Factors affecting bleeding risk during anticoagulant

therapy in patients with atrial fibrillation:

Observations from the Atrial Fibrillation Follow-up
Investigation of Rhythm Management (AFFIRM) Study
John P. DiMarco, MD, PhD,
a
Gregory Flaker, MD,
b
Albert L. Waldo, MD,
c
Scott D. Corley, BS,
d
H. Leon Greene, MD,
Robert E. Safford, MD,
e
Lynda E. Rosenfeld, MD,
f
Gladys Mitrani, PharmD,
g
Margit Nemeth, MD,
a
and
The AFFIRM Investigators Charlottesville, Va, Columbia, Mo, Cleveland, Ohio, Seattle, Wash, Jacksonville, Fla,
New Haven, Conn, and Los Angeles, Calif
Background Stroke and systemic thromboembolism are serious problems for patients with atrial fibrillation (AF), but
their incidence can be substantially reduced by appropriate anticoagulation. Bleeding is the major complication of
anticoagulant treatment, and the relative risks for bleeding vs stroke must be considered when starting anticoagulation.
Methods The AFFIRM trial included patients with AF and at least one risk factor for stroke, randomly assigning them to
either a rate-control or rhythm-control strategy. All patients were initially treated with warfarin. The incidence of protocol-
defined major and minor bleeding was documented during follow-up. Variables associated with bleeding were determined
using a Cox proportional hazards model, using baseline and time- dependent covariates.
Results The 4060 patients in the AFFIRM trial were followed for an average of 3.5 years. Major bleeding occurred in
260 patients, an annual incidence of approximately 2% per year, with no significant difference between the rate- control and
rhythm-control groups. Increased age, heart failure, hepatic or renal disease, diabetes, first AF episode, warfarin use, and
aspirin use were significantly associated with major bleeding. Minor bleeding was common in both treatment arms, with 738
patients reporting this problem in one or more visits.
Conclusions Bleeding is a significant problem that complicates management of patients with AF. Risk factors for
bleeding can be identified, and knowledge of these risk factors can be used to plan therapy. (Am Heart J 2005;149:650- 6.)
Stroke and systemic thromboembolic events are the
most common serious complications of atrial fibrillation
(AF).
1-3
In patients with AF, the risk of stroke increases
with age and other risk factors including hypertension,
diabetes, atrial enlargement, and left ventricular dys-
function.
4
Anticoagulant therapy with warfarin un-
equivocally decreases the risk of stroke in AF. As a result,
warfarin anticoagulation is now recommended for
patients with AF and risk factors for stroke.
4-10
Bleeding is the major complication associated with
warfarin therapy.
11,12
Up to one third of patients
screened for participation in prior clinical trials on the use
of warfarin in AF were deemed ineligible for chronic
anticoagulation, primarily because of a high perceived
bleeding risk.
5,11
After enrollment, the reported annual
rates for major bleeding in the randomized clinical trials
that evaluated anticoagulation in patients with AF were
between 0.4% and 2.6% per year.
6,11-13
Rates of minor
bleeding, which was not uniformly defined, were as high
as 15.4%per year.
6
The risk of bleeding was related to the
intensity of anticoagulation and to selected patient
characteristics including hypertension, female gender,
severe cardiac disease, and renal insufficiency.
11,12
Drug
interactions with warfarin are also common. Pharmaco-
kinetic interactions may contribute to unstable antico-
agulation intensities that can increase risks for both
bleeding and thromboembolism. Pharmacodynamic
interactions with other agents commonly used in elderly
patients with cardiovascular disease that may indepen-
dently promote bleeding also occur.
From the
a
Cardiovascular Division, University of Virginia Health System, Charlottesville,
Va,
b
Columbia, Mo,
c
Cleveland, Ohio,
d
Seattle, Wash,
e
Jacksonville, Fla,
f
New Haven,
Conn, and
g
Los Angeles, Calif.
The AFFIRM investigators and their affiliations are listed in Ref. [13].
This study was supported by contract no. N01-HC-55139 with the National Heart, Lung,
and Blood Institute, Bethesda, MD. No other financial disclosures.
Submitted April 14, 2004; accepted November 13, 2004.
Reprint requests: John P. DiMarco, MD, PhD, Cardiovascular Division, University of
Virginia Health System, Box 800158, Charlottesville, VA 22908.
