may be
higher than physicians would choose. In a community practice evaluation of 100
patients with AF who were at risk for embolization, 20 declined warfarin at least in part
because they wanted a significantly greater level of benefit (mean 4.1 percent
reduction in risk per year compared to 2.4 percent in those who were willing to take
warfarin) [99]. Better patient education can improve understanding of the benefits and
risks of warfarin therapy [100].

As mentioned above, TEE measures of stasis of atrial flow, atrial thrombus, and
complex aortic plaque are predictors of stroke risk [30,31]. However, these
abnormalities are more likely to be present in patients with clinical risk factors [30].
Although some of these TEE abnormalities appear to be independent predictors of risk,
their predictive value has not been defined when considered in multivariate models
that include clinical predictors. As a result, routine TEE is not currently recommended
in patients with AF purely for risk stratification. (See "Transesophageal echocardiography"
above).

• Use in women — Some risk models have noted female gender to be an independent
predictor of increased thromboembolic events [55,101], while others have not [47].
Regardless of baseline risk, women have a similar or greater benefit from warfarin
therapy compared to men [60,102]. (See "Risk stratification" above and see "Overview of
the presentation and management of atrial fibrillation", section on Gender differences).

Paroxysmal AF — Patients with paroxysmal AF should usually be anticoagulated

according to the same criteria if AF is present for a substantial portion of the time
[49,59]. Embolic events can occur in patients with acute AF for as little as 72 hours
[103]. Although the incidence of embolization had been thought to be lower in
paroxysmal AF than in chronic AF, two large trials found a similar risk (show figure 2)
[20,22]. In addition, the meta-analysis described above found that the reduction in
ischemic stroke risk with warfarin was similar in patients with paroxysmal and chronic
AF [65]. (See "Paroxysmal atrial fibrillation").

Similarly, the AFFIRM and RACE trials showed that most patients in whom a strategy of
rhythm rather than rate control is chosen should be chronically anticoagulated with
warfarin or a comparable agent [25,26]. (See "Rhythm versus rate control" above and see
"Rhythm control versus rate control in atrial fibrillation").

Goal INR — An INR between 2.0 and 3.0 has been generally recommended for most
patients with AF who receive warfarin anticoagulation (show table 3 and show table 4)
[19,59]. This is based upon the risk of bleeding associated with higher degrees of
anticoagulation, and the increased incidence of stroke with an INR below 2.0 (show
figure 11) [104-107].

The severity of stroke and the mortality rate in patients with AF are also increased
when the INR is below 2.0. This was illustrated in a cohort of 596 patients with
nonvalvular AF who experienced an ischemic stroke [108]. Those with an INR below
2.0 on admission had an increased likelihood of severe stroke (odds ratio 1.9) and of
death at 30 days (16 versus 6 percent, hazard ratio 3.4) compared to those with an
INR above 2.0.

Somewhat higher goal INR values may be desirable in patients at increased risk. A
report from the European Atrial Fibrillation Trial Study Group compared the incidence
of both ischemic (embolic) and major hemorrhagic events according to the INR in 214
patients with nonrheumatic AF and recent cerebral ischemia [106]. The incidence of
total events was highest at an INR below 2 or above 5 (show figure 11). The ideal range
was between 2.0 and 3.9. Virtually identical findings have been noted in another report
[105]. Thus, a reasonable goal INR for patients at particularly high risk for embolization
(eg, prior thromboembolism, rheumatic heart disease, prosthetic heart valves) is
between 2.5 and 3.5 (show table 4).

On the other hand, somewhat lower values may be desirable in patients over the age
of 75 years, including those with a previous ischemic event, given the uncertainty
about the safety of INRs above 2.5 in these patients (show table 4) [109,110]. A target
INR of 1.8 to 2.5 may be a reasonable compromise between toxicity and efficacy for
this age group. (See "Anticoagulation in the elderly").

Except potentially in the very elderly, INR values below 2.0 should generally be
avoided because of the marked increase in the risk of stroke (four to six fold at an INR
of 1.3 compared with an INR of 2.0 or above) (show figure 9) [49,105].

Initiation of therapy — The desired degree of anticoagulation can usually be achieved

by giving 5 to 10 mg of warfarin daily for two days, with subsequent doses being based
upon the INR. One trial that used laboratory markers (not clinical outcomes) for safety
and efficacy, found that a loading dose of 5 mg, when compared with 10 mg, was
associated with less risk of excess anticoagulation and need for vitamin K, and a lower
likelihood of the development of a hypercoagulable state due to precipitous decreases
in the first 36 hours in the serum concentration of protein C, an inhibitor of coagulation
[111]. Avoidance of transient hypercoagulability with the lower dose may be
particularly helpful in patients with chronic AF who are typically begun on warfarin in
the outpatient setting without heparin overlap.

Monitoring — The INR should be monitored every four weeks once a steady state has
been established. Follow-up may be provided by a nurse-led anticoagulation clinic, or
the patient may monitor his or her own INR with a portable device at home. (See
"Therapeutic use of warfarin", section on Laboratory monitoring).

Concurrent therapy with aspirin — A separate issue is the use of aspirin for secondary
prevention of cardiovascular disease in patients treated with warfarin for AF. The 2004
ACCP Consensus Conference suggested that a low dose of aspirin (less than 100 mg
per day) or clopidogrel (75 mg per day) may be given concurrently with anticoagulation,
but that these strategies have not been evaluated sufficiently and may be associated
with an increased risk of bleeding, particularly in elderly patients [59,77]. In the cohort
study in the elderly discussed above, concurrent aspirin use was associated with an
absolute increase in major bleeding and intracranial hemorrhage of 0.6 percent at 90
days, compared to warfarin alone [77]. (See "Risk of bleeding" above).

There is no evidence that such combined therapy should be used solely to increase
protection against embolization. However, combined therapy may be reasonable in
selected patients with coronary artery disease in whom the potential benefits outweigh
the increased risk of hemorrhage. (See "Chronic therapy" above).

Temporary reversal of anticoagulation — Patients on long-term warfarin therapy may

occasionally require reversal of warfarin anticoagulation to prevent bleeding or other
harmful effects of warfarin (eg, teratogenesis). The most common situations in which
this is true are to facilitate the performance of invasive procedures, in the
perioperative period of elective surgery, and during pregnancy. Less often, reversal of
anticoagulation may be required for emergent surgery or other urgent indications.
These issues are discussed in detail elsewhere. (See "Management of anticoagulation
before and after elective surgery" and see "Gastroenterologic procedures in patients with
disorders of hemostasis" and see "Anticoagulation during pregnancy" and see "Correcting
excess anticoagulation after warfarin", section on Temporary reversal of warfarin).

The possible role of low molecular weight heparin in these settings was evaluated in a
uncontrolled study of 112 patients with AF and at least one risk factor for embolism
who were undergoing elective noncardiac surgery or an invasive procedure [112].
Warfarin was held for five days prior to the procedure and restarted the evening
afterward. Dalteparin was given for three days before and at least four days after the
procedure and until the INR was >1.9. There were three thromboembolic events (two
myocardial infarctions and one stroke) and seven episodes of major bleeding. Because
there was no control group, it is not clear whether dalteparin reduced or increased the
frequency of adverse events compared to some other approach.

Although there are no data demonstrating the efficacy of this approach, we often use
LMW heparin in the periprocedural period in patients at especially high risk of an
 embolic event (prior thromboembolism, rheumatic mitral stenosis, a mechanical heart
valve, or prior intracardiac thrombus). For other patients, we discontinue warfarin three
to four days prior to the procedure and resume warfarin on the evening of the
procedure.

