1) The study investigated outcomes in AF patients with 0 or 1 non-gender related (NGR) stroke risk factor (CHA2DS2-VASc score of 0-1 in males and 1-2 in females) who were treated or not treated with oral anticoagulation (OAC).
2) Among 2208 AF patients with 0-1 NGR risk factors, those not treated with OAC and with 1 risk factor had higher rates of stroke/embolism (2.09% per year) compared to those with 0 risk factors (adjusted hazard ratio 2.82).
3) Treating patients with 1 NGR risk factor with OAC was associated with a positive net
2. 2 Stroke July 2016
recommending OAC only to high-risk patients with at least 2
NGR stroke risk factors (CHA2
DS2
-VASc ≥2 in males and ≥3
in females) is appropriate.
Methods
Study Population
The detailed methods and design of the Loire Valley AF Project
have been previously reported.6–8
We included all patients seen in the
cardiology department at the University Hospital of Tours between
January 2000 and December 2010 with a diagnosis of AF and identi-
fied patients who were categorized as having 0 or 1 NGR stroke risk
factors (ie, CHA2
DS2
-VASc score of 0 or 1 in males; and 1 or 2 in
females).
AF (paroxysmal, persistent, or permanent) was defined on the
ECG by the replacement of consistent P waves by rapid oscillations
or fibrillatory waves that vary in amplitude, shape, and timing, asso-
ciated with an irregular, frequently rapid ventricular response when
atrioventricular conduction was intact. Treatment at discharge was at
the discretion of physician in charge and was obtained by the screen-
ing of hospitalization reports. Patients were excluded from the study
if their antithrombotic treatment at discharge was unknown. We also
excluded from the analysis patients with a known mitral stenosis or
any valvular prosthesis in whom OAC was theoretically indicated.
Characteristics of the patients were obtained by the coding system
filled in for each patient hospitalized through the computerized sys-
tem of the institution, based on the International Classification of
Diseases Tenth Revision. With these characteristics, the CHA2
DS2
-
VASc score could be calculated retrospectively, as previously
described2
: that is, 2 points assigned for a history of stroke/tran-
sient ischemic attack/thromboembolism and age ≥75 years; 1 point
assigned for age 65 to 74 years, history of hypertension, diabetes
mellitus, recent cardiac failure, vascular disease (myocardial infarc-
tion, complex aortic plaque, and peripheral arterial disease), and
female sex. VKA therapy was the only form of OAC used during
the study period.
We defined 4 groups of patients. Group A=patients not treated with
OAC with 0 NGR stroke risk factor, group B=patients not treated
with OAC with 1 NGR stroke risk factor, group C=patients treated
with OAC with 0 NGR stroke risk factor, and group D=patients
treated with OAC with 1 NGR stroke risk factor, with subgroups A.1,
B.1, C.1, and D.1 being not treated with antiplatelet therapy (APT),
and subgroups A.2, B.2, C.2, and D.2 being treated with APT. Figure
shows distribution of patients with AF, their CHA2
DS2
-VASc score
and use of antithrombotic strategies in these different groups and
subgroups.
During the follow-up of the patients, deaths from all causes and
events of interest were recorded whenever they occurred in our insti-
tution, which includes a total of 4 hospitals covering all medical and
surgical specialties. Our institution covers an area of 4000 km2
and a
population of 400.000 inhabitants and is the only public institution in
the area. In addition, mortality data were obtained using a search tool
from a dedicated website for the Région Center (http://nrco.lanouvel-
lerepublique.fr/dossiers/necro/index.php).
OAC use reduces the risk of stroke/systemic embolism and all-
cause mortality. Thus, another adverse end point for this study was the
composite of stroke/systemic embolism/death. Bleeding was defined
with International Classification of Diseases Tenth version codes for
bleed in any location.9,10
We also considered major bleedings, using
the Bleeding Academic Research Consortium bleeding definitions.11
We then compared the rate of events in nonanticoagulated patients
with 0 (group A) or 1 NGR stroke risk (group B).