E-mail: jpd4h@virginia.edu
0002-8703/$ - see front matter
n 2005, Elsevier Inc. All rights reserved.
doi:10.1016/j.ahj.2004.11.015
The AFFIRM Study
14-16
compared rate-control and
rhythm-control strategies in patients with AF who had
risk factors for stroke. All patients were eligible for
warfarin at baseline. Patients in the rate-control group
were supposed to continue their warfarin regimen with
a target internationalized normalized ratio ( INR) of 2 to 3
throughout the study. Warfarin anticoagulation was
encouraged, but not mandated, for patients who
remained in sinus rhythm in the rhythm-control group.
Most, however, continued their warfarin regimen.
Amiodarone and aspirin, 2 drugs with well-described
pharmacokinetic or pharmacodynamic interactions with
warfarin that might promote bleeding, were used in
many patients in the AFFIRM trial. In this report, we
describe the rates of and risk factors for bleeding in the
AFFIRM trial.
Methods
Four thousand sixty patients were randomized in the AFFIRM
trial and their clinical characteristics have been previously
reported.
15,16
The average length of follow-up was 3.5 years
(range 0 to 5.9 years). The primary end point was total
mortality, analyzed by intention-to-treat. Secondary end points
included composites of total mortality, disabling intracranial
bleeding (subdural and/or subarachnoid hemorrhage, intra-
parenchymal hemorrhage), stroke (embolus, thrombosis,
hemorrhage), disabling anoxic encephalopathy, cardiac arrest,
and major noncentral nervous system (CNS) bleeding. Other
secondary end points were cost, quality of life, and functional
status. This paper evaluates bleeding.
Patients were seen at the time of randomization and at
follow-up visits at 2 months, 4 months, and every 4 months
thereafter. At each visit, the study coordinator documented any
interim bleeding event that occurred and whether warfarin,
aspirin, and antiarrhythmic drugs were used at any point during
the preceding time interval. A diagnosis of major bleeding
outside the CNS was defined as bleeding that required
transfusion of z2 units of blood, hospitalization in an intensive
Table I. Baseline characteristics
All patients
No major
bleeding
Major
bleeding P
n (%) 4060 3800 260
Randomized to
rhythm control
2033 (50) 1909 (50) 124 (48) .427
Age (y) (mean F SD) 69.7 F 9.0 69.6 F 9.0 72.3 F 8.2 b.001*
Women 1594 (39) 1478 (39) 116 (45) .068
Minority 461 (11) 428 (11) 33 (13) .482
History of hypertension 2876 (71) 2686 (71) 190 (73) .412
History of CAD 1551 (38) 1439 (38) 112 (43) .094
History of CHF 939 (23) 857 (23) 82 (32) .001*
History of diabetes 813 (20) 748 (20) 65 (25) .038*
History of stroke or TIA 542 (13) 497 (13) 45 (17) .052
History of hepatic
or renal disease
231 (6) 205 (5) 26 (10) .002*
Recent history of smoking 496 (12) 471 (12) 25 (10) .186
Qualifying episode
of AF is first
episode documented
1391 (36) 1291 (35) 100 (40) .113
Left atrial enlargement
(size N4.0 cm)
2023 (65) 1888 (65) 135 (66) .724
Left ventricular dysfunction
(ejection fraction b50%)
788 (26) 724 (26) 64 (32) .063
Mitral regurgitation N2+ 647 (20) 603 (20) 44 (21) .799
Figures in parentheses are percent values. CAD, coronary artery disease; CHF, congestive heart failure; TIA, transient ischemic attack.
*P b .05.
Table II. Number of patients who had major bleeding events*
Site of
bleeding
All
patients
Rate
control
patients
Rhythm
control
patients P
n (%) 4060 2027 2033
Ally 260 (9.2) 136 (9.6) 124 (8.9) .452
Non-CNS 203 (7.3) 107 (7.7) 96 (6.9) .436
CNSz 59 (2.1) 29 (1.9) 30 (2.2) .892
Primary
intraparenchymal
hemorrhage
34 (1.2) 18 (1.1) 16 (1.3) .732
Subdural or
subarachnoid
hemorrhage
24 (0.8) 11 (0.8) 13 (0.8) .677
Figures in parentheses are percent values.