Aspirin — Aspirin is generally less effective than anticoagulation with warfarin, but more
effective than placebo (show table 6) [65,67]. Data from a meta-analysis suggested that
treating 100 AF patients for one year with oral anticoagulants rather than aspirin would
prevent 2.3 ischemic strokes (2.0 versus 4.3 percent) [65]. However, aspirin is more
effective than placebo [60,64] and the following subgroups of low risk patients who
may benefit from aspirin therapy have been identified:

• The SPAF-II trial suggested that aspirin is useful in younger patients (less than age 65
years) without organic heart disease, in whom the stroke rate is quite low on aspirin
(0.5 percent per year), and in patients over age 75 years, in whom the absolute
reduction in all strokes with warfarin is relatively small when compared with aspirin
[63].

• The pooled analysis of five prevention, placebo-controlled trials found aspirin of benefit
in patients between the ages of 65 and 75 years who had no risk factors (show figure 7)
[60].

However, in terms of risk stratification, we believe that the CHADS2 score is currently
the best validated and most clinically useful model (show table 1). Its main advantage
compared to other risk models is that it was tested in a trial cohort from the National
Registry of Atrial Fibrillation, and then validated in a large clinical practice case series
[9,53]. (See "Summary of risk models" above).

• Patients with a CHADS2 score of 0 are at low risk of embolization (0.5 percent per year
in the absence of warfarin) and can be managed with aspirin.

• Patients with a CHADS2 score 3 are at high risk (5.3 to 6.9 percent per year) and
should, in the absence of a contraindication, be treated with warfarin.

• Patients with a CHADS2 score of 1 or 2 are at intermediate risk of embolization (1.5 to

2.5 percent per year).

In the last group, the choice between anticoagulation with warfarin and the use of
aspirin will depend upon many factors, including the clinician's assessment of risk, the
ability to provide high-quality monitoring of the intensity of oral anticoagulation, the
patient's risk of bleeding with oral anticoagulation, and patient preference.

It has been estimated that approximately one-third of patients with AF (range 14 to 45

percent in different reports) are at low risk and can be safely treated with aspirin [62].
We also give aspirin in the hope of benefit in patients who are noncompliant or have a
major contraindication to warfarin but not aspirin.

A separate issue is the use of aspirin for secondary prevention of cardiovascular disease
in patients treated with warfarin for AF. (See "Concurrent therapy with aspirin" above).
 Alternative approaches — Alternative approaches for patients with a contraindication
to anticoagulation have been used in an attempt to prevent recurrent embolism in AF.
These include LA appendage exclusion or amputation with surgery, occlusion with an
implanted device, or the maze procedure [113-115]. However, the clinical efficacy and
risk-benefit ratio of such procedures are not yet known. Furthermore, the low stroke
risk profile in AF patients without complex aortic plaque raises doubt about the value of
surgical or medical treatment approaches solely directed to the heart for the
prevention of embolism [31]. (See "Nonpharmacologic options" above).

Thus, most patients with contraindications to warfarin should be treated with aspirin
rather than with interventional alternatives.

Underutilization and underanticoagulation — Despite the compelling evidence that

anticoagulation with warfarin reduces the risk of stroke in most patients with AF, this
therapy continues to be underutilized [116-119]. The magnitude of this problem was
examined in a review of 13,428 ambulatory patients with nonvalvular AF [116]. The
following findings were noted:

• Among patients without a known contraindication to anticoagulation, only 53 percent

were receiving warfarin; warfarin use was lower in those younger than 55 (44 percent)
and older than 85 years of age (35 percent).

• Among patients without a contraindication to anticoagulation who had one or more risk
factors for stroke, only 59 percent were receiving warfarin.

• The strongest predictors for warfarin use were previous stroke and heart failure, while
the strongest predictors for not prescribing warfarin therapy were previous intracranial
or gastrointestinal hemorrhage and age over 84 years. (See "Anticoagulation in the
elderly").

Even when warfarin is prescribed, maintaining the goal INR is often not achieved, and
the failure to maintain a therapeutic INR is associated with worse outcomes, as
illustrated by the following:

• In the SPAF-III trial only 61 percent of INR values were between 2.0 and 3.0, and 25
percent were <2.0, despite the use of a warfarin nomogram with a nurse carefully
followed monthly INRs and adjusting the warfarin dose with the assistance of a
physician [49].

• In a systematic review of four studies, the INR was <2.0 on 26 percent of

measurements [68]. An INR at this level was associated with a five-fold increase in
ischemic events compared to values in the therapeutic range.

• In a retrospective analysis of the SPORTIF III and V trials, patients assigned to

warfarin therapy were categorized as having poor, moderate, or good control of
anticoagulation (therapeutic INRs <60 percent, 60 to 75 percent, or >75 percent of
the time, respectively) [120]. Patients with poor control had significantly higher annual
rates of mortality and major bleeding (4.2 and 3.9 percent, respectively) compared to
those with moderate (1.8 and 2.0 percent) or good (1.7 and 1.6 percent) control.
The consistency of adequate anticoagulation is likely to be even lower in the
community. This was illustrated in a review of 660 patients managed by general
internists and family practitioners [121]. The INR was within the target range in only
44 percent and was below the target range in 38 percent.

Finally, even when anticoagulation is appropriately initiated, it is often discontinued.

Among 1005 patients in the FRACTAL registry with new atrial fibrillation, warfarin was
initially prescribed in 65 percent. However, at 30 months warfarin use had declined to
44 percent [118]. In this cohort, recurrent episodes of AF were correlated with higher
rates of continued warfarin therapy. However, the risks of termination of warfarin
therapy, even in patients in whom sinus rhythm has been restored, were highlighted
the AFFIRM and RACE trials, in which 70 to 80 percent of ischemic strokes occurred
either after discontinuation of warfarin or when the INR was subtherapeutic [25,26].
(See "Paroxysmal AF" above).