The NCB of antithrombotic strategy was calculated for patients
with 1 NGR stroke risk factor in group B and group D, as originally
proposed by Singer et al12
using the formula:
NCB IS rate on no treatment IS rate on antithrombotic agen= − tt
15 ICH rate on no treatment
ICH rate on antithromboti
)
. (−
− cc agent
where IS is the ischemic stroke and ICH, the intracerebral hemor-
rhage, which is the most serious form of bleeding associated with
antithrombotic agent use. The NCB is used by clinicians and research-
ers as a validated method of balancing risk of IS against ICH.
We also calculated the NCB of treatment using an alternate method,
as proposed by Connolly et al,13
which uses a weighted sum of rate
differences ΔR=rate not treated−rate treated:
NCB w1 RIS w2 RICH
w3 Rmajor bleeding w4 RMI
= × + ×
+ × + ×
∆ ∆
∆ ∆
where major bleeding refers to major extracranial bleeding, MI is
the myocardial infarction and weights w1=1, w2=3.08, w3=0.67,
and w4=0.95.
Statistical Analysis
Patient characteristics are reported as percentages and medians with
interquartile range. Comparisons between groups were made using
χ2
tests for comparing categorical variables and the Student t test or
nonparametric Kruskal–Wallis test were appropriate for continuous
variables. Cumulative incidence rates of stroke, systemic thrombo-
embolism, bleeding events, and all-cause mortality were calculated
for all patients by groups and subgroups of interest. A Cox propor-
tional hazards regression model was used to calculate the hazard ratio
of some predictive factors and their 95% confidence interval for the
incidence of events. We performed unadjusted and adjusted analyses
(adjusted for baseline acetylsalicylic acid use for nonanticoagulated
patients). A P value of <0.05 was considered statistically significant.
Statistical analysis was carried out with the Statview 5.0 software
(Abacus Concepts, Berkley, CA).
Ethics Approval
The study was approved by the institutional review board of the Pole
Coeur Thorax Vaisseaux from the Trousseau University Hospital
(Tours, France) on December 7, 2010 and registered as a clinical
audit. Ethical review was therefore not required. Patient consent was
not sought. Patient identifying data were used only to facilitate the
cross referencing of data sources and records were otherwise anony-
mous. The study was conducted retrospectively, patients were not
involved in its conduct, and there was no impact on their care.
Results
From 8962 unselected and consecutive patients with AF seen
between 2000 and 2010, there were 2208 (25%) with <2 NGR
stroke risk factors (ie, CHA2
DS2
-VASc score 0 or 1 in males;
and 1 or 2 in females). Mean age was 55±14 and 685 (31%)
were female. Baseline characteristics of the patients with AF
and <2 NGR stroke risk factors are shown in Table 1.
During a follow-up of 1028±1189 days (median, 495; inter-
quartile range, 5–1882 days), outcomes (stroke, IS, stroke/
systemic embolism, myocardial infarction, death, bleeding,
and the composite of death/stroke/systemic embolism) for
nonanticoagulated AF patients with 0 compared with 1 NGR
stroke risk factors are shown in Table 2.
The yearly rate of stroke/systemic embolism in non-
anticoagulated AF patients with 1 NGR stroke risk factor
(CHA2
DS2
-VASc 1 in males and 2 in females) was 2.09%
(95% confidence interval, 1.37–3.18). This corresponded to
an adjusted hazard ratio of 2.82 (95% confidence interval,
1.32–6.04) relative to the group with 0 NGR stroke risk fac-
tor. For the death and the composite end point of death/stroke/
systemic embolism, the yearly rates were 3.78% and 5.59%,
respectively, in nonanticoagulated patients with 1 NGR stroke
risk factor versus 0.87% and 1.42% in nonanticoagulated
at University College London (ucl) / England on May 26, 2016http://stroke.ahajournals.org/Downloaded from
3. Fauchier et al Oral Anticoagulation and Atrial Fibrillation 3
patients with 0 NGR risk factors. In nonanticoagulated AF
patients with 0 or 1 CHA2
DS2
-VASc factor (groups A+B),
yearly rate of event was 0.65% for major Bleeding Academic
Research Consortium bleeding and 0.43% for intracranial
hemorrhage. There was a nonsignificant increase in hazard
ratio for these events among the nonanticoagulated patients
with 1 NGR risk factor (group B) relative to those with 0
NGR stroke risk factor (group A; Table 2).