*Percentages were derived by Kaplan-Meier analysis. P values were based on the
log-rank statistic.
yThe sum of non-CNS and CNS bleeding events is greater than the number for ball Q
types because there were 2 patients who had both non-CNS and CNS events.
zThe sum of primary intraparenchymal hemorrhage and subdural or subarachnoid
hemorrhage is less than the number for bCNSQ because information on type of CNS
event was missing for one patient.
American Heart Journal
Volume 149, Number 4
DiMarco et al 651
care unit, and/or discontinuation of anticoagulant or antiplate-
let therapy. Major bleeding included CNS (intraparenchymal,
subdural, or subarachnoid) and non-CNS hemorrhage. Minor
bleeding included hematuria, gastrointestinal bleeding, epi-
staxis, and other reported bleedings that did not meet the major
bleeding criteria listed above. The specific sites of non-CNS
bleeding were not recorded for each episode. There was no
difference between patients with and those without major
bleeding in the number of forms collected. In the group
without bleeding, 80.5%, 11%, and 8.6% had no, 1, or 2 or more
forms missing, respectively. In the group with major bleeding,
82.9%, 10.5%, and 6.6% had no, 1, or 2 or more forms missing,
respectively ( P = .6).
All patients were eligible for long-term anticoagulation at
enrollment. Physicians were encouraged to maintain anti-
coagulation in both treatment arms unless contraindications
developed. However, the protocol allowed discontinuation of
warfarin use after a minimum of 4 (and preferably 12) weeks
if sinus rhythm had apparently been maintained by antiar-
rhythmic drugs.
Statistics
Baseline characteristics of patients were compared with
m
2
tests and t tests as appropriate. The primary analysis
was an intention-to-treat comparison of time to a major
bleeding episode. Rates were estimated by the method of
Kaplan and Meier and compared by the log-rank test.
Patients were censored at last contact, at withdrawal from
the study, or at death if the outcome variable did not
include stroke.
A secondary analysis used multivariate Cox proportional
hazards regression to assess the relationship of certain
variables (ie, bcovariatesQ) with risk of major bleeding after
adjusting for the other covariates included in the analysis.
Data from 3788 patients were available for this analysis. Two
hundred seventy-two patients had incomplete data and were
excluded from the analysis but the major bleeding rate
among these patients was similar to that among those
included (log-rank statistic 0.58, P = .45). Covariates
included randomized treatment arm, age, sex, history of
coronary artery disease, history of congestive heart failure,
history of hypertension, history of diabetes, history of stroke
or transient ischemic attack, history of hepatic or renal
disease, recent history of smoking, and qualifying for
enrollment with a first episode of AF. In those patients with
echocardiographic data available (n = 3024), left atrial
enlargement (ie, size N4.0 cm), left ventricular dysfunction
(ie, ejection fraction b50%), and mitral regurgitation were
also considered.
Also included in the Cox analysis were 3 variables whose
values changed over time (ie, time-dependent covariates):
warfarin use, aspirin use, and amiodarone use. Each patients
use of the 3 drugs was determined at various time points
over the course of follow-up based on the responses
recorded on the patients data forms. Specific start and stop
dates for use of these and other drugs were not recorded.
Instead, responses on the forms indicated whether the
patient had used a particular drug since the previous follow-
up. A patient was considered to have used a drug if it was
recorded as such on the most recent available form before
the time point of interest.
Stepwise analytical procedures were performed. A stepwise
procedure is similar to a forward-selection procedure except
that the variables already in the model do not necessarily
remain in the model, as each forward selection step is followed
by a backward elimination step.
Results
Baseline characteristics for patients with and those
without major bleeding events are summarized in Table I.
Patients with major bleeding events were older and
more likely to have a history of congestive heart failure,
diabetes, or hepatic or renal disease.
Numbers and actuarial rates of major bleeding
events are shown in Table II. Two hundred sixty
patients (9.2%) had at least one major bleeding event.
Of these, 136 had been randomized to the rate-control
group and 124 to the rhythm-control group, a
difference that was not significant. Major bleeding
outside the CNS was observed in 203 patients (7.3%),
Figure 1
Time to major bleeding. One major bleeding event that occurred
after 5 years of follow-up is not shown.
Table III. Internationalized normalized ratio values and major
bleeding events
INR range No. of major bleeding events
0-1.2 13
1.3-1.9 34
2.0-3.0 85
3.1-4.0 27
4.1-8.0 32
N8.0* 20
Total 211
*Three outliers (INR values 73.6, 81.0, and 91.7) excluded.