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES
1. Rockson, SG, Albers, GW. Comparing the guidelines: anticoagulation therapy to
optimize stroke prevention in patients with atrial fibrillation. J Am Coll Cardiol 2004;
43:929.
2. Ezekowitz, MD, Falk, RH. The increasing need for anticoagulant therapy to prevent
stroke in patients with atrial fibrillation. Mayo Clin Proc 2004; 79:904.
3. Wolf, PA, Abbott, RD, Kannel, WB. Atrial fibrillation: A major contributor to stroke in
the elderly. Arch Intern Med 1987; 147:1561.
4. Kannel, WB, Abbott, RD, Savage, DD, McNamara, PM. Epidemiologic features of
chronic atrial fibrillation. N Engl J Med 1982; 306:1018.
5. Feinberg, WM, Blackshear, JL, Laupacis, A, et al. Prevalence, age distribution, and
gender of patients with atrial fibrillation: Analysis and implication. Arch Intern Med
1995; 155:469.
6. Krahn, AD, Manfreda, J, Tate, RB, et al. The natural history of atrial fibrillation:
Incidence, risk factors, and prognosis in the Manitoba Follow-up Study. Am J Med
1995; 98:476.
7. Wolf, PA, Abbott, RD, Kannel, WB. Atrial fibrillation as an independent risk factor for
stroke: The Framingham Study. Stroke 1991; 22:983.
8. Frost, L, Engholm, G, Johnsen, S, et al. Incident stroke after discharge from the
hospital with a diagnosis of atrial fibrillation. Am J Med 2000; 108:36.
9. Go, AS, Hylek, EM, Chang, Y, et al. Anticoagulation therapy for stroke prevention in
atrial fibrillation: how well do randomized trials translate into clinical practice?. JAMA
2003; 290:2685.
10. Anderson, DC, Kappelle, LJ, Eliasziw, M, et al. Occurrence of hemispheric and retinal
ischemia in atrial fibrillation compared with carotid stenosis. Stroke 2002; 33:1963.
11. Harrison, MJ, Marshall, J. Atrial fibrillation, TIAs and completed strokes. Stroke 1984;
15:441.
12. Ezekowitz, MD, James, KE, Nazarian, SM, et al. Silent cerebral infarction in patients
with non-rheumatic atrial fibrillation. Circulation 1995; 92:2178.
13. Kempster, PA, Gerraty, RP, Gates, PC. Asymptomatic cerebral infarction in patients
with chronic atrial fibrillation. Stroke 1988; 19:955.
14. Cullinane, M, Wainwright, R, Brown, A, et al. Asymptomatic embolization in subjects
with atrial fibrillation not taking anticoagulants: A prospective study. Stroke 1998;
 29:1810.
15. Lin, HJ, Wolf, PA, Kelly-Hayes, M, et al. Stroke severity in atrial fibrillation. The
Framingham Study. Stroke 1996; 27:1760.
16. Jorgensen HS, Nakayama H, Reith J, et al Acute stroke with atrial fibrillation. The
Copenhagen Stroke Study. Stroke 1996; 27:1765.
17. Lamassa, M, Di Carlo, AA, Pracucci, G, et al. Characteristics, outcome, and care of
stroke associated with atrial fibrillation in Europe: data from a multicenter
multinational hospital-based registry (The European Community Stroke Project).
Stroke 2001; 32:392.
18. Carter, AM, Catto, AJ, Grant, PJ. Association of the alpha-fibrinogen Thr312Ala
polymorphism with poststroke mortality in subjects with atrial fibrillation. Circulation
1999; 99:2423.
19. Fuster, V, Ryden, LE, Cannom, DS, et al. ACC/AHA/ESC 2006 Guidelines for the
Management of Patients With Atrial Fibrillation A Report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the
European Society of Cardiology Committee for Practice Guidelines (Writing Committee
to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation).
J Am Coll Cardiol 2006; 48:e149.
20. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of
low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.
N Engl J Med 1990; 323:1505.
21. Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial
fibrillation study: Final results. Circulation 1991; 84:527.
22. Hart, RG, Pearce, LA, Rothbart, RM, et al. Stroke with intermittent atrial fibrillation:
incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation
Investigators. J Am Coll Cardiol 2000; 35:183.
23. Israel, CW, Gronefeld, G, Ehrlich, JR, et al. Long-term risk of recurrent atrial fibrillation
as documented by an implantable monitoring device. Implications for optimal patient
care. J Am Coll Cardiol 2004; 43:47.
24. Page, RL, Wilkinson, WE, Clair, WK, et al. Asymptomatic arrhythmias in patients with
symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular
tachycardia. Circulation 1994; 89:224.
25. Wyse, DG, Waldo, AL, DiMarco, JP, et al. A comparison of rate control and rhythm
control in patients with atrial fibrillation. The atrial fibrillation follow-up investigation of
rhythm management (AFFIRM) investigators. N Engl J Med 2002; 347:1825.
26. Van Gelder, IC, Hagens, VE, Bosker, HA, et al. A comparison of rate control and
rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med
2002; 347:1834.
27. Stoddard, MF. Risk of thromboembolism in new onset or transient atrial fibrillation.
Prog Cardiovasc Dis 1996; 39:69.
28. Al-Saady, NM, Obel, OA, Camm, AJ. Left atrial appendage: structure, function, and
role in thromboembolism. Heart 1999; 82:547.
29. Shively, BK, Gelgand, EA, Crawford, MH. Regional left atrial stasis during atrial
fibrillation and flutter: Determinants and relation to stroke. J Am Coll Cardiol 1996;
27:1722.
30. Zabalgoitia, M, Halperin, JL, Pearce, LA, et al. Transesophageal echocardiographic
correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. J Am
Coll Cardiol 1998; 31:1622.
31. Transesophageal echocardiographic correlates of thromboembolism in high-risk
patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation
Investigators Committee on Echocardiography. Ann Intern Med 1998; 128:639.
32. Black, IW, Chesterman, CN, Hopkins, AP, et al. Hematologic correlates of left atrial
spontaneous echo contrast and thromboembolism in nonvalvular atrial fibrillation. J
 Am Coll Cardiol 1993; 21:451.
33. Fatkin, D, Herbert, E, Feneley, MP. Hematologic correlates of spontaneous echo
contrast in patients with atrial fibrillation and implications for thromboembolic risk. Am
J Cardiol 1994; 73:672.
34. Sigel, B, Coelho, JC, Spigos, DC, et al. Ultrasonography of blood during stasis and
coagulation. Invest Radiol 1981; 16:71.
35. Black, IW, Hopkins, AP, Lee, LC, Walsh, WF. Left atrial spontaneous echo contrast: A
clinical and echocardiographic analysis. J Am Coll Cardiol 1991; 18:398.
36. Tsai, LM, Chen, JH, Tsao, CJ. Relation of left atrial spontaneous echo contrast with
prethrombotic state in atrial fibrillation associated with systemic hypertension,
idiopathic dilated cardiomyopathy, or no identifiable cause (lone). Am J Cardiol 1998;
81:1249.
37. Tsai, LM, Chen, JH, Lin, LJ, Teng, JK. Natural history of left atrial spontaneous echo
contrast in nonrheumatic atrial fibrillation. Am J Cardiol 1997; 80:897.
38. Bernhardt, P, Schmidt, H, Hammerstingl, C, et al. Patients with atrial fibrillation and
dense spontaneous echo contrast at high risk a prospective and serial follow-up over
12 months with transesophageal echocardiography and cerebral magnetic resonance
imaging. J Am Coll Cardiol 2005; 45:1807.
39. Uno, M, Tsuji, H, Sawada, S, et al. Fibrinopeptide A (FPA) levels in atrial fibrillation and
the effects of heparin administration. Jpn Circ J 1988; 52:9.
40. Mitusch, R, Siemens, HJ, Garbe, M, et al. Detection of a hypercoagulable state in
nonvalvular atrial fibrillation and the effect of anticoagulation therapy. Thromb
Haemost 1996; 75:219.
41. Gustafsson, C, Blomback, M, Britton, M, et al. Coagulation factors and the increased
risk of stroke in nonvalvular atrial fibrillation. Stroke 1990; 21:47.
