Content uploaded by Antonis Manolis
Author content
All content in this area was uploaded by Antonis Manolis on Jan 29, 2017
Content may be subject to copyright.
Send Orders for Reprints to reprints@benthamscience.ae
Current Drug Targets, 2017, 18, 000-000 1
REVIEW ARTICLE
1389-4501/17 $58.00+.00 © 2017 Bentham Science Publishers
Stroke Risk Stratification Schemes in Atrial Fibrillation in the Era of Non-
Vitamin K Anticoagulants: Misleading and Obsolete, At Least for the
“Low-Risk” Patients?!
Antonis S. Manolis*, Theodora A. Manolis, Antonis A. Manolis and Helen Melita!
Third Department of Cardiology, Athens University School of Medicine, and Onassis Cardiac Surgery Center, Athens,
Greece
A R T I C L E H I S T O R Y
Received: June 25, 2016
Revised: August 24, 2016
Accepted: August 30, 2016
DOI:
10.2174/138945011766616090511
1822
Abstract:!The thromboembolic risk of atrial fibrillation (AF) is significantly mitigated by oral antico-
agulation (OAC) therapy, albeit at an increasing bleeding risk. The general principle is that the expected
protective benefit of OAC must not exceed the potential harm conferred by possible bleeding. Over the
recent years, the CHA2DS2-VASc score has been proven to be superior to other scores in identifying
‘low risk’ AF patients. However, even this latest score does not incorporate all possible risk factors
causing a h igh thromboembolic risk, while the individual components of the CHA2DS2-VASc score do
not seem to carry equal thromboembolic risk. Thus, the quest for more reliable risk stratification
schemes and identification of “truly low-risk” patients has been continued. A variety of clinical, echo-
cardiographic, g enetic and bioch emical or coagulation parameters can also predict adverse thromboem-
bolic events. Nevertheless, the addition or adoption of more complex schemes may defeat the purpose
of simplicity and practicality, demanding more extensive and costly assessments to decide on a rela-
tively simple qu estion, that of the need for anticoagulation. In th e era of non-vitamin K oral anticoagu-
lants (NOACs), this may not be necessary any more, and a simple recommendation of dispensing OAC
therapy almost to every patient afflicted by AF may prove to be a more practical and a ubiquitous ap-
proach, as long as safety is ensured by these newer agents. In this article, data concerning the risk strati-
fication schemes and particularly the CHA2DS2-VASc score of 1 and 0, are critically reviewed and a
practical algorithm is proposed for all and more specifically for the “low-risk” patients.
Keywords: Anticoagulation, vitamin K anticoagulants, bleeding, non-vitamin K anticoagulants, risk stratification schemes,
CHA2DS2-VASc score, lone atrial fibrillation.!
INTRODUCTION!
Atrial fibrillation (AF) confers a high risk of throm-
boembolism, particularly stroke, which is significantly miti-
gated by oral anticoagulation (OAC) therapy, albeit at an
increasing bleeding risk [1]. The general principle is that the
expected protective benefit of anticoagulation in lowering
the thromboembolic risk must not exceed the potential harm
conferred by possible bleeding [2]. Indeed, in a Medicare
patient population, a continued, steady decline in ischemic
stroke rates between 1992 and 2007 in patients with preva-
lent AF was reported in parallel to increasing warfarin use
(26.7% in 1992; 63.1% in 2007), while the hemorrhagic
stroke rate remained constant at nearly 2 per 1000 patient-
years throughout the study period [3]. In a large Danish co-
hort study comprising 132,373 patients with non-valvular AF
and assessing both the thromboembolic and bleeding risk,
there was increased risk of bleeding but the net clinical bene-
fit was clearly positive, in favour of warfarin, the classical
*Address correspondence to this author at the Athens University School of
Medicine, Athen s, Greece; Tel/ Fax: +30-213-2088470 / +30-213-2088676;
E-mail: asm@otenet.gr
vitamin K antagonist (VKA), in patients with increased risk
of stroke/thromboembolism; furthermore, the study con-
firmed the efficacy of VKA and no effect of aspirin treat-
ment on the thromboembolic risk [4]. !
Earlier on, an attempt was made to identify clinical risk
factors for stroke in patients with non-valvular AF [5, 6]. In
1994, an analysis of pooled data from 5 early randomized
studies evaluating VKAs in AF patients identified age >65
years, history of hypertension, previous transient ischemic
attack (TIA) or stroke, and diabetes as stroke predictive risk
factors [5]. Patients younger than 65 years who had none of
the other predictive factors (constituting 15% of the popula-
tion) had an annual rate of stroke of 1%. Initially, the
CHADS2 (defined as congestive heart failure, hypertension,
age ≥75 years, type 2 diabetes mellitus, previous stroke
[doubled]) score was devised and heavily promoted as a
popular scoring system for over 10 years because of its sim-
plicity in identifying “high-risk” patients [7]. However, its
discriminatory power for low-risk AF patients who may not
require OAC was very poor, as the annual stroke rate was
still around 2% for patients with a CHADS2 score of 0, sug-
gesting that the CHADS2 score was inadequate and mislead-
2 Current Drug Targets, 2017, Vol. 18, No. 5 Manolis et al.
ing in identifying truly low-risk patients; indeed, among pa-
tients with a low-risk CHADS2 (score = 0), the stroke rate
could be as high as 3.2-4.5%/year when substratified by the
CHA2DS2-VASc score [8, 9]. Thus, the CHA2DS2-VASc
score was introduced and has been proven to be superior to
the CHADS2 score in identifying “low risk” AF patients [9-
11]. In this new score, the number of risk factors was ex-
panded to include the following additional factors, such as
age 65-74 years, presence of vascular disease and female
gender, and the increased allotment of 2 points (vs 1 point in
CHADS2) for age >75 years. Nevertheless, the quest for
more reliable risk stratification schemes and identification of
“truly low-risk” patients has not ceased since the introduc-
tion and wider acceptance of the CHA2DS2-VASc score, the
main reason being that even this latest score does not incor-
porate all possible risk factors causing a high thromboem-
bolic risk, [12-14] while the individual components of the
CHA2DS2-VASc score do not seem to carry equal throm-
boembolic risk [15]. Factors such as renal dysfunction, obe-
sity, obstructive sleep apnea, tobacco and ethanol use, eth-
nicity, genetics, echocardiographic (e.g. left atrial size, left
atrial appendage-LAA morphology, etc) and biochemical or
coagulation parameters (e.g. troponin I, B-type natriuretic
peptide, C-reactive protein, von Willebrand factor, D-dimer,
etc) can also predict adverse thromboembolic events [13, 14,
16-19]. However, in the long run, the addition or adoption of
more complex schemes may defeat the purpose of simplicity
and practicality, demanding more extensive and costly as-
sessments to decide on a relatively simple question, that of
the need for anticoagulation. In the era of non-vitamin K oral
anticoagulants (NOACs),[20] this may not be necessary any
more, and a simple recommendation of dispensing OAC
therapy to every patient afflicted by AF may prove to be a
more practical and ubiquitous approach, as long as safety is
ensured by these newer agents (NOACs: dabigatran, rivarox-
aban, apixaban, endoxaban). !
CHA2DS2-VASc SCORE!
The CHA2DS2-VASc score (congestive heart failure;
hypertension; age ≥75 years [doubled]; diabetes; previous
stroke, transient ischemic attack, or thromboembolism [dou-
bled]; vascular disease; age 65 to 75 years; and sex category)
was introduced in 2009 [21] and is currently the recom-
mended tool as a refined risk score for estimating the risk for
thromboembolism in non-valvular AF patients and determin-
ing the need for OAC therapy. Adoption of this risk score by
the revised 2012 ESC and the revised 2014 ACC/AHA
guideline and partial adoption by the 2014 Canadian guide-
line appears to have substantially increased the proportion of
patients recommended for OAC, with near-universal indica-
tion for patients older than 65 years [22-25]. Even the most
recent 2016 ESC guidelines are heavily relying on this risk
score [26]. !
As there is usually great confusion whether the risk of a
female patient assigned a CHA2DS2-VASc score of 1 when
aged <65 years is equivalent to a score of 0 of a male patient
aged<65 years without other risk factors, and for the sake of
simplicity, some refer to all patients aged <65 years without
co-morbidities regardless of gender as low-risk patients,
while others consider that female gender is a true risk factor
regardless of age [27]. That is to say, women appear to have
increased thrombogenicity for various reasons and when
aged <65 years are assigned a score of 1 based solely on
their gender, and when they reach the age of 65 years will be
automatically assigned a CHA2DS2-VASc score of 2. !