Rates of IS, ICH, major extracranial bleeding, and myocar-
dial infarction in AF patients with 1 NGR stroke risk treated
with no VKA and no antiplatelet agent (subgroup B.1), anti-
platelet agents and no VKA (subgroup B.2) and VKA and
no antiplatelet agents (subgroup D.1) are shown in Table 3.
When the benefit of IS reduction was balanced against the
increased risk of ICH among patients with 1 NGR stroke risk
factor, the NCB was positive in favor of VKA use versus no
Table 1. Baseline Characteristics for Atrial Fibrillation Patients With <2 NGR Stroke Risk Factors (CHA2
DS2
-VASc 0 or 1 in Males;
and 1 or 2 in Females)
Group A No OAC, 0 NGR Stroke
Risk Factors (CHA2
DS2
VASc 0
in Males; 1 in Females)
Group B No OAC, 1 NGR Stroke
Risk Factors (CHA2
DS2
VASc 1
in Males; 2 in Females)
Group C OAC, 0 NGR Stroke
Risk Factors (CHA2
DS2
VASc 0
in Males; 1 in Females)
Group D OAC, 1 NGR Stroke
Risk Factors (CHA2
DS2
VASc 1
in Males; 2 in Females)
n (%) 616 (27.9) 385 (17.4) 489 (22.1) 718 (32.5)
Age (median, interquartile
range)
46.5 (33.8–56.5) 62.8 (54.1–69.2) 54.4 (48.2–60.2) 64.0 (57.0–70.1)
Female sex 228 (37.0) 124 (32.2) 124 (25.4) 209 (29.1)
Previous systemic embolism 0 0 0 0
Previous left ventricular
dysfunction
0 133 (34.5) 0 266 (37.0)
Previous hypertension 0 44 (11.4) 0 80 (11.1)
Previous diabetes mellitus 0 14 (3.6) 0 22 (3.1)
Previous vascular disease 0 32 (8.3) 0 27 (3.8)
Aspirin 252 (41.0) 162 (42.3) 19 (3.9) 52 (7.5)
Clopidogrel 12 (2.0) 37 (9.7) 7 (1.5) 22 (3.2)
CHA2
DS2
-VASc score, n (%)
Men=0/women=1 616 0 489 0
1 (men) 0 261 (67.8) 0 509 (70.9)
2 0 124 (32.2) 0 209 (29.1)
HAS-BLED score (median,
interquartile range)
0 (0–0) 1 (0–1) 0 (0–0) 1 (0–1)
CHA2
DS2
-VASc indicates congestive heart failure, hypertension, age (≥75 years; 2 points), diabetes, stroke/transient ischemic attack (2 points), vascular disease, age
(65–74 years), sex (female); HAS-BLED, hypertension, age, stroke, bleeding tendency/predisposition, labile INRs, elderly age/frailty, drugs such as concomitant aspirin/
NSAIDs or alcohol excess; NGR, nongender-related; and OAC, oral anticoagulation.
Figure. Flow chart of patients with atrial
fibrillation (AF) with risk of stroke and use
of antithrombotic strategies. APT indicates
antiplatelet therapy; and CHA2
DS2
-VASc,
congestive heart failure, hypertension, age
(≥75 years; 2 points), diabetes, stroke/tran-
sient ischemic attack (2 points), vascular
disease, age (65–74 years), sex (female).
at University College London (ucl) / England on May 26, 2016http://stroke.ahajournals.org/Downloaded from
4. 4 Stroke July 2016
antithrombotic treatment or VKA versus APT use, whether
using the formula proposed by Singer et al12
or that proposed
by Connolly et al13
(Table 4). By contrast, NCB was negative
for APT use versus no antithrombotic therapy.
Discussion
The NICE and European guidelines currently advise anti-
coagulation for patients with 1 NGR CHA2
DS2
-VASc score
factor (ie, CHA2
DS2
-VASc 1 in males or 2 in females). In
the US guidelines, OAC is recommended for patients with
2 NGR factors; whereas anticoagulation, APT, or no anti-
thrombotic agent are all considered reasonable options
for patients with CHA2
DS2
-VASc score 1. In this cohort
study, our principal finding was that nonanticoagulated
AF patients with 1 as opposed to 0 NGR stroke risk factor
(CHA2
DS2
-VASc score of 1 versus 0 in males; and 2 versus
1 in females) had an increased risk of serious cardiovascular
events during follow-up. Importantly, VKA use was associ-
ated with a positive NCB for the prevention of stroke and
thromboembolic events in these patients.
