J Thromb Thrombolysis (2007) 23:65–71
DOI 10.1007/s11239-006-9012-9
Misuse of antithrombotic therapy in atrial fibrillation patients:
frequent, pervasive and persistent
Luciana S. Fornari Æ Daniela Calderaro Æ
Ivana B. Nassar Æ Cristiane Lauretti Æ
Lidia Nakamura Æ Renato Bagnatori Æ
Walter Ageno Æ Bruno Caramelli
Published online: 22 December 2006
Ó Springer Science+Business Media, LLC 2006
Abstract
Purpose To assess the use of antithrombotic therapy
among atrial fibrillation (AF) patients in a Brazilian
University Heart Hospital (InCor).
Methods and results In a cross-sectional study we
analyzed the charts of all patients treated at InCor in
five separate days of 2002 (Phase 1). To assess the
impact of admission to a cardiology hospital, a follow-
up of the AF patients selected in Phase 1 was carried
out after 1 year (Phase 2). The prevalence of AF in the
3,764 assessed charts was 8.0% (301 patients). In Phase
1, antiplatelets were prescribed to 21.2% and antico-
agulant therapy (ACT) to 46.5% of AF patients; in
Phase 2, to 19.9 and 57.8%, respectively. Thus, 32.2%
(Phase 1) and 22.2% (Phase 2) of AF patients were not
receiving any antithrombotic drug. Among AF patients
with previous ischemic stroke (17.6%), only 49%
(Phase 1) and 60.4% (Phase 2) were receiving ACT. As
many as 34 and 22.6%, respectively, were not receiving
any antithrombotic drug. After follow-up, a new acute
embolic event was documented in 5.6% of patients,
17% died.
L. S. Fornari
D. Calderaro
I. B. Nassar

C. Lauretti
L. Nakamura
R. Bagnatori

B. Caramelli
Heart Institute, University of Sao Paulo Medical School,
Sao Paulo, Brazil
W. Ageno
Department of Clinical and Biological Sciences, University
of Insubria, Varese, Italy
L. S. Fornari (&)
Rua Barão do Teffé, 606, Jundiaı́, SP CEP 13208761, Brazil
e-mail: luciana.fornari@uol.com.br
Conclusions Anticoagulation is underused in AF pa-
tients and neither the fact of being treated by cardiol-
ogists in a University Hospital, nor the learning time-
window of 1 year seemed to improve the antithrom-
botic care significantly.
Keywords Atrial fibrillation
Anticoagulation