CHA2DS2-VASc SCORE >1-2!
Initially, with the introduction of the CHA2DS2-VASc
score, OAC therapy was recommend ed when the CHA2DS2-
VASc score was >2 for both genders, while the recommen-
dations for CHA2DS2-VASc score of 1 were not consistent.
For CHA2DS2-VASc score of 1, the 2010 ESC guidelines
recommended OAC (preferred) or aspirin [28]. However, the
2012 ESC and the most recent 2016 ESC guidelines recom-
mend OAC (preferably NOAC) therapy for patients with
CHA2DS2-VASc score >1, when score of 1 is not due to
gender [22, 26]. For patients with nonvalvular AF and a
CHA2DS2-VASc score of 1, the 2014 American guidelines
recommend no antithrombotic therapy or treatment with an
OAC or aspirin [23]. The 2014 Canadian guidelines recom-
mend use of OAC for all patients who are aged > 65 years or
most patients who have a CHADS2 score > 1; they consider
that women with vascular disease do not qualify for OAC
therapy unless they are aged > 65 or have an additional
CHADS2 risk factor [24]. Latest (2014) guidelines by NICE
recommend anticoagulation for men with a CHA2DS2-
VASc score of >1 (https://www.nice.org.uk/guidance/
cg180). This recommendation change was prompted by am-
ple evidence from studies showing a high annual stroke risk
in AF patien ts with a CHA2DS2-VASc score of 1 and no
OAC treatment, ranging from 0.5% to 6.6%/year (Table 1)
[11, 15, 29, 30]. !
CHA2DS2-VASc >1 IN MEN / >2 IN WOMEN
Thus, OAC is now recommended for more AF patients
by the new guidelines by including men with a CHA2DS2-
VASc score of >1, and practically every patient of either
gender older than 65 years. According to the ORBIT AF
Registry , two-thirds of patients with AF who were previ-
ously not recommended for OAC are newly recommended
under the 2014 American guidelines [25]. !
Post-hoc analysis of a cohort derived from merged
datasets of SPORTIF III and V trials indicated that among
1,097 patients of non-valvular AF with only one additional
stroke risk factor (i.e. CHA2DS2-VASc= 1 in males or 2 in
females), the rates of major adverse events (stroke/systemic
thromboembolic event, mortality) were high, despite being
anticoagulated [31]. Time in therapeutic range (TTR) in war-
farin-treated patients was inversely associated with the oc-
currence of both stroke/systemic thromboembolic event and
all-cause death. !
Among 2,177 (24%) of 8,962 AF patients having zero or
one additional stroke risk factor, ie, CHA2DS2-VASc score
= 1 in men, 2 in women (53% were prescribed OAC), over a
mean follow-up of 2.7 years, OAC use was independently
associated with an improved prognosis for stroke/systemic
thromboembolism/death) (adjusted hazard ratio-HR, 0.59; P
= 0.007) [32]. !
According to a meta-analysis of 6 reports enrolling a total
of 2594 patients with AF, a high CHA2DS2-VASc score was
Dispensing with the Risk Stratification Schemes in AF? Current Drug Targets, 2017, Vol. 18, No. 5 3
Table 1. Thromboembolic event rates in AF patients with CHA2DS2-VASc score of 1.
Study!
Patients/Group (n/N)!
Gender!
Annual Event Rate!
OAC!
NOAC!
Poli 201 1 [42]!
35/662!
Both!
0.8%!
√!
--!
Olesen 2011 [4]!
15,866/132,372!
Both!
1.6%!
-- / √!
--!
Olesen 2011 [11]!
8,203/73,538!
Both!
2.01%!
--!
--!
Friberg 2012 [43]!
6770/90,706!
Both!
0.6% †!
-- / √!
--!
Singer 2 013 [44]!
NR/10,927!
Both!
0.55%!
--!
--!
Huang 2014 [29]!
358/9,727!
Both!
6.6%!
--!
--!
Chao 2014 [36]!
19,325/186,570!
Both!
1.72%!
--!
--!
Lip 2014 [45]!
12,756/72,452!
Both!
2.94%!
--!
--!
Chao 2015 [15]!
12,935/186,570!
Male!
2.75%!
--!
--!
van den Ham 2015 [46]!
6,544/60,594!
Both!
0.78%!
--!
--!
Abumuaileq 2015 [18]!
95/1,065!
Both!
1.05%!
√!
--!
Lip 2015 [47]!
NR/22,582!
Male!
4.32%!
--!
--!
Lip 2015 [30]!
18,287/39,400!
Both!
1.55% *!
--/√!
--!
Friberg 2015 [48]!
12,298/140,420!
Both!
0.5-0.9%‡!
--!
--!
Chao 2016 [9]!
19,325/186,570!
Both!
2.11%!
--!
--!
Aspberg 2016 [77]!
15,694/152,153!
Both!
0.7%!
--!
--!
Proietti 2016 [31]!
1,097/7,329!
Both**!
1.4% ***!
-- / √!
--!
Chan 2016 [49]!
27,521/190,210!
Both!
1.98%!
--!
--!
AF = atrial fibrillation; NOAC = non-vitamin oral anticoagulant; OAC = oral anticoagulant; NR = not reported
1.3% for those who were anticoagulated!
† 0.3% for those who were anticoagulated!
‡ ischemic stroke rate for wom en 0.1-0.2% / event rate of 1.3% in men for TIA, pulmonary embolism, arterial embolism, and all stroke s (ischemic or hemorrhagic) !
* 1.06% for those who were anticoagulated!
** CHA2DS2-VASc= 1 in males, or 2 in females!
*** 0.9% for those who were anticoagulated.
independently associated with the presence of left atrial
thrombus/spontaneous echocardiographic contrast in patients
with non-valvular AF [33]. This pooled analysis demonstrated
a statistically significant 70% increase in detection of throm-
bus or echo contrast with higher CHA2DS2-VASc score to
lower CHA2DS2-VASc score in the random effects model
(OR, 1.70; P = 0.006); only patients with a CHA2DS2-VASc
score of 0 were free of left atrial thrombus.
The CHA2DS2-VASc score is also predictive of throm-
boembolism in conjunction with cardioversion [34]. Among
22,874 AF patients undergoing electrical cardioversion,
10,722 with and 12,152 without OAC pre-treatment, those
with low stroke risk (CHA2DS2-VASc 0–1) did not suffer
from any thromboembolic complications within 30 days after
cardioversion. However, cardioversion without prior antico-
agulation was not safe for patients with risk factors for
thromboembolism (CHA2DS2-VASc score >1 point).
Among patients with medium and high thromboembolic risk,
there were fewer thromboembolic complications among
those using OAC prior to cardioversion. After adjustment for
risk factors included in CHA2DS2-VASc, the odds ratio
(OR) for thromboembolic complications within 30 days after
cardioversion was 2.54 (p < 0.001) for patients without anti-
coagulation, compared to patients with anticoagulation. !
Among 8981 patients (mean age, 65 years; 42% male)
admitted to the hospital with a diagnosis of AF, over a mean
follow-up of 46 months, the CHA2DS2-VASc score was an
independent prognostic marker of poor outcomes following
hospitalization [35]. Specifically, mortality rates of patients
with CHA2DS2-VASc scores of 0, 1, and ≥2 were 23.2,
42.3, and 54% for total population, and 21.5, 41.4, and
54.2% for those without rheumatic heart disease respec-
tively. By multivariate analysis, a high CHA2DS2-VASc
score and the presence of chronic kidney disease were
among the worst prognostic factors. Compared to
CHA2DS2-VASc 0, a CHA2DS2-VASc 1 had a hazard ratio
of 1.33 and a CHA2DS2-VASc of 2 a hazard ratio of 1.50
for death after AF hospitalization [35]. !
CHA2DS2-VASc 0-1!