42. Kumagai, K, Fukunami, M, Ohmori, M, et al. Increased intracardiovascular clotting in
patients with chronic atrial fibrillation. J Am Coll Cardiol 1990; 16:377.
43. Vene, N, Mavri, A, Kosmelj, K, Stegnar, M. High D-dimer levels predict cardiovascular
events in patients with chronic atrial fibrillation during oral anticoagulant therapy.
Thromb Haemost 2003; 90:1163.
44. Ezekowitz, MD, Bridgers, SL, James, KE, et al. Warfarin in the prevention of stroke
associated with nonrheumatic atrial fibrillation. N Engl J Med 1992; 327:1406.
45. Petersen, P, Boysen, G, Godtfredsen, J, et al. Placebo-controlled, randomized trial of
warfarin and aspirin for prevention of thromboembolic complications in chronic atrial
fibrillation. The Copenhagen AFASAK Study. Lancet 1989; 1:175.
46. Connolly, SJ, Laupacis, A, Gent, M, et al. Canadian Atrial Fibrillation Anticoagulation
(CAFA) Study. J Am Coll Cardiol 1991; 18:349.
47. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation.
Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;
154:1449.
48. Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with
aspirin: Stroke Prevention in Atrial Fibrillation III Study. The SPAF III Writing
Committee for the Stroke Prevention in Atrial Fibrillation Investigators. JAMA 1998;
279:1273.
49. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-
risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III
randomised clinical trial. Lancet 1996; 348:633.
50. Sudlow, CM, Rodgers, H, Kenny, RA, et al. Service provision and use of anticoagulants
in atrial fibrillation. Br Med J 1995; 311:558.
51. Gottlieb, LK, Salem-Schatz, S. Anticoagulation in atrial fibrillation. Does efficacy in
clinical trials translate into effectiveness in practice? Arch Intern Med 1994; 154:1945.
52. Evans, A, Kalra, L. Are the results of randomized controlled trials on anticoagulation in
patients with atrial fibrillation generalizable to clinical practice?. Arch Intern Med 2001;
 161:1443.
53. Gage, BF, Waterman, AD, Shannon, W, et al. Validation of clinical classification
schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
JAMA 2001; 285:2864.
54. Gage, BF, van Walraven, C, Pearce, L, et al. Selecting patients with atrial fibrillation for
anticoagulation: stroke risk stratification in patients taking aspirin. Circulation 2004;
110:2287.
55. Wang, TJ, Massaro, JM, Levy, D, et al. A risk score for predicting stroke or death in
individuals with new-onset atrial fibrillation in the community: the Framingham Heart
Study. JAMA 2003; 290:1049.
56. Risk functions for stroke and for stroke or death available at
www.nhlbi.nih.gov/about/framingham/stroke.htm (Accessed 3/7/05).
57. Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic features of
patients at risk. The Stroke Prevention in Atrial Fibrillation Investigators. Ann Intern
Med 1992; 116:6.
58. Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective
study of 1066 patients from 3 clinical trials. Arch Intern Med 1998; 158:1316.
59. Singer, DE, Albers, GW, Dalen, JE, et al. Antithrombotic therapy in atrial fibrillation:
the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest
2004; 126:429S.
60. Ezekowitz, MD, Levine, JA. Preventing stroke in patients with atrial fibrillation. JAMA
1999; 281:1830.
61. Straus, SE, Majumdar, SR, McAlister, FA. New evidence for stroke prevention:
scientific review. JAMA 2002; 288:1388.
62. Pearce, LA, Hart, RG, Halperin, JL. Assessment of three schemes for stratifying stroke
risk in patients with nonvalvular atrial fibrillation. Am J Med 2000; 109:45.
63. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke
Prevention in Atrial Fibrillation II Study. Lancet 1994; 343:687.
64. Hart, RG, Benavente, O, McBride, R, Pearce, LA. Antithrombotic therapy to prevent
stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 1999;
131:492.
65. Van Walraven, C, Hart, RG, Singer, DE, et al. Oral anticoagulants vs aspirin in
nonvalvular atrial fibrillation: An individual patient meta-analysis. JAMA 2002;
288:2441.
66. Cooper, NJ, Sutton, AJ, Lu, G, Khunti, K. Mixed comparison of stroke prevention
treatments in individuals with nonrheumatic atrial fibrillation. Arch Intern Med 2006;
166:1269.
67. McNamara, RL, Tamariz, LJ, Segal, JB, Bass, EB. Management of atrial fibrillation:
review of the evidence for the role of pharmacologic therapy, electrical cardioversion,
and echocardiography. Ann Intern Med 2003; 139:1018.
68. Reynolds, MW, Fahrbach, K, Hauch, O, et al. Warfarin anticoagulation and outcomes in
patients with atrial fibrillation: a systematic review and metaanalysis. Chest 2004;
126:1938.
69. Bleeding during antithrombotic therapy in patients with atrial fibrillation. The Stroke
Prevention in Atrial Fibrillation Investigators. Arch Intern Med 1996; 156:409.
70. Gullov, AL, Koefoed, BG, Petersen, P, et al. Fixed minidose warfarin and aspirin alone
and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation:
Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern
Med 1998; 158:1513.
71. Perez-Gomez, F, Alegria, E, Berjon, J, et al. Comparative effects of antiplatelet,
anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial
fibrillation: a randomized multicenter study. J Am Coll Cardiol 2004; 44:1557.
72. Connolly, S, Pogue, J, Hart, R, et al. Clopidogrel plus aspirin versus oral
 anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with
Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled
trial. Lancet 2006; 367:1903.
73. Olsson, SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran
compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III):
randomised controlled trial. Lancet 2003; 362:1691.
74. Albers, GW, Diener, HC, Frison, L, et al. Ximelagatran vs warfarin for stroke prevention
in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 2005; 293:690.
75. Hylek, EM, Singer, DE. Risk factors for intracranial hemorrhage in outpatients taking
warfarin. Ann Intern Med 1994; 120:897.
76. Hart, RG. Benavente, O, Pearce, LA. Increased risk of intracranial hemorrhage when
aspirin is combined with warfarin: A meta-analysis and hypothesis. Cerebrovasc Dis
1999; 9:215.
77. Shireman, TI, Howard, PA, Kresowik, TF, Ellerbeck, EF. Combined anticoagulant-
antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke
2004; 35:2362.
78. Woeber, KA. Thyrotoxicosis and the heart. N Engl J Med 1992; 327:94.
79. Bonow, RO, Carabello, BA, Chatterjee, K, et al. ACC/AHA 2006 guidelines for the
management of patients with valvular heart disease. A report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing
committee to revise the 1998 guidelines for the management of patients with valvular
heart disease). J Am Coll Cardiol 2006; 48:e1.
80. Garcia-Fernandez, MA, Perez-David, E, Quiles, J, et al. Role of left atrial appendage
obliteration in stroke reduction in patients with mitral valve prosthesis: a
transesophageal echocardiographic study. J Am Coll Cardiol 2003; 42:1253.
81. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic
attack or minor stroke. Lancet 1993; 342:1255.
82. Sandercock, P, Bamford, J, Dennis, M, et al. Atrial fibrillation and stroke: prevalence in
different types of stroke and influence on early and long term prognosis (Oxfordshire
community stroke project). BMJ 1992; 305:1460.
83. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous
heparin, both, or neither among 19435 patients with acute ischaemic stroke.
International Stroke Trial Collaborative Group. Lancet 1997; 349:1569.