Antithrombotics
Embolic stroke
Introduction
Atrial fibrillation (AF) is the most common sustained
cardiac arrhythmia occurring in 0.4% of the general
population. Its prevalence increases with age, reaching
13% in patients older than 80 years [1–9]. The inci-
dence of AF has been increasing [10], and the reported
hospitalization rate has doubled to tripled [11]. AF is
associated with increased mortality, with a rate ratio
for death of 1.5 for men and from 1.9 to 2.2 for women
after adjusting for other risk factors [12, 13].
Patients with AF are more susceptible to thrombo-
embolic events. In non-rheumatic AF, ischemic stroke
rate is around 5% per year, approximately 2–7 times
higher than the general population [2, 3, 14–19]. The
incidence of this complication increases with age, rising
from 1.5% for those aged 50–59 years to 23.5% for
those aged 80–89 years [3]. Anticoagulant therapy has
been shown to be the most effective treatment and the
optimal range for the International Normalized Ratio
(INR) to prevent thromboembolic events without
exposing patients to unacceptably high risks of bleed-
ing is between 2.0 and 3.0 [20–23].
Currently, the guidelines on antithrombotic therapy
in patients with AF are based on risk stratification
123
66
[24–26]. The main risk factors are: advanced age (above
75 years), congestive heart failure, left ventricle ejection
fraction below 35%, systemic arterial hypertension,
diabetes, thyrotoxicosis, previous thromboembolic
event, rheumatic heart disease, cardiac valvular pros-
thesis or the presence of persistent thrombus in trans-
esophageal echocardiogram. Coronary artery disease is
also considered in some, but not all, atrial fibrillation
guidelines to indicate use of warfarin in patients
with AF.
However, reports from clinical practice have been
alerting to the excessive underuse of antithrombotic
therapy in patients with AF [27–39]. The reasons
pointed out to justify this fact include inconvenience
due to the repeated laboratory tests, physicians’ fear of
hemorrhage, low patient compliance, physicians
unawareness of the existing guidelines and the gener-
ally precarious INR control, with less than half of the
treated patients being within the recommended levels
[27–29, 39].
The objectives of this study were to determine the
rate of use of antithrombotic treatment strategies (oral
anticoagulant and antiplatelet) in AF patients treated
at the Heart Institute from the University of Sao Paulo,
a tertiary care hospital specialized in the treatment of
heart diseases in Brazil, and to assess if this therapy is
in conformity with the latest guidelines [24–26].
Methods
The study is structured in two phases. Phase 1 is an
observational cross-sectional study in which a group of
four trained physicians examined the medical charts of
all ambulatory and hospitalized patients treated in a
single day, for five different days, with an interval of at
least 1 month between each day. The aim of this
strategy was to avoid repeated patients. In each of
the 5 days, medical charts of patients with AF were
selected.
Phase 2 is a prospective cohort in which the medical
charts of the AF patients selected in Phase 1 were
reviewed after a period of at least 1 year from the
initial analysis. These charts were recovered in the
Hospital Medical Information Unit where we can call
for all the chats that are attended in the hospital and
ambulatory of the hospital. These charts were reviewed
by a cardiologist that analyze all the medical records of
this patient in the last year, exams, emergency and
ambulatory records, and the data for the Phase 2 were
collected by this analysis.
The population of this study consisted of patients
older than 18 years. The presence of AF was docu-
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J Thromb Thrombolysis (2007) 23:65–71
mented by EKG. Patients with a history of paroxysmal
AF who did not present this arrhythmia at the moment
of the analysis were excluded.
The following information was collected for each
patient: age, gender, ongoing treatments including
antiplatelet agents (aspirin, ticlopidine, clopidogrel)
and oral anticoagulants (warfarin), contraindications to
antiplatelet agents and to oral anticoagulants (bleed-
ing, peptic ulcers, liver failure), previous history of
ischemic stroke, transient ischemic attack, and systemic
embolism. In phase 2, the following information was
collected: ongoing treatments, occurrence of new epi-
sodes of ischemic stroke, transient ischemic attack
(TIA), systemic embolism, occurrence of any bleeding.
The occurrence of new episodes of stroke and TIA was
confirmed by the analysis of a neurologist documented
in the charts and the realization of CT imaging studies.
This study was approved by the Scientific and
Ethical Committee of the Heat Institute of University
of Sao Paulo Medical School, where the study
develops.
Statistics
Descriptive statistics were used to report data. Linear
regression model was used to analyze the relation
between age and oral anticoagulation therapy. Fisher’s
exact test was used to compare the rates of anticoag-
ulation in Phases 1 and 2. Level of significance accepts
was 0.005.
Results
Phase 1 of the study occurred in 2002, when the med-
ical charts of 3,764 patients (2,271 ambulatory patients
and 1,493 hospitalized) were identified. A total of 301
AF patients were selected, showing a prevalence of 8%
in the studied sample. The average age of the patients
was 63 years (18–102), and 44.8% (135 patients) were
males. The average time interval between Phase 1 and
Phase 2 was 13.7 months.
Prescription of antithrombotic therapy
According to the latest anticoagulant therapy guide-
lines, all AF patients were eligible for anticoagulant
therapy in Phase 1 [24]. However, only 46.5% (140
patients) were receiving anticoagulant therapy, 21.2%
(64 patients) were on antiplatelets, and 32.2% (97
patients) were not receiving any antithrombotic ther-
apy (Fig. 1). Among patients receiving anticoagulant
J Thromb Thrombolysis (2007) 23:65–71 67

100 ACO APT no ATT

90 100
Phase 1 Phase 2
80
% of AF patients

70 57.81 80

% of AF patients
60 46.51

50 60
32.23
40
21.26 22.26
30 19.93 40

20
20
10
0
ACT APT NATT 0
18-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
antithrombotic therapy
years
Fig. 1 Proportion of atrial fibrillation patients receiving anti-
Fig. 3 Proportion of atrial fibrillation (AF) patients receiving
thrombotic therapy (ATT) in Phases 1 and 2 of the study (ACT:
anticoagulant therapy (ACT), antiplatelets (APT) and no
anticoagulant therapy; APT: antiplatelet therapy; NATT: not
antithrombotic therapy (no ATT), according to age group, in
receiving antithrombotic therapy; AF: atrial fibrillation)
Phases 1 and 2 of the study