A CHA2DS2-VASc score of 0 has been considered to
predict a truly low incidence of stroke, with an annual
4 Current Drug Targets, 2017, Vol. 18, No. 5 Manolis et al.
ischemic stroke rate of approximately 1% [36]. More spe-
cifically, a CHA2DS2-VASc score of 0 identified a cohort at
low, albeit non-negligible, risk with annual event rates at 1-,
5-, 10-, and 15-year follow-up examinations of 1.06, 1.00,
1.09, and 1.15 per 100 person-years, respectively [36]. Other
studies have also shown low, but non-zero, stroke risk with a
CHA2DS2-VASc score of 0 (Table 2). A nationwide Danish
cohort study validating the CHA2DS2-VASc score indicated
that among 73,538 patients with non-valvular AF, the rate of
thromboembolism per 100 person-years was 0.78 in patients
at "low risk" (score = 0) at one year's follow-up [11]. In an-
other study comprising 39,400 patients discharged with inci-
dent nonvalvular AF with 0 or 1 CHA2DS2-VASc risk fac-
tor (23,572 not treated, 5,353 placed on aspirin, and 10,475
on warfarin), stroke event rates for untreated low-risk pa-
tients with a CHA2DS2-VASc score of 0 (male) or 1 (fe-
male) were 0.49 per 100 person-years at 1 year and 0.47 per
100 person-years at full follow-up (mean 5.9 years) [30].
The problem with the newer CHA2DS2-VASc score, as
was with its predecessor, relates to the fact that it was vali-
dated in different patient populations, leading to markedly
different estimated stroke risks [37]. Nevertheless, as men-
tioned, the data indicate that CHA2DS2-VASc score better
stratifies AF patients who are truly low-risk (score of 0 for
male or 1 for female) who should not be offered anticoagula-
tion as the risks outweigh the benefits. However, th ese data
emanate mostly or exclusively from studies utilizing VKAs
(Tables 1 & 2) [32]. Some data indicate that the strategy for
thromboprophylaxis may need to be different for male AF
patients with no additional risk factors (CHA2DS2-VASc
score 0) from the one needed for female patients with no
additional risk factors who though have a CHA2DS2-VASc
score of 1 (solely attributable to female gender) [38]. Al-
though the former group appear to be of truly low risk, the
latter group may be of much higher stroke risk. !
CHA2DS2-VASc 1 IN WOMEN
Although there is universal agreement that AF women
over 65 years (CHA2DS2-VASc score 2) with no additional
risk factors have a higher risk than their male counterparts
(CHA2DS2-VASc score 1), [39] there is dispute whether
younger (<65 years) women with no other risk factors
(CHA2DS2-VASc score 1) still have a higher risk than men
(CHA2DS2-VASc score 0). In a study comprising 509 males
(CHA2DS2-VASc score 0) and 320 females (CHA2DS2-
VASc score 1) with AF not receiving OAC therapy, the
event rate did not differ between groups with and without AF
for male patients (1.6% vs 1.6%; P=NS) [38]. In contrast, AF
was a significant risk factor for ischemic stroke among fe-
males (hazard ratio, 7.77), with event rates of 4.4% and 0.7%
for female patients with and without AF (P=0.001). Among
358 Chinese AF patients with CHA2DS2-VASc score of 1,
105 female patients had > 2-fold higher risk of stroke (haz-
ard ratio of 2.3) compared with 190 patients with
CHA2DS2-VASc score of 0. !
A higher risk of stroke and mortality over a median of
~15 years has also been confirmed for 1011 women (2.9%)
who developed AF among 34,722 women aged > 45 years
participating in the Women’s Health Study who were free of
AF and cardiovascular disease at baseline [40]. Women who
developed AF compared with those who did not, had higher
incidence rates of all-cause mortality per 1000 person-years
Table 2. Thromboembolic event rates in AF patients with CHA2DS2-VASc score of 0.
Study!
Patients/Group (n/N)!
Gender!
Annual Event Rate!
OAC!
NOAC!
Poli 201 1 [42]!
12/662!
Male!
0%!
√!
--!
Olesen 2011 [11]!
6,369/73,538!
Male!
0.78%!
--!
--!
Friberg 2012 [43]!
5,538/90,706!
Male!
0.2%!
-- / √!
--!
Taillandier 2012 [55]!
616/8,962!
Male!
0.69%!
-- / √!
--!
Singer 2 013 [44]!
NR/10,927!
Male!
0.04%!
--!
--!
Huang 2014 [29]!
190/9,727!
Male!
2.4%!
--!
--!
Chao 2014 [36]!
9,416/186,570!
Male!
1.06%!
--!
--!
Lip 2014 [45]!
20,851/72,452!
Male!
1.13%!
--!
--!
van den Ham 2015 [46]!
4000/60,594!
Male!
0.38%!
--!
--!
Abumuaileq 2015 [18]!
67/1,065!
Male!
0%!
√!
--!
Lip 2015 [47]!
NR/22,582!
Male!
1.13%!
--!
--!
Lip 2015 [30]!
12,685/39,400!
Male!
0.49-0.88%!
--/√!
--!
Chao 2016 [9]!
9,416/186,570!
Male!
1.15%!
--!
--!
Aspberg 2016 [77]!
12,266/152,153!
Male!
0.4%!
--!
--!
Chan 2016 [49]!
27,521/190,210!
Male!
1.18%!
--!
--!
Dispensing with the Risk Stratification Schemes in AF? Current Drug Targets, 2017, Vol. 18, No. 5 5
(10.8 vs 3.1), cardiovascular (4.3 vs 0.57) and noncardiovas-
cular mortality (6.5 vs 2.5). In multivariable models, hazard
ratios (HRs) of new-onset AF for all-cause, cardiovascular,
and noncardiovascu lar mortality were 2.14, 4.18, and 1.66,
respectively. Adjustment for nonfatal cardiovascular events
potentially leading to death attenuated these risks, but inci-
dent AF remained associated with all mortality components
(all-cause: HR, 1.70; cardiovascular: HR, 2.57; and noncar-
diovascular: HR, 1.42). Among women with paroxysmal AF
(n=656), the increase in mortality risk was limited to cardio-
vascular causes (HR, 2.94), raising the possibility that indi-
viduals with paroxysmal AF may have a lower mortality risk
than those with other AF patterns (persistent or permanent).
Thus, newly identified AF in apparently healthy women,
initially free of any risk factor, portends a worrisome prog-
nosis and should be treated aggressively with OAC therapy
which is known to reduce stroke and mortality risk, as there
is no reliable way to apriori identify those who will not sub-
sequently develop cardiovascular risk factors and will thus
continue remaining at low risk. !
Somewhat contrasting findings came from a Swedish co-
hort study of 100,802 patients with AF followed-up for a
median 1.2 years. Women with AF had a moderately in-
creased risk of stroke compared with men (6.2% vs 4.2% per
year; hazard ratio 1.47, P<0.0001), and thus, female gender
should be considered when making decisions about antico-
agulation treatment [41]. However, women younger than 65
years and without other risk factors ("lone atrial fibrillation")
had a low risk for stroke similar to men (0.7% vs 0.5%,
P=0.09), and thus inevitably one may argue that they may
not need anticoagulant treatment, at least when considering
VKA therapy. !
In the 2010 ESC guideline, female gender was designated
as a ‘clinically relevant non-major’ risk factor and the guide-
line recommended OA C (preferred) or aspirin [28]. How-
ever, in the 2012 ESC guideline update, female gender alone
as a single risk factor (still a CHA2DS2-VASc score of 1) is
ascribed a hazard ratio of 1.17 for thromboembolic event and
OAC is not recommended if they clearly fulfil the criteria of
“age < 65 and lone AF” [22]. The 2014 American guideline
for nonvalvular AF and a CHA2DS2-VASc score of 1 (not
discerning men from women) recommends to consider no
antithrombotic therapy or treatment with OAC or aspirin
(class IIb) [23]. The 2014 Canadian guideline stated that
“female sex should not factor into antithrombotic therapy
selection because of the low associated stroke risk and the
nonsignificant hazard ratio compared with men”. Similarly,
the most recent 2016 ESC guidelines, although they adopt
the CHA2DS2-VASc score, they do not accept female gen-
der as a risk factor recommending no anticoagulation in the
absence of any other risk factor, which is really an oxymoron
as they continue assigning 1 point in their tabular display of
the risk score for female gender (!) [26]. !
CHA2DS2-VASc 1 (MEN < 65 YEARS WITH 1 RISK
FACTOR OR >65 YEARS BUT <75 YEARS WITH NO
OTHER RISK FACTOR/ WOMEN <65 YEARS WITH
NO OTHER RISK FACTOR)
It appears that evidence is accumulating that patients
(men or women) with a CHA2DS2-VASc score of 1 are at a
risk of stroke justifying the use of OAC therapy, preferably
with a NOAC (Table 1) [4, 9, 11, 15, 18, 29-31, 36, 42-49].