American Heart Journal
April 2005
652 DiMarco et al
with 107 of these randomized to the rate-control
group and 96 to the rhythm-control group. Major
bleeding within the CNS (including primary intra-
parenchymal hemorrhage and subdural or subarach-
noid hemorrhage) was observed in 59 patients (2.1%).
Two of these patients also experienced a major non-
CNS bleeding episode. Of the patients who had a CNS
bleeding event, 29 were in the rate-control group and
30 were in the rhythm-control group. Thirty-four of
the patients with CNS bleeding had a primary intra-
parenchymal hemorrhage, and 24 patients had a
subdural or subarachnoid hemorrhage (the type of
CNS hemorrhage was unknown for one patient).
The incidence of major bleeding through 5 years of
follow-up by treatment group is shown in Figure 1. The
incidence of bleeding was constant throughout the
trial, approximately 2% per year in both randomized
groups. There was also no difference by treatment
group in the incidence of a combined end point of
major bleeding and death (log-rank statistic 0.81, P = .37,
data not shown).
A measured INR at the time of major bleeding was
available for 214 of the 260 patients. There were 3 outliers
who had reported INR values (ie, 91.7, 81.0, 73.6) that
were outside acceptable standards. These values were
removed from all quantitative analyses. The median INR
at the time of major bleeding was 2.6 (n = 211,
interquartile range 2.0-4.0). Fifty-two (24.6%) of the
values, excluding those of the 3 outliers, were above 4.0
(Table III). The median INR at the time of a CNS bleed was
2.9 (n = 54, interquartile range 1.7-3.2 ), with 9 (16.7%) of
the values above 4.0. Warfarin was being used at the
time of major bleeding in 217 (83.8%) of 259 patients.
Information on warfarin use was missing for one patient.
Minor bleeding was frequent in the AFFIRM Study
(Figure 2), reported in one or more occasions by 738
patients. It was reported once by 559 patients, twice by
115, and more than twice by 64. Minor bleeding was
more frequent in the initial months of study participa-
tion then occurred at a relatively constant rate during
the rest of follow-up. Because minor bleeding likely
influenced subsequent use of anticoagulants, we did not
include minor bleeding in our analysis of predictors for
major bleeding. However, 45 of the 260 patients who
experienced a major bleeding episode had previously
reported a minor bleeding one.
Warfarin discontinuation
During the AFFIRM trial, 1365 (33.6%) of the trial
participants discontinued warfarin use for some period.
Apparent maintenance of sinus rhythm in a rhythm-
control patient was the listed reason for 613 (44.9%)
discontinuations. Bleeding, reported for 285 patients
(20.9%), was the second most common reason for
warfarin discontinuation. Physical frailty, physician or
patient refusal, and surgery were reported by smaller
numbers. Some patients started and stopped warfarin
use multiple times during the trial. The numbers given
above are for the first discontinuation only.
Risk factors for bleeding
Several clinical factors were associated with an
increased risk of major bleeding. In the multivariate
model, age, history of congestive heart failure, history of
diabetes, history of hepatic or renal disease, qualifying
for enrollment with a first episode of AF, warfarin use,
and aspirin use were associated with an increased risk of
major bleeding (Table IV). Other factors examined did
not show a significant association.
Discussion
Randomized clinical trials have shown that antico-
agulation with warfarin results in a 60% to 70%
reduction in the risk of stroke and systemic thrombo-
embolism during AF.
4-10
The efficacy of warfarin is even
higher if an on-therapy, rather than an intention-to-treat
analysis, is used.
16
Because chronic anticoagulation also
raises the risk of bleeding complications, current
guidelines recommend warfarin only for those patients
with AF in whom the risk for thromboembolic events
outweighs the risk for serious bleeding.
2,3,17
All patients
in the AFFIRM trial had one or more risk factors for
thromboembolism. The expected embolic event rate, if
not on anticoagulation, based on individual patient
characteristics, ranged from 2.5% to over 12% per
year.
18,19
The data presented here confirm that the risks
for major bleeding during anticoagulation in this
population are considerably lower than the anticipated
benefit in stroke reduction.
In the AFFIRM trial, all patients were considered
eligible at baseline for chronic anticoagulation. Anti-
Figure 2
Time to minor bleeding.