84. Saxena, R, Lewis, S, Berge, E, et al. Risk of early death and recurrent stroke and
effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in
the International Stroke Trial. Stroke 2001; 32:2333.
85. Hart, RG, Pearce, LA, Miller, VT, et al. Cardioembolic vs. noncardioembolic strokes in
atrial fibrillation: frequency and effect of antithrombotic agents in the stroke
prevention in atrial fibrillation studies. Cerebrovasc Dis 2000; 10:39.
86. Manning, WJ, Silverman, DI, Keighley, KS, et al. Prevalence of residual left atrial
thrombi among patients with acute thromboembolism and newly recognized atrial
fibrillation. Arch Intern Med 1995; 155:2193.
87. Fisher, CM. Embolism in atrial fibrillation. In: Atrial Fibrillation, Kulbertus, HE, Olsson,
SB, Schlepper, M (Eds), Alindgren & Soner AB, Moindal, Sweden 1981. p.192.
88. Wardlaw, JM, del Zoppo, G, Yamaguchi, T. Thrombolysis for acute ischaemic stroke.
Cochrane Database Syst Rev 2000; :CD000213.
89. Tissue plasminogen activator for acute ischemic stroke. The National Institute of
Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;
333:1581.
90. Hart, RG, Palacio, S, Pearce, LA. Atrial fibrillation, stroke, and acute antithrombotic
therapy: analysis of randomized clinical trials. Stroke 2002; 33:2722.
91. Berge, E, Abdelnoor, M, Nakstad, PH. Low molecular-weight heparin versus aspirin in
patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised
 study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial. Lancet 2000;
355:1205.
92. Paciaroni, M, Agnelli, G, Micheli, S, Caso, V. Efficacy and safety of anticoagulant
treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled
trials. Stroke 2007; 38:423.
93. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with
acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet
1997; 349:1641.
94. Chen, Z, Sandercock, P, Pan, H, et al. Indications for early aspirin use in acute
ischemic stroke: A combined analysis of 40 000 randomized patients from the Chinese
Acute Stroke Trial and the International Stroke Trial. Stroke 2000; 31:1240.
95. Albers, GW, Amarenco, P, Easton, JD, et al. Antithrombotic and thrombolytic therapy
for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic
Therapy. Chest 2004; 126:483S.
96. Thijs, VN, Lansberg, MG, Beaulieu, C, et al. Is early ischemic lesion volume on
diffusion-weighted imaging an independent predictor of stroke outcome? A
multivariable analysis. Stroke 2000; 31:2597.
97. Hart, RG, Pearce, LA, Koudstaal, PJ. Transient ischemic attacks in patients with atrial
fibrillation: implications for secondary prevention: the European Atrial Fibrillation Trial
and Stroke Prevention in Atrial Fibrillation III trial. Stroke 2004; 35:948.
98. Arima, H, Hart, RG, Colman, S, et al. Perindopril-based blood pressure-lowering
reduces major vascular events in patients with atrial fibrillation and prior stroke or
transient ischemic attack. Stroke 2005; 36:2164.
99. Howitt, A, Armstrong, D. Implementing evidence based medicine in general practice:
audit and qualitative study of antithrombotic treatment for atrial fibrillation. BMJ 1999;
318:1324.
100. Man-Son-Hing, M, Laupacis, A, O'Connor, AM, et al. A patient decision aid regarding
antithrombotic therapy for stroke prevention in atrial fibrillation: a randomized
controlled trial. JAMA 1999; 282:737.
101. Hart, RG, Pearce, LA, McBride, R, et al. Factors associated with ischemic stroke during
aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III
clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke
1999; 30:1223.
102. Hart, RG, Halperin, JL, Pearce, LA, et al. Lessons from the Stroke Prevention in Atrial
Fibrillation trials. Ann Intern Med 2003; 138:831.
103. Stoddard, MF, Dawkins, PR, Prince, CR, Ammash, NM. Left atrial appendage thrombus
is not uncommon in patients with acute atrial fibrillation and a recent embolic event: A
transesophageal echocardiographic study. J Am Coll Cardiol 1995; 25:452.
104. Perret-Guillaume, C, Wahl, DG. Low-dose warfarin in atrial fibrillation leads to more
thromboembolic events without reducing major bleeding when compared to adjusted-
dose--a meta-analysis. Thromb Haemost 2004; 91:394.
105. Hylek, EM, Skates, SJ, Sheehan, MA, Singer, DE. An analysis of the lowest effective
intensity of prophylactic anticoagulation for patients with nonrheumatic atrial
fibrillation. N Engl J Med 1996; 335:540.
106. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and
recent cerebral ischemia. The European Atrial Fibrillation Trial Study Group. N Engl J
Med 1995; 333:5.
107. Torn, M, Van Der Meer, FJ, Rosendaal, FR. Lowering the intensity of oral anticoagulant
therapy: effects on the risk of hemorrhage and thromboembolism.. Arch Intern Med
2004; 164:668.
108. Hylek, EM, Go, AS, Chang, Y, et al. Effect of intensity of oral anticoagulation on stroke
severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019.
109. Yamaguchi, T for Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary
 Prevention Cooperative Study Group. Optimal intensity of warfarin therapy for
secondary prevention of stroke in patients with nonvalvular atrial fibrillation. A
multicenter, prospective, randomized trial. Stroke 2000; 31:817.
110. Gage, BF, Fihn, SD, White, RH. Warfarin therapy for an octogenarian who has atrial
fibrillation. Ann Intern Med 2001; 134:465.
111. Harrison, L, Johnston, M, Massicotte, MP, et al. Comparison of 5 mg and 10 mg loading
doses in initiation of warfarin therapy. Ann Intern Med 1997; 126:133.
112. Kovacs, MJ, Kearon, C, Rodger, M, et al. Single-arm study of bridging therapy with
low-molecular-weight heparin for patients at risk of arterial embolism who require
temporary interruption of warfarin. Circulation 2004; 110:1658.
113. Cox, JL, Ad, N, Palazzo, T. Impact of the maze procedure on the stroke rate in patients
with atrial fibrillation. J Thorac Cardiovasc Surg 1999; 118:833.
114. Nakai, T, Lesh, MD, Gerstenfeld, EP, et al. Percutaneous left atrial appendage
occlusion (PLAATO) for preventing cardioembolism: first experience in canine model.
Circulation 2002; 105:2217.
115. Kosakai, Y, Kawaguchi, AT, Isobe, F, et al. Cox maze procedure for chronic atrial
fibrillation associated with mitral valve disease. J Thorac Cardiovasc Surg 1994;
108:1049.
116. Go, AS, Hylek, EM, Borowsky, LH, et al. Warfarin use among ambulatory patients with
nonvalvular atrial fibrillation: The AnTicoagulation and Risk Factors in Atrial Fibrillation
(ATRIA) study. Ann Intern Med 1999; 131:927.
117. Gage, BF, Boechler, M, Doggette, AL, et al. Adverse outcomes and predictors of
underuse of antithrombotic therapy in medicare beneficiaries with chronic atrial
fibrillation. Stroke 2000; 31:822.
118. Reynolds, MR, Shah, J, Essebag, V, et al. Patterns and Predictors of Warfarin Use in
Patients With New-Onset Atrial Fibrillation from the FRACTAL Registry. Am J Cardiol
2006; 97:538.
119. Glazer, NL, Dublin, S, Smith, NL, et al. Newly detected atrial fibrillation and
compliance with antithrombotic guidelines. Arch Intern Med 2007; 167:246.
120. White, HD, Gruber, M, Feyzi, J, et al. Comparison of outcomes among patients
randomized to warfarin therapy according to anticoagulant control: results from
SPORTIF III and V. Arch Intern Med 2007; 167:239.
121. Samsa, GP, Matchar, DB, Goldstein, LB, et al. Quality of anticoagulation management
among patients with atrial fibrillation: results of a review of medical records from 2
communities. Arch Intern Med 2000; 160:967.