In a Swedish Register comprising 182,678 patients with AF
who were studied for an average of 1.5 years, patients with a
CHA2DS2-VASc score of 1 had a net clinical beneft when
treated with warfarin [43]. According to a modelling analysis
based on nationwide cohort study, in patients with
CHA2DS2-VASc score of 1, apixaban and both doses of
dabigatran (110 mg and 150 mg bid) had a positive net clini-
cal benefit [50]. Thus, particularly for men, based on clinical
significance of age > 65 years as a risk factor, use of OAC is
recommended for AF patients who are aged >65 years with
no other risk factor [4, 8, 22, 24, 51] (www.nice.org.uk/
guidance/cg180). Of course, this also holds true for women
aged > 65 years, who by definition have a CHA2DS2-VASc
score of 2. The risk of thromboembolism increases with in-
creasing age > 65 years, [52] rising approximately 1.5-fold
per decade [53]. !
The issue of the need for OAC therapy remains contro-
versial for women with AF aged <65 years who have a
CHA2DS2-VASc score of 1 by definition because of their
gender and no other risk factor. However, as already alluded
to, evidence is emerging that this group of patients still re-
mains at higher risk for ischemic events than non-AF female
patients [11, 38]. Indeed in a Taiwanese cohort of 320 AF
females younger than 65 years, over a mean follow-up of 4.5
years, the stroke risk was 4.4% vs 0.7% in 3200 non-AF fe-
males (p<0.001) [38]. In a Danish population this risk was
lower, but still at 1.24% at one year for hospital admissio n
and death due to thromboembolism per 100 person years
[11]. This high event rate in females with AF supports the
recommendation that thromboprophylaxis is still necessary
for patients who have only 1 risk factor (female gender) of
the CHA2DS2-VASc scoring scheme [11, 28, 38]. !
Recent data indicate that in the patient category with only
one additional stroke risk factor beyond gender (i.e.
CHA2DS2-VASc= 1 in males or 2 in females), rates of ma-
jor adverse events may still be high (stroke/systemic throm-
boembolism 0.9/100 patient-years, all-cause death 1.6/100
patient-years and composite outcome of stroke/systemic
thromboembolism/all-cause death 2.3%/100 patient-years),
despite anticoagulation, attributable to poor quality time in
therapeutic range (TTR), [31] indirectly favoring the use of
NOAC. !
Thus, among those patients previously considered low-
risk patients, i.e. those aged younger than 65 years with no
stroke risk factors (a CHA2DS2-VASc score of 0 for males
or 1 for females), recent data seem to separate females as-
cribed a CHA2DS2-VASc score of 1 as intermediate risk and
tend to recommend OAC therapy, but with th e provision that
NOAC may be the preferred approach [50, 54]. There remain
the male AF patients aged <65 years with no other risk fac-
tors as “truly low-risk” patients whom we may afford not to
treat with anticoagulation. The question remains, is this
really true and prudent in the era of NOACs?!
CHA2DS2-VASc 0 (MEN < 65 YEARS WITH NO RISK
FACTOR)
Male patients aged <65 years with no risk factors may fi-
nally be the only group with a truly low risk that may not
need OAC. However, in the era of NOAC, this may be
6 Current Drug Targets, 2017, Vol. 18, No. 5 Manolis et al.
changing in the future. In the initial validation cohort, this
group had a thromboembolic risk of 0% at 1 year, [21] but
subsequent studies raised it higher, even up to 2.4% (Table
2) [9, 11, 29, 36, 45, 47, 49, 55]. !
Among patients with CHA2DS2-VASc score of 0, hence
very low risk of ischemic stroke, only those with moderately
elevated bleeding risk appear to have a net clinical disadvan-
tage from warfarin treatment (ie, 1.7%/year), [43] and this
may not prove to be so with NOAC therapy. Indeed, accord-
ing with this Swedish Register comprising 182 678 patients
with AF who were studied for an average of 1.5 years, in
almost all AF patients, the risk of ischemic stroke without
OAC treatment was higher than the risk of intracranial bleed-
ing with OAC treatment, the exception being only for pa-
tients at very low risk of ischemic stroke with a CHA2DS2-
VASc score of 0 and moderately elevated bleeding risk [43].
Patients with a CHA2DS2-VASc score of 1 in this study and
another cohort study had a net clinical beneft with either
warfarin or a NOAC [43, 50]. In general, according to 'real
world' data, when the risk of bleeding and stroke are both
high, NOACs appear to have a greater net clinical benefit
compared to warfarin [50, 56]. !
The threshold for initiating OAC treatment has been cal-
culated as a stroke rate of 0.9% per year, based on the bal-
ance of ischemic stroke reduction vs intracerebral bleeding
with the availability of NOACs [54]. It appears that almost
all AF patients with a CHA2DS2-VASc score of 1 belong to
this category (Table 1). The question remains whether this
also applies to AF patients with a CHA2DS2-VASc score of
0 (Table 2). !
Several observational studies of “lone” AF patients
(younger patients in whom AF develops in the absence of
any recognizable cardiac or other disease), comprising 10-
20% of all AF patients, showed that the prognosis of such
patients is favourable as long as they stay free of overt un-
derlying cardiac or other diseases and known clinical stroke
risk factors [57-60]. The CHA2DS2-VASc score by defini-
tion equals 0 in male “lone” AF patients and 1 in females
with ‘lone’ AF. Comorbidities that may develop subsequent
to the initial diagnosis can significantly modulate progres-
sion and complications of AF, with main problems relating
to age or development of hypertension which increase
thromboembolic risk. Importantly, baseline risk stratification
score is not predictive for thromboembolism in these patients
[58].
Thus, although “lone” AF patients were initially thought
to have a good prognosis with reg ards to thromboembolism
and mortality, compared with the general AF population, a
closer look at some old data and emerging more recent data
suggest otherwise [61-63]. Such contradicting results ini-
tially came from the Paris Study I in 25 middle-aged (42-53
years) Frenchmen with idiopathic AF, who were followed-up
for a period of 23 years [61]. Idiopathic AF in this group was
associated with higher mortality, with a relative risk of 4.22
for cardiovascular mortality (P=0.0001) and 1. 97 for total
mortality (P=0.01). When age, systolic blood pressure, cho-
lesterol, body mass index and tobacco consumption were
entered into a Cox model, idiopathic AF remained an inde-
pendent risk factor for cardiovascular (P=0.0008) and total
death (P=0.04) [61]. Although this entity of “lone” or “idio-
pathic” AF is currently disputed, [64] it is usually a diagnosis
of exclusion. However, conditions that are increasingly rec-
ognized over the recent years as associated with AF, such as
obesity, [65] sleep apnea, [19] alcohol intake, exercise and
sports activity, [66] or genetic factors make the exclusion
diagnosis of “lone AF” more complicated [67, 68].
According to the current guidelines, “lone” AF patients
do not need any long-term thromboprophylaxis, but regular
clinical re-assessment of stroke risk is mandatory [22, 59].
Other arrhythmias, such as regular supraventricular tachy-
cardias, that may trigger AF should b e considered in some,
particularly young, patients, in whom ablation of the tachy-
cardia may also abolish AF recurrences [69]. !
According with a Danish nationwide cohort study com-
prising 73,538 AF patients not treated with OAC, in patients
at “low risk” (CHA2DS2-VASc score=0), the rate of throm-
boembolism per 100 person years was 0.78 (0.58 to 1.04) at
one year’s follow-up [11]. !
In a Swedish nation-wide, retrospective, cohort study,
9,519 patients diagnosed with incidental “lone” or “idio-
pathic” AF (31% women) were compared with 12,468
matched controls [62]. Relative risks (RR) versus controls
for stroke or TIA in women were 19.6 (age <55 years), 4.4
(55-64 years), 3.4 (65-74 years) and 2.5 in the age category
75−85 years; corresponding figures for men were 3.4, 2.5,
1.7 and 1.9. Relative risks (RR) for heart failure were 6.6,
6.6, 6.3 and 3.8 in women and 7.8, 4.6, 4.9 and 2.9 in men.
All RR were statistically significant with p < 0.01. RR for
myocardial infarction and all-cause mortality were statisti-
cally significantly increased only in the two oldest age cate-
gories in women and 65−74 years in men. The authors con-
cluded that patients with AF and no co-morbidities at inclu-
sion had at least a doubled risk of stroke or TIA and a tripled
risk of heart failure, through all age categories, as compared
to controls. Women were at higher RR of stroke or TIA than
men. !