The CHA2
DS2
-VASc score and older CHADS2
score have
5 stroke risk factors in common, and previous guidelines
already recommended OAC in patients with 1 stroke risk fac-
tor (eg, CHA2
DS2
score of 1).14,15
Thus, treatment guidelines
unduly focused on identifying high-risk AF patients and only
treating at least 2 NGR stroke risk factors (CHA2
DS2
-VASc
score of ≥2 in males and ≥3 in females) with OAC should
reconsider the positive NCB of OAC stroke prevention in AF
patients with 1 NGR stroke risk factor. Indeed, strokes asso-
ciated with AF are more likely to be fatal and disabling, and
Table 2. Event Rates for Different Outcomes for Nonanticoagulated Atrial Fibrillation Patients With 2 NGR Stroke Risk Factors
Stratified According to the Presence of 0 (CHA2
DS2
VASc 0 in Males and 1 in Females, Group A) or 1 NGR Stroke Risk Factor
(CHA2
DS2
-VASc 1 in Males or 2 in Females, Group B)
n Person-Years Events Event Rate, %/y (95% CI) Crude HR (95% CI) P Value Adjusted HR (95% CI) P Value
Stroke
Group A 616 1474 9 0.61 (0.32–1.16) Reference Reference
Group B 385 1018 18 1.77 (1.12–2.78) 2.78 (1.23–6.16) 0.01 2.62 (1.16–5.89) 0.02
Ischemic Stroke
Group A 616 1484 5 0.34 (0.14–0.79) Reference Reference
Group B 385 1021 12 1.18 (0.67–2.04) 3.45 (1.22–9.80) 0.02 3.21 (1.11–9.26) 0.03
Stroke/TE
Group A 616 1474 10 0.68 (0.37–1.24) Reference Reference
Group B 385 1002 21 2.09 (1.37–3.18) 2.95 (1.38–6.28) 0.005 2.82 (1.32–6.04) 0.008
Myocardial infarction
Group A 616 1479 6 0.41 (0.19–0.88) Reference Reference
Group B 385 1022 20 1.96 (1.27–3.00) 4.67 (1.88–11.62) 0.0009 4.69 (1.88–11.63) 0.0009
Death
Group A 616 1491 13 0.87 (0.51–1.49) Reference Reference
Group B 385 1057 40 3.78 (2.79–5.11) 4.16 (2.22–7.78) 0.0001 4.20 (2.24–7.86) 0.0001
Bleeding event
Group A 616 1459 15 1.03 (0.62–1.69) Reference Reference
Group B 385 1012 38 3.76 (2.75–5.11) 3.51 (1.93–6.39) 0.0001 3.45 (1.89–6.29) 0.0001
Major BARC bleeding event
Group A 616 1459 6 0.41 (0.19–0.89) Reference Reference
Group B 385 1012 10 0.99 (0.54–1.81) 2.37 (0.86–6.52) 0.10 2.39 (0.87–6.57) 0.09
Intracranial hemorrhage
Group A 616 1482 4 0.27 (0.11–0.69) Reference Reference
Group B 385 1052 7 0.67 (0.32–1.37) 2.16 (0.62–7.52) 0.22 1.88 (0.52–6.76) 0.33
Death/Stroke/TE
Group A 616 1474 21 1.42 (0.93–2.17) Reference Reference
Group B 385 1002 56 5.59 (4.33–7.19) 3.89 (2.52–6.00) 0.0001 3.88 (2.51–6.00) 0.0001
Adjusted HR indicates adjusted for baseline acetylsalicylic acid use; BARC, Bleeding Academic Research Consortium; CHA2
DS2
-VASc, congestive heart failure,
hypertension, age (≥75 years; 2 points), diabetes, stroke/transient ischemic attack (2 points), vascular disease, age (65–74 years), sex (female); CI, confidence interval;
HR, hazard ratio; and NGR, nongender-related.