therapy in Phase 1, only 47 (15.6 %) were within the

recommended INR levels (Fig. 2).
In Phase 2, the rate of patients receiving anticoag-
ulant therapy increased to 57.8% (p = 0.007) while
19.9% were on antiplatelets and 22.2% were not
receiving any antithrombotic therapy (Fig. 1). Among
patients who were receiving anticoagulant therapy,
only 70 (23.25%) were within the recommended INR
levels (Fig. 2).
Antithrombotic therapy prescription rates compari-
son showed decreased anticoagulation prescription in
older patients (r squared = 0.037, p=0.0008). On the
other hand, the prescription of antiplatelets and the
prevalence of patients receiving no antithrombotic
therapy were increased in the elderly (Fig. 3).
Antithrombotic therapy in patients with previous
stroke
In Phase 1, 53 (17.6%) of the AF patients presented a
previous history of ischemic stroke. In this group, 26
100
Phase 1
90
80
% of AF patients
patients (49%) were receiving anticoagulant therapy, 9
(17%) were on antiplatelets and 18 (34%) were not
receiving any antithrombotic medication. Among
these, only 10 (19%) were in the recommended INR
levels.
In Phase 2, 32 (60.4%) patients were receiving
anticoagulant therapy, 9 (17%) were on antiplatelets
and 12 (22.6%) were not receiving any antithrombotic
therapy. Among these patients, only 14 (26.4%) were
in the recommended INR levels.
Clinical events between Phase 1 and Phase 2
New embolic events were reported in 17 (5.6%) pa-
tients: 17.6% were transitory ischemic attacks, 64.7%
ischemic strokes and 17.7% were embolic events to
other organs. In this same period, 51 (16.9%) deaths
occurred. The main causes of death were septic shock
in 19 patients (37.3%) and cardiogenic shock in 17
(33.3%). We verified that, before dying, 12 patients
(23.52%) were using anticoagulant therapy, 9 (17.65%)
were on antiplatelets, and 30 (58.8%) were not using
Phase 2
any antithrombotic therapy.

57.81
70
60 46.51 Reasons for interrupting anticoagulant therapy
50
40 23.25 In Phases 1 and 2, we observed that 17% (51 patients)
15.60
30 of the AF patients were previously treated with anti-
20
coagulant therapy and that this was interrupted in the
10
0
past and never reintroduced. The reasons for inter-
ACT INR rupting the therapy are shown in Fig. 4. In this analysis,
transient pause of the anticoagulant therapy related to
Fig. 2 Proportion of atrial fibrillation (AF) patients receiving
anticoagulant therapy (ACT) and patients with adequate INR surgical procedure was not considered interruption of
level (INR) in Phases 1 and 2 of the study the therapy.