GRAPHICS

Incidence of AF with age

Increasing incidence of AF with age

Incidence of atrial fibrillation according to age in almost 4000 male air crew recruits
followed continuously for 44 years in the Manitoba Follow-up Study. Data from Krahn,
AD, Manfreda, J, Tate, RB, et al, Am J Med 1995; 98:476.

Stroke rates AF risk category

Rate of ischemic stroke is related to risk category

The incidence of a stroke in patients with either intermittent or sustained atrial

fibrillation (AF) is related to risk category; the patients were treated with aspirin and
followed for a mean of two years. Among those with intermittent AF, 24 percent were
high risk, 32 percent are moderate risk and 43 percent are low risk; among those with
sustaind AF, the respective values were 30, 34, and 36 percent. The stroke risk was
similar in patients with intermittent and sustained AF.
High risk: any of the following - age >75 and hypertension, age >75 and female,
systolic BP >160 mmHg, prior stroke or transient ischemic attack; Moderate risk:
either of - hypertension and age 75 or diabetes and no high risk features; Low risk:
no moderate or high risk features.
Data from Hart, RG, Pearce, LA, Rothbart, RM, et al, J Am Coll Cardiol 2000; 35:183.
CHADS2 score stroke risk AF

CHADS2 score, thromboembolic risk, and effect of warfarin in 11,526

patients with nonvalvular atrial fibrillation and no contraindications to
warfarin therapy

Clinical parameter Points

Congestive heart failure (any history) 1

Hypertension (prior history) 1

Age 75 1

Diabetes mellitus 1

Secondary prevention in patients with a prior ischemic stroke or a transient 2

ischemic attack; most experts also include patients with a systemic embolic
event

Events per 100 person-years*

CHADS2 score Warfarin No warfarin NNT

0 0.25 0.49 417

1 0.72 1.52 125

2 1.27 2.50 81

3 2.20 5.27 33

4 2.35 6.02 27

5 or 6 4.60 6.88 44

NNT: number needed to treat to prevent one stroke per year with warfarin.
* The CHADS2 score estimates the risk of stroke, which is defined as focal neurologic
signs or symptoms that persist for more than 24 hours and that cannot be explained
by hemorrhage, trauma, or other factors, or peripheral embolization, which is much
less common. Transient ischemic attacks are not included. All differences between
warfarin and no warfarin groups are statistically significant except for a trend with a
CHADS2 score of 0. Patients are considered to be at low risk with a score of 0, at
intermediate risk with a score of 1 or 2, and at high risk with a score 3. One
exception is that most experts would consider patients with a prior ischemic stroke,
transient ischemic attack, or systemic embolic event to be at high risk even if they had
no other risk factors and therefore a score of 2. However, the great majority of these
patients have some other risk factor and a score of at least 3.
Data from Go, AS, Hylek, EM, Chang, Y, et al, JAMA 2003; 290:2685; and CHADS2
score from Gage, BF, Waterman, AD, Shannon, W, JAMA 2001; 285:2864.
Predicted 5 year risk stroke

Predicted 5-year risk of stroke

Step 1 Predicted 5-year risk of stroke

Age, y Points Total 5-year risk,

points percent
55-59 0
0-1 5
60-62 1
2-3 6
63-66 2
4 7
67-71 3
5 8
72-74 4
6-7 9
75-77 5
8 11
78-81 6
9 12
82-85 7
10 13
86-90 8
11 14
91-93 9
12 16
>93 10
13 18
Step 2
14 19
Sex Points
15 21
Men 0
16 24
Women 6
17 26
Step 3
18 28
Systolic blood pressure,
mmHG Points 19 31
<120 0
20 34
120-139 1
21 37
140-159 2
22 41
160-179 3
23 44
 >179 4 24 48

Step 4 25 51

Diabetes Points 26 55

No 0 27 59

Yes 5 28 63

Step 5 29 67

Prior stroke or TIA Points 30 71

No 0
31 75
Yes 5

Step 6

Add up points from steps 1 through 5

Look up predicted 5-year risk of stroke in

table

The point-based risk estimate approximates the more precise equation-based risk
function provided as an Excel spreadsheet available at
http://www.nhlbi.nih.gov/about/framingham/stroke.htm. The point- based risk
estimate may differ from the equation-based one, particularly for patients with
uncommon combinations of characteristics.
TIA: transient ischemic attack.
Reproduced with permission from: Want, TJ, Massaro, JM, Levy, D, et al. A risk score
for predicting stroke or death in individuals with new-onset atrial fibrillation in the
community: the Framingham Heart Study. JAMA 2003; 290:1049. Copyright © 2003
American Medical Association.

Risk score stroke or death

Risk score for stroke or death

Step 1 Step 2 Predicted 5-year risk
of stroke or death
Age, Systolic blood
y Points pressure, mmHg Points Total 5-year risk,
points percent
55 0 <120 0
0 8
56 1 120-139 1
1 9
57 2 140-159 2
2-3 10
58- 3 160-179 3
59 >179 5 4 11

60 4 Step 3 5 12

61 5 Diabetes Points 6 13

62 6 No 0 7 15

63 7 Yes 4 8 16

64- 8 Step 4 9 17
65
Smoker Points 10 19
66 9
No 0
11 20
67 10
Yes 5
12 22
68 11
Step 5
13 24
69 12 Prior MI or CHF Points
14 26
70- 13 No 0
71 15 28
Yes 6
72 14 16 30
Step 6
73 15 17 32
Murmur Points
74 16 18 35
No 0
75 17 19 37
Yes 4
76- 18 20 40
77 Step 7
21 43
78 19 ECG LVH Points
22 46
79 20 No 0
23 49
80 21 Yes 2
24 52
81 22 Step 8
25 55
Add up points from steps 1
82- 23
through 7
83 26 58
Look up predicted 5-year risk
84 24 27 61
of stroke or death in table
85 25 28 65

86 26 29 68
 87 27 30 71

88 28 31 75

89 29 32 78

90- 30 33 >80
91

92 31

93 32

94 33

The point-based risk estimate approximates the more precise equation-based risk
function provided as an Excel spreadsheet available at
http://www.nhlbi.nih.gov/about/framingham/stroke.htm. The point- based risk
estimate may differ from the equation-based one, particularly for patients with
uncommon combinations of characteristics.
TIA: transient ischemic attack.
Reproduced with permission from: Want, TJ, Massaro, JM, Levy, D, et al. A risk score
for predicting stroke or death in individuals with new-onset atrial fibrillation in the
community: the Framingham Heart Study. JAMA 2003; 290:1049. Copyright © 2003
American Medical Association.

Impact risk factors stroke

Impact of selected risk factors on the predicted 5-year risk of stroke or

death
Predicted even rates apply to men and women without clinical valvular disease.
ECG LVH: electrocardiographic left ventricular hypertrophy; MI: myocardial infarction.
Reproduced with permission from: Wang, TJ, Massaro, JM, Levy, D, et al. A risk score
for predicting stroke or death in individuals with new-onset atrial fibrillation in the
community: the Framingham Heart Study. JAMA 2003; 290:1049. Copyright © 2003
American Medical Association.

LV function stroke risk in AF

Significant left ventricular dysfunction predicts stroke in AF

In a prospective study of 1066 patients entered into three clinical trials evaluating the
role of anticoagulation in nonvalvular AF (BAATAF, SPINAF, and SPAF) the incidence of
a stroke was 9.3 percent per year in patients with moderate to severe left ventricular
dysfunction compared to 4.4 percent per year in those with normal or mildly abnormal
left ventricular function. Data from Atrial Fibrillation Investigators, Arch Intern Med
1998; 158:1316.