More data that are worrisome for “lone” AF come from a
most recent analysis of the Framingham Heart Study, whereby
the risk of cardiovascular outcomes and mortality among indi-
viduals with AF without comorbidities was lower than typical
AF, but was significantly higher compared with matched indi-
viduals without AF [63]. Among 1,961 AF patients of 10,311
participants, 173 individuals had AF without comorbidities
(47% women, mean age 71±12 years; prevalence of 1.7% of
the entire cohort, annual incidence of 0.5 per 1000 person-
years). During a median follow-up of 9.7 years after initial
AF, mortality (HR 0.67, P < 0.001) and total cardiovascular
events (HR 0.66, P < 0.001) were significantly lower in this
group compared with typical AF, albeit higher than age-, gen-
der-, and cohort-matched individuals without AF (mortality:
HR 1.43, P < 0.001; risk of total cardiovascular events : HR
1.73, P < 0.001) [63]. The investigators of this study demon-
strated that AF without recognized comorbidities had worse
clinical outcomes than individuals without AF, refuting the
conviction that “lone” AF is a benign condition. Hence, these
patients should not be deprived of effective management
strategies regarding OAC treatment, based only on their pre-
sumed low risk as deduced by any stratification scheme, in-
cluding the most recent and most broadly applied, the
CHA2DS2-VASc score. Indeed, literature suggests that AF,
even in the absence of other comorbidities, remains associated
with higher mortality and cardiovascular outcomes, with up to
Dispensing with the Risk Stratification Schemes in AF? Current Drug Targets, 2017, Vol. 18, No. 5 7
four-fold increase in stroke, four-fold increase in cardiovascu-
lar death rate, and two-fold higher risk for overall adverse
cardiovascular outcomes than the general population without
AF [61]. This was further corroborated by the nationwide
Swedish study population, detailed above, whereby patients
with AF and no co-morbidities at inclusion had at least a dou-
bled risk of stroke or TIA as compared to controls, with
women being at higher relative risk of stroke or TIA than men
[62]. Finally, in a systematic review and metaanalysis of 6
cohort studies, among 1774 patients with CHA2DS2-VASc
score of 0, there were still 45 (2.5%) ischemic
stroke/thromboembolic events during follow-up [10].
In summary, despite prior encouraging reports, AF pa-
tients initially presenting with no comorbidities (hence
CHA2DS2-VASc score of 0 in males and 1 in females when
aged <65 years) do not seem to fare well during follow-up
compared with individuals without AF, and according with
more recent data, these individuals are at higher risk for
stroke and other cardiovascular events and total death. Thus,
we can no longer assume that these patients will have a be-
nign course. Some emerging data regarding female patients
appear to receive some acceptance of their moderate risk and
many clinicians consider OAC therapy, particularly with the
safer use of NOACs. However, due to lack of current guide-
line recommendations for OAC therapy for men aged <65
years and CHA2DS2-VASc score of 0, our approach to this
group should at least be individualized (Fig. 1) and close and
regular follow-up should be undertaken.
!
* includes also AF patients with valvular heart disease, other than those with valvular prosthesis or rheumatic mitral valve disease (moderate-
to-severe mitral stenosis)!
** bleeding risk assessment not to deter OAC but in order to modify bleeding risk factors. Short-term anticoagulation should always be con-
sidered before and after cardioversion irrespective of the risk score (see text for discussion)!
†SAMe-TT2R2 score : Sex female, Age < 60 years, Medical history with >2 comorbidities, Treatment with interacting drugs, eg, amiodar-
one, Tobacco use [doubled], Race [doubled])!
Fig. (1). A proposed algorithm to guide oral anticoagulation therapy in patients with atrial fibrillation (AF) with emphasis on an
individualized and shared decision-making strategy, at least for the “low-risk” patients.
N.B.: A general compass fo r individual management decision-making may rely for now on a Markov state transition decision model analysis
suggesting that OAC (VKA or NOAC) therapy should be considered for all patients with a stroke risk >1.7% per year (which appears to be
the case for the majority of patients with a CHA2DS2-VASc score >1), whereas treatment with the safer NOACs should be considered for
patients with a stroke risk >0.9% per year (which appears to include several patients with CHA2DS2-VASc score 1 or even 0, see Tables 1 &
2) [54]. The calculation of this latter threshold for initiating OAC treatment (stroke rate of 0.9% per year) is based on the balance of ischemic
stroke reduction vs intracerebral b leeding with th e availability of NOACs. !
CRI = chronic renal insufficiency; ETOH = ethanol; FU = follow-up; LA = left atrium; LAA = left atrial appendage; NOAC = non-vitamin K
oral anticoagulant; OAC = oral anticoagulant; OSA = obstructive sleep apnea; RF = risk factor; SEC = spontaneous echo contrast; VKA =
vitamin K antagonist.!
8 Current Drug Targets, 2017, Vol. 18, No. 5 Manolis et al.
OTHER RISK FACTORS / OTHER SCORES!
In addition to the risk factors included in the CHA2DS2-
VASc score, investigators have sorted out and studied sev-
eral other risk factors and comorbidities documenting their
close association with AF and its attendant risks and compli-
cations. Th ese factors also relate to the fundamental mecha-
nism of thrombosis, as described by Virchow, the three
broad categories of factors that are thought to contribute to
thrombosis, i.e. hypercoagulability, hemodynamic changes
(stasis, turbulence) and endothelial injury/dysfunction. Such
factors may include obesity, obstructive sleep apnea,
impaired renal function, structural left atrial and left atrial
appendage (LAA) abnormalities, blood or metabolic
abnormalities, tobacco use, and perhaps heavy AF burden or
permanent AF [12-14, 17-19, 46, 65, 70, 71]. As is the case
with the CHA2DS2-VASc score, [51] it is possible that any
single risk factor may confer thromboembolic risk, and if left
untreated, patients with AF may be exposed to a disabling
stroke or fatal event. !
Ethnicity may be an important caveat in risk stratifying
patients. According to a Taiwanese study comprising
186,570 non-anticoagulated AF patients, those aged 50 to 64
years had an annual ischemic stroke risk of 1.78% compared
to a 0.53% stroke risk for AF patients <50 years of age [72].
The authors wondered whether resetting the age threshold
from <65 years to <50 years old could refine current clinical
risk stratification for Asian AF patients. !
With regards to obesity as a risk factor for AF patients,
overweight and obesity have been shown to be independ-
ently associated with increased AF risk in a cohort of 18,290
individuals [73]. Among 3135 patients (2025 men and 1110
women) who developed incident AF during follow-up in the
Danish Diet, Cancer and Health study, overweight and obe-
sity were risk factors for "ischemic stroke, thromboembolism
or death", even after adjustment for CHADS2 and
CHA2DS2-VASc scores (hazard ratio 1.3-1.5) [74]. Multi-
variate analysis in a study comprising 1286 AF Chinese
patients (males, 78%; mean age, 74.50 years; 94%
paroxysmal AF; only 13% receiving OAC), followed up for
a median of 2.1 years, showed that overweight (25≤BMI<30
kg/m2) and age ≥75 years were independent risk factors for
ischemic stroke (both P<0.01) [65]. However, when such
patients are being anticoagulated, the “obesity paradox”
phenomenon may be observed, i.e. being overweight or
obese is associated with a lower risk of adverse outcomes
[75]. Concerning sleep apnea, patients w ith AF are more
likely to have sleep apnea and vice versa [19]. AF is signifi-
cantly more common in the sleep apnea patients with stroke.
Significantly higher rates of stroke have been reported in AF
patients with CHA2DS2-VASc scores of 0 and 1 and co-
morbid obstructive sleep apnea [76]. Impaired renal function
is an independent predictor of stroke in patients with
nonvalvular AF and inclusion of renal function in the risk
straification schemes has been suggested to improve stroke
risk stratification in patients with AF [12, 17]. !
Thus, aiming to improve upon thromboembolic risk pre-
diction, other scores than the CHA2DS2-VASc score, have
recently been proposed, such as R2CHADS2 and ATRIA,
which embed renal function as the additional parameter, but
found inferior to CHA2DS2-VASc score [18, 36] although
in other comparisons, the R2CHADS2 and ATRIA scores
outperformed the CHA2DS2-VASc score [46, 77, 78]. How-
ever, even in these studies, the low-risk groups (0 score) still
had a stroke rate of about 0.40-2.40 per 100 person-years
(Table 2), but not zero, as initially claimed [79]. !
Of course, there is a debate about the threshold at which a
patient should be treated with anticoagulation, whether this
should be <1.5% or <1%, etc. However, with the advent of
NOACs, this threshold may be lower compared to VKAs. !