American Heart Journal
Volume 149, Number 4
DiMarco et al 653
coagulation was mandated by the protocol for all
patients in the rate-control group unless contraindica-
tions developed. Over 85% of the rate-control group
patients at each follow-up visit continued their warfarin
regimen. In the rhythm-control group, chronic anti-
coagulation was recommended, but, in accordance with
then current guidelines, anticoagulants could be dis-
continued at the local physicians discretion if sinus
rhythm was apparently maintained for at least 4 (and
preferably 12) weeks. Despite this provision, most
patients in the rhythm-control group continued their use
of anticoagulants, with N70% reporting current warfarin
use at each follow-up visit. In both groups, most
ischemic strokes occurred if warfarin had either been
discontinued (49% overall) or if the INR at the time of
the event was subtherapeutic (32% overall).
14
The rate of major bleeding in the AFFIRM trial was
approximately 2% per year. This figure is well below the
expected stroke rate in similar populations with AF in
the absence of anticoagulation
18,19
and is similar to that
seen in other trials of warfarin anticoagulation in AF.
4-13
Seven covariates were significantly associated with an
increased risk of bleeding: increased age, history of
congestive heart failure, diabetes, hepatic or renal
disease, first episode of AF, warfarin use, and aspirin use.
The first 3 of these covariates are also risk factors that
increase the probability of stroke, such that a favorable
risk/benefit ratio is likely to be maintained in patients
with these characteristics. Patients with renal disease are
at increased risk for both thromboembolic events and
bleeding because of their underlying condition. Signifi-
cant hepatic disease is associated with a high incidence
of bleeding and may contribute to variable warfarin
metabolism, resulting in unstable INR values, a known
risk factor for bleeding.
20
We also noted an increase in
bleeding risk associated with the first episode of AF.
Others have reported that the risk of bleeding is
increased during the first few months after anticoagula-
tion is begun then becomes constant at a lower rate in
those who continue therapy.
20-22
It is likely that many
patients in the AFFIRM trial with recurrent episodes of
AF had already received several months of anticoagula-
tion before enrollment, whereas those with a first
episode of AF were still in the higher-risk, early
treatment phase.
It is not surprising that warfarin use was a risk factor for
bleeding. As in other studies,
2,16
patients with major
bleeding in the AFFIRM trial commonly had INR values
above the desired range of 2 to 3. Even after the 3 outliers
with unreliable INR values are excluded, the observation
that the mean INR at the time of bleeding was
substantially elevated emphasizes the fact that antico-
agulation therapy must be carefully managed to minimize
the potential for bleeding. The increased risk of bleeding
associated with aspirin use is also clinically important.
Aspirin has many uses and is commonly recommended in
patients at risk for cardiovascular disease. However, use
of aspirin is a known risk factor for bleeding, especially
gastrointestinal bleeding, via aspirins effects on platelets
and the gastrointestinal mucosa.
Concomitant use of warfarin and aspirin has been
recommended for patients with mechanical heart valves
who are at very high risk for thromboembolism
23
because it may permit use of a lower-target INR without
compromising protection against stroke. However, in
studies on this issue, bleeding has been increased when
aspirin is added to warfarin.
23
A potentiation of risk with
combined aspirin and warfarin therapy has also been
reported in patients with ischemic heart disease.
24
It is
likely that aspirin was most commonly used in the
AFFIRM trial as part of a treatment program for patients
with coronary, cerebral, or peripheral vascular disease.
In some patients, the risks associated with those
disorders may be high enough to justify combined
therapy. However, physicians will need to be particu-
larly cautious in their selection of patients for such
treatment. The potential value of adding aspirin must be
clearly justified. Careful INR monitoring, use of the
Table IV. Covariates significantly associated with major bleeding
Covariate P Hazard ratio
HR: 95% confidence limits
Increase/decrease
Lower Upper in risk
Age at entry b.0001 1.05 1.04 1.07 +5%*
Congestive
heart failure
.0108 1.43 1.09 1.89 +43%
Diabetes .0152 1.44 1.07 1.93 +44%
Hepatic or
renal disease
.0021 1.93 1.27 2.93 +93%
First episode of AF .0476 1.30 1.00 1.68 +30%
Warfarin use .0073 1.78 1.17 2.70 +78%
Aspirin use b.0001 2.01 1.45 2.77 +101%
*Per year of age.