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5. Fauchier et al Oral Anticoagulation and Atrial Fibrillation 5
even 1 stroke risk factor confers a significant risk. The differ-
ence in annual IS rates between nonanticoagulated patients
with 1 NGR stroke risk factor (1.08%) and those treated
with OAC (0.91%) was statistically nonsignificant, probably
because of a lack of power, but in these nonrandomized sub-
groups there was a lower rate of myocardial infarction in
anticoagulated patients.
In contrast to VKA, APT was associated with a negative
NCB when compared with no antithrombotic therapy, even
when 1 NGR CHA2
DS2
-VASc stroke risk factor was pres-
ent. The American College of Cardiology (ACC)/American
Heart Association (AHA)/Heart Rhythm Society guidelines
recommend no antithrombotic therapy, aspirin, or OAC for
CHA2
DS2
-VASc score of 1; however, our findings do not sup-
port this strategy. Recent trials with non-VKA oral anticoagu-
lant agents also provide data for benefit even with a single
risk factor albeit with using the CHADS2
score. Thus, phy-
sicians should appreciate that even a single NGR risk factor
confers real risks of stroke/systemic thromboembolism/death,
and OAC would reduce this overall risk, providing a positive
NCB. Overall, this study supports the strategy for OAC pro-
posed in the current ESC and NICE guidelines.3,5
We see the ability to report nonrandomized, real-world reg-
istry data from a large cohort of consecutive patients recruited
as an advantage, not a weakness, in that the data are comple-
mentary (and supportive) to the data reported in randomized,
clinical trials. In fact, a large randomized control trial address-
ing the issues presented here will probably not be performed.
Observational studies such as ours may be of value because
they shed light on the use of competing treatment options in
current practice.
Limitations
The main limitation of this study is in its observational nature.
Although adjusted for several variables, some patients might
have more acute or severe illness and remains possible that
residual confounding factors could exist in the analysis.
Table 3. Event Rates for Different Outcomes for Atrial Fibrillation Patients With 1 NGR Stroke Risk Factors
(CHA2
DS2
-VASc 1 in Males or 2 in Females, Group B) Stratified According to Antithrombotic Therapy (Events
Needed for the Net Clinical Benefit Analysis, Table 4)
n Person-Years Events Event Rate, %/y (95% CI) HR (95% CI) P Value
Ischemic Stroke
Subgroup B.1 213 554 6 1.08 (0.50–2.34) Reference
Subgroup B.2 170 462 5 1.08 (0.46–2.51) 1.00 (0.31–3.25) 1.00
Subgroup D.1 637 1976 18 0.91 (0.58–1.44) 0.84 (0.34–2.11) 0.72
Intracranial hemorrhage
Subroup B.1 213 562 3 0.53 (0.18–1.56) Reference
Subroup B.2 170 485 3 0.62 (0.21–1.80) 1.16 (0.24–5.71) 0.75
Subroup D.1 637 2021 9 0.45 (0.23–0.84) 0.83 (0.23–3.07) 0.82
Major extracranial bleeding event
Subgroup B.1 213 490 3 0.61 (0.21–1.78) Reference
Subgroup B.2 170 449 1 0.22 (0.04–1.25) 0.36 (0.04–3.48) 0.68
Subgroup D.1 637 1824 10 0.55 (0.30–1.01) 0.90 (0.25–3.24) 0.86
Myocardial infarction
Subgroup B.1 213 553 9 1.63 (0.86–3.06) Reference
Subgroup B.2 170 462 11 2.38 (1.33–4.21) 1.46 (0.61–3.50) 0.38
Subgroup D.1 637 2014 13 0.65 (0.38–1.10) 0.40 (0.17–0.92) 0.04
CHA2
DS2
-VASc indicates congestive heart failure, hypertension, age (≥75 years; 2 points), diabetes, stroke/transient ischemic attack (2
points), vascular disease, age (65–74 years), sex (female); CI, confidence interval; and HR, hazard ratio.