123
68
Fig. 4 Proportion of the rea-
sons for interrupting
anticoagulant therapy in % therapy
Phases 1and 2 of the study
5,9
7,8
13,7
Discussion
The initial assessment of the clinical and demographic
characteristics showed that the prevalence of AF in our
study (8.0%) and the gender distribution (44.8%
males) are similar to those reported by Ageno et al.,
who found a 7.2% prevalence of AF in a sample of
3,121 patients (49.1% men) [30]. However, while the
mean age of our patients was 63 years, the mean age of
the patients in Ageno’s study was 78 years. This dif-
ference may be related to the fact that our study was
carried out in a tertiary-level heart hospital with a high
prevalence of valvular heart disease (44.8%), mostly of
rheumatic etiology, which occurs in younger patients.
The results of our study confirm the reports from
other countries regarding the underuse of anticoagu-
lant therapy in this population, despite the proven
efficacy of this treatment in the prevention of throm-
boembolic events associated with AF. The benefit of
anticoagulant therapy with warfarin as primary pre-
vention for patients with non-rheumatic AF was dem-
onstrated for the first time in 1989, in the Copenhagen
AFASAK study [20], and later by the American
BAATAF [40], SPAF [41], SPINAF [42] and by the
Canadian CAFA [43]. The first four studies were
interrupted prematurely due to the significantly higher
prevalence of thromboembolic events in the placebo
group. The CAFA study was suspended because of the
indisputable positive results of the previous studies.
A meta-analysis conducted by Hart et al. of 16
studies involving 9,874 patients comparing warfarin,
aspirin and placebo in patients with non-valvular AF
showed that anticoagulant therapy with warfarin
reduced the risk for stroke (ischemic and hemorrhagic)
by 62% (95% CI, 48–72%) [21]. These results were
123
J Thromb Thrombolysis (2007) 23:65–71
Surgical procedure and no
reintroduction of antithrombotic
5,9
Hemorrhagic complication
Unknown
45,1
Socioeconomic status
21,6 Patient refusal
Coagulopathy
similar to both primary and secondary prevention. The
hemorrhagic complications were also higher in this
group with an increase of absolute risk of 0.3% per
year. On the other hand, aspirin reduced the risk for
stroke by 22% (CI, 2–38%), showing that warfarin is
significantly more efficacious than aspirin, with a rela-
tive risk reduction of 36% (CI, 14–52%) for stroke.
The only controlled and randomized study on sec-
ondary prevention, EAFT, comparing warfarin, aspirin
and placebo in patients with AF and stroke or transient
ischemic attack within the previous 3 months showed
that warfarin reduced the risk for stroke by 68% when
compared with placebo, while aspirin reduced the
risk for stroke by 16%, which was not statistically
significant [44].
Despite these scientific evidences, the utilization
rate of anticoagulant therapy was very low in our study.
There was a small but significant increase in the use of
anticoagulant therapy between Phase 1 and Phase 2
(p = 0.007), but the numbers are still far from ideal
considering that all the patients were eligible for anti-
coagulant therapy according to the current guidelines
[24–26]. Our findings of anticoagulant therapy unde-
ruse are similar to those found in the literature abroad
[27–33, 45]. Furthermore, we observed that in Phases 1
and 2, respectively, only 15.6% and 23.2% of the
patients presented therapeutic INR levels. This sce-
nario persisted even among secondary prevention
candidates, that is, those with AF and a history of
stroke or embolic events, despite being a higher risk
group for thromboembolic complications.
We found that anticoagulation is underused for
stroke prevention especially in the elderly (p =
0.0008), where the therapeutic shift from anticoagula-
tion to antiplatelet therapy observed suggests that
J Thromb Thrombolysis (2007) 23:65–71
cardiologists from a University Hospital recognize the
situation, and deliver a less harmful but less effective
treatment. There is no consensus regarding the reasons
for anticoagulant therapy underuse. In our sample, an
interesting fact was observed: many patients had the
anticoagulant therapy interrupted without further
reintroduction until the moment of the analysis (17%).
In most cases, therapy interruption could have been
avoided, ameliorating the underutilization scenario. On
the other hand, as many as 21.6% of patients in both
Phases 1 and 2 had anticoagulant treatment interrupted
because of the occurrence of hemorrhagic complica-
tion. This bleeding rate is far higher than that reported
in the literature [25], suggesting, together with the
observed low rate of patients with an INR within the
therapeutic range, that a more careful monitoring of
the oral anticoagulation therapy could have favorably
influenced the management of these patients.
Indeed, the recently published European multicen-
tric SAFE II study, designed to answer the question on
why physicians underuse oral anticoagulant treatment
in AF patients, reported that the main reasons given by
general practitioners and cardiologists were: the pres-
ence of a potential contraindications, which was often
inappropriate, followed by no indication, low compli-
ance and fear of bleeding. This study concluded that
the most important reason for anticoagulant therapy
underuse was the lack of knowledge regarding the
guidelines and scientific evidence [39].
In addition, the small penetration of evidence-based
guidelines into a medical mentality founded on the
‘‘primum non nocere’’ concept may have contributed
for this fact. Solutions would go from medical educa-
tional programs directed towards the benefits of anti-
coagulant therapy in higher risk AF patients, to the
development of an adequate structure, possibly multi-
disciplinary, promoting assurance for the adequate
management of these patients, including the basis of
the anticoagulation clinics to educate and care for at-
rial fibrillation patients on anticoagulation, with the
attention of cardiologists, nurses, social assistants,
nutritionists, enrolling a group of professionals that
could support these patients.
Previous studies conducted to evaluate the use of
antithrombotic therapy in AF were also based on the
analysis of the information from medical charts. We
supplied data from a specific university environment
specialized in cardiology, using a longitudinal approach
to determine the rate of underuse of anticoagulants in
AF at two specific time points (13 months apart). We
show that anticoagulants are still underused but the
rate has increased quite a bit. This is an aspect of the
69
study which is quite novel and suggests that treatment
gaps persist over time.
In conclusion, patients with atrial fibrillation seen in
a Brazilian Heart Hospital presented clinical charac-
teristics compatible with a population at high risk for
thromboembolic events. Based on recommendations
from international guidelines, anticoagulant therapy is
being underused in these patients, and when used the
quality of the treatment was poor. Considering that the
majority of the reasons for not using oral anticoagulant
treatment reflect conditions that could be avoided,
efforts must be urgently made to improve this situation.
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