TEE abnormalities stroke risk

Left atrial abnormalities and complex aortic plaque correlate with the risk
of thromboembolism in atrial fibrillation
Correlation of clinical risk for thromboembolism (TE) and transesophageal
echocardiographic (TEE) findings in 786 patients with atrial fibrillation. Patients were
deemed to be at high risk if they one or more of the following clinical features: prior
TE, women >75 years of age, systolic blood pressure >160 mmHg, and heart failure or
poor left ventricular function. Patients with none of these features were either at low
risk or, if they had a history of hypertension, moderate risk. Panel A: There was an
increasing incidence of a left atrial appendage (LAA) abnormality (thrombus, dense
spontaneous echo contrast, or flow velocity 20 cm/s) or a complex aortic plaque risk
with increasing clinical risk of TE. Panel B: The frequency of LAA abnormalities and
complex aortic plaque in patients with a single high risk factor. Redrawn from
Zabalgoitia, M, Halperin, JL, Pearce, LA, et al, for the Stroke Prevention in Atrial
Fibrillation III Investigators. J Am Coll Cardiol 1998; 31:1622.

Risk of thromboembolism in AF

Risk of systemic thromboembolism in nonvalvular atrial fibrillation from

the SPAF-III trial in patients treated with aspirin

Risk Thromboembolic risk, General

category percent per year NNT* recommendations

Prior stroke or 10 14 Warfarin

TIA
Primary prevention
High 6 33 Warfarin

Moderate 3 66 Warfarin or aspirn

Low 1 200 Aspirin

Definitions

High - one or more of the following

Previous thromboembolism

Woman older than 75 years of age

Systolic pressure >160 mmHg

Heart failure or severe left ventricular dysfunction

Moderate - none of the above but a history of hypertension

Low - none of the above

* NNT: number needed to treat with warfarin rather than aspirin for one year to
prevent one event.
Adapated from Stroke Prevention in Atrial Fibrillation III randomised clinical trial.
Lancet 1996; 348:633; and The SPAF III Writing Committee for the Stroke Prevention
in Atrial Fibrillation Investigators. JAMA 1998; 279:1273.

Anticoagulation AF ACCP

American College of Chest Physicians recommendations for

anticoagulation in chronic atrial fibrillation

Risk
group¶ Recommendation*

Low Aspirin (325 mg/day)

Moderate Aspirin or warfarin (target INR 2.5; range 2.0-

3.0)#

High Warfarin (target INR 2.5; range 2.0-3.0)#

¶ Patients are classified into the following risk

groups:

High risk Patients with risk factors including prior

transient ischemic attack, systemic embolism or
stroke; history of hypertension; clinical
evidence of valve disease (rheumatic mitral
valve disease or prosthetic heart valve); heart
 failure or impaired left ventricular function on
echocardiography; diabetes mellitus; or age
75.

Moderate Patients age 65 to 75 years with no other risk

risk factors

Low risk Patient under age 65 with no other risk factors

* In patients treated with warfarin (INR 2.0 to 3.0) who have coronary heart disease,
it is acceptable to add aspirin in doses up to 100 mg/d for added prevention of
ischemic coronary events, although this combination is associated with a higher risk of
bleeding than treatment with either agent alone.
# Individual lower-risk patients may rationally choose anticoagulation over aspirin
therapy to gain greater protection against ischemic stroke if they value protection
against stroke much more highly than reducing risk of hemorrhage and burden of
managing anticoagulation.
Data from Singer, DE, Albers, GW, Dalen, JE, et al. Antithrombotic therapy in atrial
fibrillation. Chest 2004; 126:429S.

ACC AHA ESC anticoag AF

ACC/AHA/ESC guideline summary: Chronic antithrombotic therapy to

prevent thromboembolism in atrial fibrillation (AF) and atrial flutter (AFl)
Class I - There is evidence and/or general agreement that the following
approaches to antithrombotic therapy are effective in patients with AF or
AFl

General principles
1. All patients should be treated except for those with lone AF or contraindications to
antithrombotic therapy.

2. The choice of drug should be based upon the absolute risks of thromboembolism and
bleeding and the relative risk and benefit for the patient.

3. Among patients treated with warfarin or other oral vitamin K antagonist, the INR
should be measured at least once per week at the initiation of therapy and monthly
when the degree of anticoagulation is stable.

Anticoagulation with warfarin or other vitamin K antagonist unless

contraindicated:
1. Mechanical heart valves in patients at high risk for thromboembolism* - goal INR 2.0
to 3.0.

2. Mechanical heart valves in patients with atrial fibrillation - goal INR 2.5 or greater
based upon the type of valve.

3. More than one validated moderate risk factor# for thromboembolism - goal INR 2.0 to
3.0.

Aspirin (81 to 325 mg/day) is an alternative to vitamin K antagonists in patients at

low risk or contraindications to oral anticoagulants.

Class IIa - The weight of evidence or opinion is in favor of the usefulness

of the following approaches to antithrombotic therapy in patients with AF
or AFl

The choice of antithrombotic therapy is based upon the same criteria in paroxysmal,
persistent, and permanent AF.

The need for anticoagulation can be reevaluated at regular intervals.

Either aspirin or oral anticoagulation based upon estimation of bleeding risk and
ability to safely sustain dose-adjusted oral anticoagulation, and patient preference.
1. Nonvalvular AF or AFl with only one validated moderate risk factor#.

2. Nonvalvular AF or AFl who have at least less well validated risk factor¶.

In patients without mechanical prosthetic heart valves who are treated with oral
coagulation, interruption of therapy for up to one week without heparin substitution for
surgical or diagnostic procedures that are associated with a risk of bleeding.

Class IIb - The weight of evidence or opinion is less well established for
the usefulness of the following approaches to antithrombotic therapy in
patients with AF or AFl

A lower INR goal of 2.0 (range 1.6 to 2.5) in patients 75 years of age who are at
increased risk of bleeding but have no contraindication to oral anticoagulation, and in
other patients with moderate risk factors for thromboembolism*.

Among patients at high risk who undergo a surgical procedure that requires
interruption of oral anticoagulation for more than one week, unfractionated heparin or
subcutaneous low molecular weight heparin even though the efficacy of these drugs in
such patients is uncertain.

Following percutaneous coronary intervention or coronary artery bypass graft

surgery, low dose aspirin (<100 mg/day) and/or clopidogrel (75 mg/day) may be
given with oral anticoagulation, but this approach has not been thoroughly evaluated
and the risk of bleeding is increased.

Among patients undergoing percutaneous coronary intervention, anticoagulation

may be temporarily interrupted to prevent bleeding at the peripheral arterial puncture
site but should be restarted as soon as possible after the procedure. The maintenance
regimen should consist of warfarin plus, to prevent stent thrombosis, clopidogrel (75
mg/day) for a duration that varies with the type of stent. When warfarin is given with
clopidogrel or aspirin, the dose intensity must be carefully regulated.

Among patients 60 years of age with heart disease or other risk factors for
thromboembolism (lone AF), the thromboembolism risk is low without antithrombotic
therapy and the efficacy of aspirin for primary prevention of thromboembolism in
relation to the risk of bleeding has not been established.
 Among patients who have an ischemic stroke or systemic embolic event despite
warfarin or other vitamin K antagonist at an INR of 2.0 to 3.0, increasing the goal INR
to a maximum goal of 3.0 to 3.5 rather than adding an antiplatelet drug.