Table 4. Net Clinical Benefit Analysis of Stroke Prevention
Strategy for Atrial Fibrillation Patients With 1 NGR Stroke Risk
Factor (CHA2
DS2
-VASc 1 in Males and 2 in Females) in Group B
and Group D
Stroke Prevention
Strategy
Net Clinical Benefit, %/y
(95% CI) According to
Singer et al12
Net Clinical Benefit, %/y
(95%CI) According to
Connolly et al13
Compared with no antithrombotic therapy
Antiplatelet drugs
(and no VKA)
−0.13 (−1.06 to −0.02) −0.72 (−1.50 to −0.34)
VKA 0.30 (0.15 to 0.61) 1.42 (1.01 to 1.99)
Compared with antiplatelet drugs (and no VKA)
VKA 0.43 (0.24 to 0.78) 2.14 (1.62 to 2.82)
NCB according to Singer et al12
=(ischemic stroke rate on no treatment minus
ischemic stroke rate on anti-thrombotic therapies)−1.5×(ICH rate on antithrombotic
therapies−ICH rate on no treatment). NCB according to Connolly et al13
=weighted
sum of rate differences ΔR=Rate not treated−Rate treated:w1×ΔRischemic
stroke+w2×ΔRICH+w3×ΔRmajor bleeding+w4×ΔRMI. CHA2
DS2
-VASc indicates
congestive heart failure, hypertension, age (≥75 years; 2 points), diabetes,
stroke/transient ischemic attack (2 points), vascular disease, age (65–74
years), sex (female); CI, confidence interval; ICH, intracerebral hemorrhage;
major bleeding, major extracranial bleeding, MI, myocardial infarction; NCB, net
clinical benefit; NGR, nongender-related; VKA, vitamin K antagonist weights w1,
1; w2, 3.08; w3, 0.67; and w4, 0.95.
at University College London (ucl) / England on May 26, 2016http://stroke.ahajournals.org/Downloaded from
6. 6 Stroke July 2016
Concomitant drug therapies differed between groups and sub-
groups, and even after multivariate adjustment, our observa-
tional study design raises a question as to whether some groups
or subgroups were merely managed better with a possible
treatment bias, particularly those with VKA use. Although we
carefully ascertained all strokes and ICH through examination
and hospitalization records, laboratory and imaging results,
patients with a milder form of stroke and ICH who were not
hospitalized may have not been seen in hospital. In this real-
world registry, some deaths could be because of undiagnosed
stroke because cerebral imaging or postmortems were not
mandated, unlike a clinical trial. Studies with a long-term
follow-up as this one are often at risk of changes in treatment
during the follow-up, which is impossible to make adjust-
ments for in the multivariable analysis. Quality of anticoagu-
lation with time in therapeutic range for patients treated with
VKA use was not available. Another caveat is that we did not
have access to data on strokes occurring outside of our area.
In conclusion, among AF patients with 1 NGR stroke risk
factor (ie, CHA2
DS2
-VASc 1 in males or 2 in females), OAC
use as indicated according to the ESC guidelines was associ-
ated with a positive NCB in favor of VKA use versus no anti-
thrombotic therapy or aspirin. The NCB was negative for APT
use versus no antithrombotic therapy. Guidelines focused on
only treating at least 2 NGR stroke risk factors (CHA2
DS2
-
VASc score of ≥2 in males and ≥3 in females) with OAC
should reconsider the positive NCB of OAC stroke preven-
tion in AF patients with only 1 NGR stroke risk factor (ie,
CHA2
DS2
-VASc 1 in males or 2 in females).
Disclosures
Dr Fauchier has served as a consultant for Bayer, BMS/Pfizer,
Boehringer Ingelheim, and Daiichi Sankyo, and he has been on the
speakers bureau from Bayer, BMS/Pfizer, and Boehringher Ingelheim.
Dr Lip has served as a consultant for Bayer/Janssen, Astellas, Merck,
Sanofi, BMS/Pfizer, Biotronik, Medtronic, Portola, Boehringer
Ingelheim, Microlife, and Daiichi-Sankyo and as a speaker for Bayer,
BMS/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche,
and Daiichi-Sankyo. Dr Angoulvant has received funding for confer-
ence travel and educational symposia from Astra Zeneca, Eli-Lilly,
Novartis, Bayer, MSD, Amgen, and Pfizer. Dr Babuty has been on the
speakers bureau from BMS/Pfizer and Medtronic. The other authors
report no conflicts.
References
1. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy
to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann
Intern Med. 2007;146:857–867.
2. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical
risk stratification for predicting stroke and thromboembolism in atrial
fibrillation using a novel risk factor-based approach: the euro heart
survey on atrial fibrillation. Chest. 2010;137:263–272. doi: 10.1378/
chest.09-1584.
3. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et
al; ESC Committee for Practice Guidelines (CPG). 2012 focused update
of the ESC Guidelines for the management of atrial fibrillation: an update
of the 2010 ESC Guidelines for the management of atrial fibrillation.
Developed with the special contribution of the European Heart Rhythm
Association. Eur Heart J. 2012;33:2719–2747. doi: 10.1093/eurheartj/
ehs253.
4. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC
Jr, et al; American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline
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 Heart Rhythm Society. J Am Coll
Cardiol. 2014;64:e1–76. doi: 10.1016/j.jacc.2014.03.022.
5. National Clinical Guideline Centre (UK). Atrial Fibrillation: The
Management of Atrial Fibrillation [Internet]. London, United Kingdom:
National Institute for Health and Care Excellence (UK); 2014. http://
www.ncbi.nlm.nih.gov/books/NBK248059/. Accessed April 14, 2016.
6. Taillandier S, Brunet Bernard A, Lallemand B, Simeon E, Pericart L,
Clementy N, et al. Prognosis in patients hospitalized with permanent
and nonpermanent atrial fibrillation in heart failure. Am J Cardiol.
2014;113:1189–1195. doi: 10.1016/j.amjcard.2013.12.024.
7. Banerjee A, Fauchier L, Vourc’h P, Andres CR, Taillandier S, Halimi JM,
et al. Renal impairment and ischemic stroke risk assessment in patients
with atrial fibrillation: the Loire Valley Atrial Fibrillation Project. J Am
Coll Cardiol. 2013;61:2079–2087. doi: 10.1016/j.jacc.2013.02.035.
8. Philippart R, Brunet-Bernard A, Clementy N, Bourguignon T, Mirza A,
Babuty D, et al. Prognostic value of CHA2DS2-VASc score in patients
with ‘non-valvular atrial fibrillation’and valvular heart disease: the Loire
Valley Atrial Fibrillation Project. Eur Heart J. 2015;36:1822–1830. doi:
10.1093/eurheartj/ehv163.
9. Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW,
et al. Clinical classification schemes for predicting hemorrhage: results
from the National Registry of Atrial Fibrillation (NRAF). Am Heart J.
2006;151:713–719. doi: 10.1016/j.ahj.2005.04.017.
10. Lip GY, Andreotti F, Fauchier L, Huber K, Hylek E, Knight E, et al;
European Heart RhythmAssociation. Bleeding risk assessment and man-
agement in atrial fibrillation patients. Executive Summary of a Position
Document from the European Heart Rhythm Association [EHRA],
endorsed by the European Society of Cardiology [ESC] Working Group
on Thrombosis. Thromb Haemost. 2011;106:997–1011. doi: 10.1160/
TH11-10-0690.
11. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et
al; Academic Research Consortium. Clinical end points in coronary stent
trials: a case for standardized definitions. Circulation. 2007;115:2344–
2351. doi: 10.1161/CIRCULATIONAHA.106.685313.
12. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK,
Udaltsova N, et al. The net clinical benefit of warfarin anticoagulation in
atrial fibrillation. Ann Intern Med. 2009;151:297–305.
13. Connolly SJ, Eikelboom JW, Ng J, Hirsh J, Yusuf S, Pogue J, et al;
ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan
for Prevention of Vascular Events) Steering Committee and
Investigators. Net clinical benefit of adding clopidogrel to aspi-
rin therapy in patients with atrial fibrillation for whom vitamin K
antagonists are unsuitable. Ann Intern Med. 2011;155:579–586. doi:
10.7326/0003-4819-155-9-201111010-00004.
14. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC,
et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.
2012;141:e531S–575S.
15. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA,
et al; Task Force on Practice Guidelines, American College of Cardiology/
American Heart Association; Committee for Practice Guidelines,
European Society of Cardiology; European Heart Rhythm Association;
Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for the manage-
ment of patients with atrial fibrillation-executive summary: 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).
Eur Heart J. 2006;27:1979–2030. doi: 10.1093/eurheartj/ehl176.
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