Increased size of the left atrium (either by left atrial di-
mension or volume) has also been considered a risk factor
for a complicated course. Although left atrial enlargement is
not the direct cause of AF, stroke, heart failure, or death, it
has consistently been shown to be the common denominator
for the pathophysiologic cascade that leads to AF, [80-82]
stroke, [83-85] heart failure, [86] and death [87]. Left atrial
fibrosis detected by magnetic resonance imaging has also
been proposed as a marker of stroke [70]. !
The morphology of the left atrial appendage (LAA) has
been reported as closely related to the thromboembolic risk.
When categorized into 4 types (cactus, chicken wing, wind-
sock, and cauliflower) by cardiac imaging (computed tomo-
graphy and/or magnetic resonance imaging), patients with
the “chicken wing” LAA morphology have a lower throm-
boembolic risk, while patients with a “cauliflower” LAA had
a higher stroke rate [14, 88]. Particularly, the LAA morphol-
ogy might be best utilized to predict stroke risk in patients
with a low CHA2DS2-VASc score [14]. !
In summary, all risk stratifications schemas applied to AF
patients have modest predictive ability for thromboem-
bolism, [42] with the CHA2DS2-VASc score currently pre-
vailing. However, due to the limitations of the CHA2DS2-
VASc score being slowly but increasingly appreciated, other
investigators have suggested that additional factors should b e
considered in those patients with a CHA2DS2-VASc score
of 0 in men or 1 in women, such as obstructive sleep apnea,
renal function impairment, left atrial thrombus or other echo-
cardiographic indices of thromboembolic risk, biochemical
thromboembolic biomarkers (uric acid, lipids, D-dimer,
BNP/NT-proBNP, vWF) or other risk factors (dyslipidemia,
smoking, etc) [13]. If many or one strong additional throm-
boembolic risk factor factor is present, then they suggest to
consider anticoagulation therapy, preferably with a NOAC. !
TYPE OF AF / CARDIOV ERSION!
The types of AF, paroxysmal vs permanent, or the fre-
quency and/or burden of paroxysmal AF, have not been
clearly shown to influence the decision on the need for OAC
therapy. Ischemic stroke is about as common in paroxysmal
AF as in permanent AF [89]. However, some studies have
indicated that the rate of thromboembolic events may be
higher in permanent nonvalvular AF than in paroxysmal AF
[40, 90-92]. Data analysis from two cohorts of patients en-
rolled in the SPORTIF III and V clinical trials (n = 7329),
the annual event rates for stroke/systemic embolic events
were 1.73% for persistent (n=6,493) and 0.93% for parox-
ysmal (n=7,329) AF (hazard ratio - HR 1.87; P = 0.037)
[91]. In the ARISTOTLE study, the rate of stroke or sys-
temic embolism was significantly higher in patients with
Dispensing with the Risk Stratification Schemes in AF? Current Drug Targets, 2017, Vol. 18, No. 5 9
persistent or permanent (n=15,412) than patients with parox-
ysmal (n=2,786) AF (1.52 vs. 0.98%; P = 0.003, adjusted P =
0.015) [92]. There was also a trend towards higher mortality
in patients with persistent or permanent AF (3.90 vs 2.81%;
P = 0.0002, adjusted P = 0.066). Furthermore, there are data
indicating th at high AF burden as in non-paroxysmal AF
may confer a higher risk of dementia [93]. According to the
results of a primary care cohort study (AFBAR), among 778
patients, change of AF status from single episode (18 pa-
tients) or r ecurrent (58 patien ts) to permanent AF, observed
in 76 patients (9.8%) over a mean of ~6 years, was an impor-
tant prognostic marker for death or hospital admissions (haz-
ard ratio - HR 1.41) [94]. High-burden AF (>10%) has been
associated with progressive left atrial structural remodeling
and disease progression, [95] suggesting that AF by itself
appears to be a key causative factor in the progression of
atrial remodeling in humans (“AF begets AF”), independent
of other known factors including hypertension, obesity, and
diabetes. This may have some therapeutic implications,
compelling us to monitor our patients with early-onset AF
for disease progression using newer echocardiography tech-
niques, and to consider early interventions via ablation [95,
96] and/or anticoagulation. !
One important parameter that needs to be taken into ac-
count is planning cardioversion (CV) for an AF patient,
whereby the evidence shows that even in low-risk patients
according to CHA2DS2-VASc score, strokes occur in pa-
tients not using anticoagulation before CV, and these typi-
cally occur 2-3 days after successful CV [97]. Unsuccessful
CV is also not without risk for thromboembolism, since later
spontaneous CVs may occur. Significant proportion of these
strokes are observed in relatively young patients with a low
CHA2DS2-VASc score supporting the view that at least
short-term anticoagulation should always be considered be-
fore and after CV. Another study comprising over 3000 pa-
tients indicated that short-term anticoagulation should be
considered also for patients with a low CHA2DS2-VASc
score especially if the delay to cardioversion is >12 hours to
prevent thromboembolic complications [98, 99]. A delay to
CV of >12 hours from symptom onset was associated with a
greater risk of thromboembolic complications (1.1%); when
the duration of AF was <12 hours, the risk of thromboem-
bolism was low (0.3%) without anticoagulation. Some data
indicate that in order to minimize thromboembolic risk for
patients receiving a VKA, the INR should be >2.5 at the time
of CV scheduled to be performed at >3 weeks after initiating
VKA therapy for an episode of AF of unknown or longer
than 2-day duration [100]. !
In summary, some data indicate that the rate of throm-
boembolic events may be higher in permanent than in parox-
ysmal AF, while high-burden AF has been associated with
progressive left atrial structural remodeling and disease pro-
gression. Also, there is a suggestion that for those receiving a
VKA and undergoing elective CV after >3 weeks of OAC,
the INR should be 2.5-3.0 at the time of CV to minimize the
risk of stroke. Finally, the most recent 2016 ESC guidelines
recommend immediate initiation of anticoagulation with
heparin or a NOAC in all patients scheduled for CV; among
patients with AF <48 hours, after successful CV, those with-
out risk factors should continue OAC for 4 weeks, while
those with risk factors indefinitely [26]. Those who have
been in AF for >48 hours should start OAC at least 3 weeks
before CV; all cardioverted AF patients should continue
OAC for 4 weeks afterwards (in patients without a need for
long-term OAC), while OAC should be continued indefi-
nitely in patients at risk of stroke as stratified by the
CHA2DS2-VASc score. Although early CV can be per-
formed without transesophag eal echocardiography (TEE) in
patients with a definite duration of AF <48 hours, TEE is
recommended to exclude cardiac thrombus as an alternative
to preprocedural anticoagulation when early (<3 weeks of
OAC) CV is planned.!
SURVEYS!
Most surveys r eport the problem of undertreatment in AF
patients regarding OAC therapy [101-104]. Overtreatment
has also been reported by applying contemporary guideline
criteria. The GARFIELD-AF Registry (2013) revealed OAC
use in those at low-risk (CHA2DS2-VASc=0), with 38.7%
receiving anticoagulant therapy, although some of these may
have been taking an anticoagulant for indications other than
stroke prevention [104]. According to a study presenting the
Asian agenda (2015), only 20% of AF patients with
CHA2DS2-VASc=0 were not receiving any antithrombotic
therapy, while 9% were receiving warfarin, 6% warfarin plus
antiplatet drug, 2% a thrombin inhibitor and 63% antiplatelet
therapy [105]. According to a Swedish population-based
register study of all 13,837 patients with incident non-
valvular AF diagnosed during 2011–2014, guideline adher-
ence increased from 47.6% in 2011 to 66.1% in 2014, mostly
due to decrease in undertreatment [106]. NOAC uptake in-
creased from 2.1% to 25.1%. Overall, 47.4% of patients with
CHA2DS2-VASc score ≥ 2 did not receive OAC. Under-
treatment was particularly common in women < 65 years
(55.8%) and in patients > 84 years (65.3% in women and
62% in men). Overtreatment of patients at low stroke risk
was ~36% in both men and women. More specifically, men
(n=245) with CHA2DS2-VASc=0 received aspirin (6.5%),
warfarin (24.1%) or NOAC (5.3%); women (n=151) with
CHA2DS2-VASc=1 received aspirin (7.9%), warfarin
(17.2%) or NOAC (11.3%). !