Class III - There is evidence and/or general agreement that the following
approaches are not useful or may be harmful in patients with AF or AFl

Long-term therapy with warfarin or other vitamin K antagonist for the primary
prevention of thromboembolism in patients under age 60 years who do not have heart
disease (lone AF) or any risk factors for thromboembolism*#¶

* Highest risk factors are prior thromboembolism and rheumatic mitral stenosis.
# Validated moderate risk factors for thromboembolism; age 75 years, especially
women, hypertension, left ventricular ejection fraction 35 percent or fractional
shortening <25 percent, heart failure, and diabetes mellitus.
¶ Less well validated risk factors for thromboembolism: age 65 to 74 years, women,
and coronary artery disease.
Data from Fuster, V, Ryden, LE, Cannom, DS, et al. ACC/AHA/ESC guidelines for the
management of patients with atrial fibrillation. A report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the
European Society of Cardiology Committee for Practice Guidelines (Writing committee
to revise the 2001 guidelines for the management of patients with atrial fibrillation). J
Am Coll Cardiol 2006; 48:e149.

Anticoag AF age risk factors

Benefit of anticoagulation in chronic atrial fibrillation is related to age and

risk factors

Pooled data from the randomized controlled trials of warfarin or aspirin in atrial
fibrillation show that the reduction in the stroke rate is associated with age and the
presence (plus sign) or absence (minus sign) of at least one risk factor (history of
hypertension, history of diabetes, previous transient ischemic attack, or heart failure).
Among patients less than 65 years of age, warfarin reduced the rate of stroke only in
those with risk factors, while the risk of stroke in those without risk factors was low
with or without warfarin therapy. Among patients 65 to 75 years of age without risk
factors, aspirin and warfarin were equally effective for stroke prevention, while in those
with risk factors warfarin significantly reduced the incidence of stroke; aspirin has not
been evaluated in this population. Among patients over 75 years of age without risk
factors, warfarin is an effective therapy while aspirin has not been evaluated; in those
with risk factors, warfarin, but not aspirin, is an effective therapy for stroke
prevention.
Data from Ezekowitz, MD, Levine, JA. JAMA 1999; 99:1830.
NNT stroke prevention a fib

Number of patients with nonrheumatic atrial fibrillation who need to be

treated to prevent one stroke

Number needed
to treat to
prevent one
Annual stroke in two
stroke risk Clinical features years*

Low (about 1 Age <65, no major risk factors (including prior Aspirin: 227 (132
percent) stroke, systemic embolism, or transient ischemic to 2500)
attack; hypertension; and poor left ventricular
function as determined by a clinical history of
heart failure or left ventricular ejection fraction
<50 percent)

Low Age 65 to 75, no major risk factors Aspirin: 152 (88 to

moderate 1667)
(about 1.5
percent) Warfarin: 54 (46 to
69)

High Age 65 to 75, no major risk factors but either Warfarin: 32 (28
moderate diabetes mellitus or coronary heart disease to 42)
(about 2.5
percent)

High (about Age <75 with hypertension, left ventricular Warfarin: 14 (12
6 percent) dysfunction, or both; or age >75 without other to 17)
risk factors

Very high Age >75 with hypertension, left ventricular Warfarin: 8 (7 to

(about 10 dysfunction, or both; or any age and prior 10)
percent) stroke, transient ischemic attack, or systemic
embolism

* Drugs listed are those recommended by 2001 ACCP Consensus Conference in

patients without contraindcations to the suggested therapy; with warfarin, the taget
INR is 2.0 to 3.0).
Adapted from Straus, SE, Majumdar, SR, McAlister, FA, JAMA 2002; 288:1388.

Warfarin in AF

Benefit of warfarin in chronic atrial fibrillation

Efficacy of anticoagulation with warfarin to prevent ischemic stroke and other
thromboemboli in four major studies. An intention to treat approach was used and
transient ischemic attack and hemorrhage were excluded. The numbers at the top
represent the risk reduction with warfarin therapy which ranged from 45 to 82 percent.
SPAF: Stroke Prevention in Atrial Fibrillation; AFASAK: Copenhagen AFASAK Study;
BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation; and CAFA: Canadian
Atrial Fibrillation Anticoagulation Study.
* The data in the warfarin group in the SPAK assumes that half of the events were
attributable to warfarin toxicity.
Data from Connolly, SJ, Laupacis, AN, Gent, M, et al, J Am Coll Cardiol 1991; 18:349.

Warfarin and aspirin in AF

Meta-analysis of randomized controlled trials of warfarin and aspirin for

primary prevention of stroke in atrial fibrillation

Stroke Major bleeding

Odds
ratio, p Odds ratio, p
Comparison 95% CI value 95 percent CI value

Conventional dose warfarin 0.31 (0.19 <0.001 1.88 (0.88 to 0.10

versus placebo to 0.50) 4.0)

Aspirin versus placebo 0.68 (0.46 0.06 0.82 (0.37 to >0.2

to 1.02) 1.78)

Conventional dose warfarin 0.66 (0.45 0.04 1.61 (0.75 to >0.2

versus aspirin to 0.99) 3.44)

Conventional dose warfarin 0.52 (0.25 0.08 2.21 (0.67 to 0.19

versus low dose warfarin to 1.08) 7.25)

Conventional dose warfarin 0.44 (0.14 0.16 1.14 (0.55 to >0.2

versus low dose warfarin plus to 1.39) 2.36)
aspirin

Low dose warfarin versus 1.01 (0.49 >0.2 1.04 (0.43 to >0.2
aspirin to 2.06) 2.48)

NOTE: The data in this table cannot be directly applied to clinical practice
since the use of warfarin or aspirin is importantly related to the patients
estimated risk of embolic events. Adapted from McNamara, RL, Tamariz, LJ, Segal,
JB, Bass, EB, Ann Intern Med 2004; 139:1018.

Low dose warfarin high risk AF

Low-dose warfarin plus aspirin is not optimal in high risk AF

Cumulative event rate of patients with atrial fibrillation (AF) at high risk for
thromboembolism in the SPAF III trial. High risk was defined as the presence of at
least one of the following: previous thromboembolism, female older than 75 years of
age, heart failure or severe left ventricular systolic dysfunction, and systolic pressure
>160 mmHg. There was a much lower incidence of events with standard adjusted-dose
warfarin therapy (INR 2 to 3) compared to treatment with aspirin and low-dose
warfarin (INR 1.2 to 1.5) (p<0.0001). Data from Stroke Prevention in Atrial Fibrillation
Investigators. Lancet 1996; 348:633.

Event rates in SPAF III

Increased stroke risk with low dose warfarin plus aspirin in AF

Results from the SPAF III trial of high-risk patients showing significantly higher event
rates for intracranial hemorrhage and ischemic stroke in patients treated with fixed low
dose warfarin plus aspirin compared with standard adjusted-dose warfarin. The risk
was greater in those with a previous thromboembolic event. Data from Stroke
Prevention in Atrial Fibrillation Investigators. Lancet 1996; 348:633.

Events in AF according to INR

Optimal INR in atrial fibrillation

Incidence of ischemic events and major bleeding episodes in 214 patients with atrial
fibrillation according to the INR. The total incidence of events was highest at INR
values below 2.0 (where all events were ischemic) and above 5.0 (where most events
were hemorrhagic). The optimal INR range was between 2.0 and 3.9. Data from The
European Atrial Fibrillation Trial Study Group, N Engl J Med 1995; 333:5.