American Heart Journal
April 2005
654 DiMarco et al
minimally effective aspirin dosage, and limitations on
therapy with other drugs that increase bleeding risk
are required.
Amiodarone potentiates the anticoagulant effects of a
fixed dose of warfarin.
25-27
Amiodarone inhibits the
metabolism of warfarin by CYP 2C9 and CYP 1A2,
thereby increasing the INR within the first days to weeks
of combined therapy. Since this interaction was
reported, it has been recommended that warfarin-treated
patients starting on amiodarone regimen should reduce
their warfarin dose by 25% to 50%. Amiodarone was the
initial drug chosen for 33% of the patients in the rhythm-
control arm in the AFFIRM trial and was eventually used
by 62% of those patients.
14
The potential for an
interaction between warfarin and amiodarone was
publicized among the investigators during the trial. With
this precaution, we did not observe an increased risk for
bleeding associated with the use of amiodarone, sug-
gesting that the potential for interaction is manageable
clinically. Propafenone, another antiarrhythmic drug
used to treat patients with AF, may also interact with
warfarin.
28
We did not look for an increased risk
associated with propafenone in the AFFIRM trial because
there were only 339 patients who used this drug even
for a short time. Nevertheless, physicians should be
aware of this potential interaction.
Warfarin therapy is often difficult because its antico-
agulant effect is influenced by dietary factors, drug
interactions that may affect absorption and metabolism,
and genetic factors.
29
The risk of bleeding while on
warfarin regimen may be increased when other drugs
that independently potentiate bleeding are also pre-
scribed. We focused our analysis on aspirin because it
was commonly used by patients in the AFFIRM trial, but
other drugs commonly used by the elderly patients (eg,
nonsteroidal anti-inflammatory agents, corticosteroids,
other platelet inhibitors) must also be prescribed
cautiously in patients receiving a warfarin regimen. The
Stroke Prevention in Atrial Fibrillation II investigators
11
and Wehinger et al
30
have reported that use of more
concomitant drugs was associated with bleeding but did
not specifically identify individual agents.
Limitations
This study has several limitations. It has been shown
that hemorrhagic risks of warfarin are lowered if patients
are followed in specialized anticoagulation clinics.
20,21
It
has also been shown that unstable INR values are potent
predictors of hemorrhagic complications.
20
In the
AFFIRM trial, anticoagulation was variably managed as
directed by the patients primary physicians. Interna-
tionalized normalized ratio values were only recorded by
the study at the regular AFFIRM protocol visits and at the
time of certain events. We therefore cannot comment on
the details of anticoagulation management nor on the
stability of INR values as a risk factor. However, we did
observe that 62% of the INR values recorded at study
visits were within the desired range, a proportion similar
to that seen in previous anticoagulation trials.
4-10,13
In the time-dependent analysis presented in this
paper, patients were considered to be taking the drug
examined as a covariate if they had received the drug at
any time during the interval since their prior study
visit. Start and stop dates for use of the various drugs
were not recorded. These limitations in data recording
potentially introduced error because a patients drug
use at the time of an event was not known with
certainty. The added error, however, would be
expected to weaken the association between the time-
dependent variables and the end point of interest (ie,
major bleeding), making it more difficult to detect
significant associations rather than falsely strengthening
the effect of one type of drug over another. Also, the
analysis was not planned at the outset of the AFFIRM
Study and is, therefore, both retrospective and non-
randomized. Accordingly, it may suffer from hidden
biases and other unidentified confounders. Because of
these data collection limitations and potential biases,
we concluded that analysis of interactions and sub-
groups involving the time-dependent covariates could
not be reliably performed.
Conclusions
In patients with nonvalvular AF and one or more risk
factors for stroke who are eligible for warfarin therapy at
baseline, major bleeding during anticoagulant therapy
occurs at a rate of approximately 2% per year. Increasing
age, congestive heart failure, diabetes, hepatic or renal
disease, recent development of AF, the use of warfarin,
and concurrent use of aspirin increase this risk. In this
population, the risk of major bleeding during antico-
agulation is lower than the expected rate of ischemic
stroke or systemic thromboembolism. Knowledge of the
risk factors associated with bleeding should help
physicians decide for or against chronic anticoagulation
in patients with AF at low or moderate embolic risk
31,32
and for or against addition of aspirin to patients
receiving warfarin.
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