In a large US cohort of young (<60 years) and healthy
outpatients with AF (no structural heart disease) who were at
the lowest risk of stroke treated by cardiovascular specialists,
approximately 25% of patients were prescribed OAC ther-
apy; particularly, 23.3% patients with a CHADS2 score of 0
and 26.6% of those with a CHA2DS2-VASc score of 0 were
prescribed an OAC [107]. In multivariable analysis of the
cohort of patients with a CHA2DS2-VASc score of 0, older
age (adjusted RR, 1.44 per 10 years; P < .001), and higher
body mass index (adjusted RR, 1.19 per 5 kg/m2; P < .001)
were associated with a higher likelihood of being pre-scribed
oral anticoagulants. !
According to a recent Canadian national chart audit of
7,019 patients with nonvalvular AF, in patients on warfarin,
30.9% had not achieved a time in therapeutic range (TTR)
>65% and, despite guideline recommendations, were contin-
ued on warfarin rather than NOACs [108]. In patients who
received no antithrombotic therapy, 65.5% met criteria for
treatment with an OAC, while 62.8% of patients who were
treated with aspirin met guideline criteria for the use of an
10 Current Drug Targets, 2017, Vol. 18, No. 5 Manolis et al.
OAC. Among 19,613 Australian patients with AF, approxi-
mately 20% with CHA2DS2-VASc-scores=0 were over-
anticoagulated [109].
In summary, despite national and international guide-
lines, all recognizing high-risk AF patients that definitely
need OAC and also low-risk patients who may not need
OAC, under- and/or over-treatment still takes place. How-
ever, it is curious that even patients at the lowest possible
risk (CHA2DS2"VASc-scores=0) are still receiving OAC
therapy at rates ranging from 17% to 39%, as if many physi-
cians in the real world practice regard any patient with AF as
being at risk for thromboembolic event. When considering
antithrombotic therapy with antiplatelet agents, these rates
culminate up to 80%! These rates may increase in the future
with a wider adoption of NOACs as a safer and more con-
venient antithrombotic therapy. !
RISK OF BLEEDING!
International guidelines recommend that bleeding risk
should not be a reason to withhold OAC in AF patients at
even modest stroke risk [22-24, 26]. The stroke reduction
benefit of OAC in AF patients outweighs the increased risk
of major bleeding, even among those patients with history of
bleeding [110]. Nevertheless, a history of bleeding identifies
a higher bleeding risk, but such history should not deter one
from considering OAC but rather prompt for potential modi-
fication of future bleeding risk by addressing correctable or
modifiable bleeding risk factors [111]. According to the
HAS-BLED score, this may be carried out by optimizin g
blood pressure therapy (“H”), avoiding nonsteroidal anti-
inflammatory drugs [112] and limiting concomitant anti-
platelet therapy (“D”), and minimizing the lability of INR in
patients on warfarin (“L”), which could alternatively be man-
aged by preferential use of a NOAC over warfarin [113]. !
NON-VITAMIN K ANTAGONISTS (NOACs)!
The availability of the NOACs (dabigatran, rivaroxaban,
apixaban, endoxaban) has changed the landscape of stroke
prevention in AF [20, 114, 115]. The new oral anticoagulants
have a favourable risk-benefit profile, with significant reduc-
tions in stroke, intracranial hemorrhage, and mortality, and
with similar major bleeding as with warfarin, but increased
gastrointestinal (GI) bleeding.(20) However, even among the
different NOAC agents, some may confer a lower GI bleed-
ing risk. In the ARISTOTLE trial, the beneficial effects of
apixaban over warfarin for stroke, hemorrhagic stroke, death,
or major bleeding remained consistent with fewer events
regardless of history of bleeding [110]. Also, a most recent
network meta-analysis showed a difference even among the
four NOAC agents with regard to the bleeding risk, again
with apixaban reporting the most favourable profile; apixa-
ban had a significantly reduced bleeding risk compared with
dabigatran (relative risk-RR 0.42) and rivaroxaban (RR 0.23)
[116]. !
Indeed, in the era of VKAs, in an attempt to maintain a
balance between ischemic stroke reduction with OAC
against increased risk for intracranial hemorrhage, it had
become a dogma that low-risk patients were considered
those with thromboembolism rates <1%/year who did not
need any OAC therapy, and the CHA2DS2- VASc score has
been shown to be clearly superior to initial CHADS2 score
in iden tifying “truly low-risk” patients with thromboem-
bolism rates <1%/year not needing anticoagulation [117,
118]. !
In the current era of NOACs, a different approach may
need to be adopted. One may either opt for use of a NOAC
considering this a safer, albeit a more expensive, approach,
or use some guidance as to potential use of a VKA agent. It
has been shown that adequate (>70%) individual time in
therapeutic range (TTR) of the INR (2.0-3.0) (ie, optimal
anticoagulation control) is associated with low stroke and
bleeding risks. A new score has been proposed to assist in
this decision by apriori assessing the SAMe-TT2R2 score
(Sex female, Age < 60 years, Medical history with >2 co-
morbidities, Treatment with interacting drugs, eg, amiodar-
one, Tobacco use [doubled], Race [doubled]) [31, 119].
Those patients with a SAMe-TT2R2 score <2 can apparently
be managed effectively with a VKA, whereas patients with a
SAMe-TT2R2 score >2 can be offered a NOAC. Another
simpler approach may be an option in the future by placing
every patient on a NOAC, which will provide optimal
ischemic stroke protection with a v ery low bleeding risk .
However, as the evidence for such a universal strategy is not
yet available, one may follow an individualized approach,
with a shared decision-making strategy, as the one recom-
mended in Figure 1. A recent European Heart Rhythm Asso-
ciation consensus document on patient values and prefer-
ences for their management articulates this principle of par-
ticipatory medicine very well with regards to critical ele-
ments of patient-physician discussion about OAC: “Ensuring
that patients understand why OAC is necessary, to reduce the
risk of stroke associated with AF, and the benefits and risks
of this treatment for them personally, are essential to enable
the patient to make an informed decision about whether or
not they want to take the medication that is recommended
and it can also increase the likelihood of adherence.” [120]. !
Guidelines selected the CHA2DS2-VASc score of 1
point for recommending anticoagulation, endorsing an ap-
proximate 1% per year stroke risk threshold, and considering
patients with a CHA2DS2-VASc score of 0 clearly as being
at low enough risk to forego OAC [22, 23]. !
A Markov state transition decision model analysis sug-
gested that VKAs may be preferable in patients with a stroke
risk >1.7% per year, whereas treatment with the safer
NOACs should be considered in patients with a stroke risk
>0.9% per year [54]. !
A recent systematic review and meta-analysis of 10 stud-
ies indicated that the summary estimate for the annual risk of
ischemic stroke was 1.61% for CHA2DS2-VASc score of 1,
meeting the theoretical threshold for using NOACs (0.9%),
but below the threshold for warfarin (1.7%) [121]. The
summary incident risk of ischemic stroke was 0.68% for
CHA2DS2-VASc score of 0 and 2.49% for CHA2DS2-
VASc score of 2. However, because of high heterogeneity in
these studdies, the authors recommended that the decisio n
should be based on individual patient characteristics. With
regards to apparently “truly low-risk” patients with
CHA2DS2-VASc 0, one may argue that an annual rate of
ischemic stroke of ~0.7% is still much higher than the risk of
intracranial hemorrhage (0.10% to 0.5%) reported in trials of
the NOACs: dabigatran, [122] rivaroxaban, [123] apixaban,
Dispensing with the Risk Stratification Schemes in AF? Current Drug Targets, 2017, Vol. 18, No. 5 11
[124] and edoxaban [125]. This will lead to more patients
receiving OAC therapy and more strokes being prevented, as
long as OAC therapy remains safe, as the case may be with
use of NOACs. !
A major limitation of the NOACs is their short half-life
and consequent rapid decline in anticoagulation activity
when doses are omitted. Hence a high degree of adherence to
NOACs is essential for reducing the risk of thromboem-
bolism in patients with nonvalvular AF. In a real-world
study, suboptimal adherence was reported to be around 30%,
and was associated with an increase risk of ischemic stroke
[126]. Nevertheless, the hypothesis that twice-daily dosing of
a NOAC might be “more forgiving” in the presence of
suboptimal adherence, was not confirmed, even though pa-
tients prescrib ed NOACs requiring twice-daily dosing were
less adherent than once-daily users. !
In summary, as major hemorrhages, particularly life-
threatening intracr anial bleeds, are reduced with use of
NOACs, the question arises, if due to the favourable side
effect profile of NOACs, the indication for oral anticoagula-
tion therapy should be broadened and expanded to almost all
patients with diagnosed AF. An important caveat relates to
patients with moderate-to-severe mitral stenosis or mechani-
cal heart valves who should remain on VKA therapy (INR
2.0–3.0 or higher) for stroke prevention, as NOACs have not
been shown to be protective in this patient group [26]. !
CONCLUSION!
The most dreaded complication of AF is a 5-fold in-
creased risk of ischemic stroke as compared to sinus rhythm
with its attendant dire consequences [127]. Hence, considera-
tion of thromboprophylaxis in every AF patient is mandatory
[28]. Rhythm control with either drugs or ablation does not
provide adequate protection due to asymptomatic or silent
AF episodes which may continue to occur [89, 128, 129].!
Non-vitamin K oral anticoagulants have been proven
equivalent or superior to VKAs in the treatment of non-
valvular AF, conferring protection from thromboembolic
events with lessened occurrence of intracerebral hemorrhage
[20, 114, 115]. This may be the impetus to generalize their
use in most, if not all, patients with nonvalvular AF regard-
less of their risk stratification score [130]. The accumulated
evidence appears compelling that at least those with a
CHA2DS2-VASc score of >1, should receive anticoagula-
tion therapy. With r egards to those w ith a CHA2DS2-VASc
score of 0, one may wish to consider additional risk factors
beyond those in scores to decide whether there is a need for
thromboembolic protection that outweighs the bleeding risk,
preferably with use of NOACs. Such factors may include
those proposed and outlined in Figure 1, until more data be-
come available from future studies that re-evaluate our
treatment strategies in these patients with use of NOACs.
Finally, an individualized strategy and clinical judgement
may be necessary by assessing patient’s clinical and finan-
cial status, preferences and choices in a shared decision-
making or participatory medicine approach.
LIST OF ABBREVIATIONS!
AF = Atrial fibrillation!
CV = Cardioversion!
LAA = Left atrial appendage!
NOACs = Non-vitamin K oral anticoagulants!
OAC = Oral anticoagulant(s)!
TEE = Transesophageal echocardiography!
TIA = Transient ischemic attack!
TTR = Time in therapeutic range!
VKAs = Vitamin K antagonists
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
Declared none.!
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(12): 857-67.
[2] Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY.
A novel user-friendly score (HAS-BLED) to assess 1-year risk of
major bleeding in patients with atrial fibrillation: the Euro Heart
Survey. Chest 2 010; 138(5): 1093-100.
[3] Shroff GR, Solid CA, Herzo g CA. Temporal trends in ischemic
stroke and anticoagulation therapy among Medicare patients with
atrial fibrillation: a 15-year perspective (1992-2007). JAMA Intern
Med 2013; 173(2): 159-60.
[4] Olesen JB, Lip GY, Lindhardsen J, et al. Risks of thromboem-
bolism and bleeding with thromboprophylaxis in patients with
atrial fibrillation: A net clinical benefit analysis using a 'real world'
nationwide cohort study. Thromb Haemost 2011; 106(4): 739-49.
[5] Atrial Fibrillation Investigators. 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(13): 1449-57.
[6] Albers GW. Atrial fibrillation and stroke. Three new studies, three
remaining questions. Arch Intern Med 19 94; 154(13): 1443-8.
[7] Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW,
Radford MJ. Validation of clinical classification schemes for pre-
dicting stroke: results from the National Registry of Atrial Fibrilla-
tion. JAMA 2001; 28 5(22): 2864-70.
[8] Olesen JB, Fauchier L, Lane DA, Taillandier S, Lip GY. Risk
factors for stroke and thromboembolism in relation to age among
patients with atrial fibrillation: the Loire Valley Atrial Fibrillation
Project. Chest 2012; 141(1): 147-53 .
[9] Chao TF, Liu CJ, Tuan TC, et al. Comparisons of CHADS2 and
CHA2DS2-VASc scores for stroke risk stratification in atrial fibril-
lation: Which scoring system should be used for Asians? Heart
Rhythm 2016; 13(1): 46-53.
[10] Xiong Q, Chen S, Senoo K, Proietti M, Hong K, Lip GY. The
CHADS2 and CHA2DS2-VASc scores for predicting ischemic
stroke among East Asian patients with atrial fibrillation: A sys-
temic review and meta-analysis. Int J Cardiol 2015; 195: 237-
42.
[11] Olesen JB, Lip GY, Hansen ML, et al. Validation of risk stratifica-
tion schemes for predicting stroke and thromboembolism in pa-
tients with at rial fibrillation: nationwide cohort study. BMJ 2011;
342: d124.
[12] Zeng WT, Sun XT, Tang K, et al. Risk of thromboembolic events
in atrial fibrillation with chronic kidney disease. Stroke 2015;
46(1): 157-63.
[13] Szymanski FM, Lip GY, Filipiak KJ, Platek AE, Hrynkiewicz-
Szyman ska A, Opolski G. Stroke Risk Factors Beyond the
CHA(2)DS(2)-VASc Score: Can We Improve Our Identification of
"High Stroke Risk" Patients With Atrial Fibrillation? Am J Cardiol
2015; 116(11): 1781-8.
12 Current Drug Targets, 2017, Vol. 18, No. 5 Manolis et al.
[14] Kimura T, Takatsuki S, Inagawa K, et al. Anatomical characteris-
tics of the left atrial appendage in cardiogenic stroke with low
CHADS2 scores. Heart Rhythm 2013; 10(6): 921-5.
[15] Chao TF, Liu CJ, Wang KL, et al. Should atrial fibrillation patients
with 1 additional risk factor of the CHA2DS2-VASc score (beyond
sex) receive oral anticoagulation? J Am Coll Cardiol 2015; 65(7):
635-42.
[16] Savino JA, 3rd, Halperin J L. Should Patients With Atrial Fibrilla-
tion and 1 Stroke Risk Factor (CHA2DS2-VASc Score 1 in Men, 2
in Women) Be Antico agulated? The CHA2 DS2-VASc 1 Conun-
drum: Decision Making at the Lower End of the Risk Spectrum.
Circulation 2016; 133(15): 1504-11.
[17] Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a
predictor of stroke and systemic embolism in patients with non-
valvular atrial fibrillation: validation of the R(2)CHADS(2) index
in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor
Xa inhibition Compared with vitamin K antagonism for prevention
of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA
(AnTicoagulation and Risk factors In Atrial fibrillation) study co-
horts. Circulation 2013; 127(2): 224-32.
[18] Abumuaileq RR, Abu-Assi E, Lopez-Lopez A, et al. Comparison
between CHA2DS2-VASc and the new R2CHADS2 and ATRIA
scores at predicting thromboembolic event in non-anticoagulated
and anticoagulated patients with non-valvular atrial fibrillation.
BMC Cardiovasc Disord 2015; 15: 156.
[19] Lipford MC, Flemming KD, Calvin AD, et al. Associations be-
tween Cardioembolic Stroke and Obstructive Sleep Apnea. Sleep
2015; 38(11): 1699-705.
[20] Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the
efficacy and safety of new oral anticoagulants with warfarin in pa-
tients with atrial fibrillation: a meta-analysis of randomised trials.
Lancet 2014; 383(9921): 955-62.
[21] Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining
clinical risk stratification for predicting stroke and thromboem-
bolism in atrial fibrillation using a novel risk factor-based ap-
proach: the euro heart survey on atrial fibrillation. Chest 2010;
137(2): 263-72.
[22] Camm AJ, Lip GY, De Caterina R, et al. 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 Euro-
pean Heart Rhythm Association. Eur Heart J 2012; 33(21): 2719-
47.
[23] January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS
guideline for the management of patients with atrial fibrillation: a
report of the American College of Cardiology/American Heart As-
sociation Task Force on practice guidelines and the Heart Rhythm
Society. Circulation 2014; 130(23 ): e199-267.
[24] Verma A, Cairns JA, Mitchell LB, et al. 2014 focused update of the
Canadian Cardiovascular Society Guidelines for the management
of atrial fibrillation. Can J Cardiol 2014; 30(10): 1114-30.
[25] O'Brien EC, K im S, Hess PL, et al. Effect of the 2014 atrial fibril-
lation guideline revisions on the proportion of patients recom-
mended for oral anticoagulation. JAMA Intern Med 2015; 175(5):
848-50.
[26] Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for
the man agement of atrial fibrillation developed in collaboration
with EACTS. Eur Heart J 2016; 37: 1-92.
[27] Cheng EY, Kong MH. Gender Differences of Thromboembolic
Events in Atrial Fibrillation. Am J Cardiol 2016; 117(6): 1021-
1027.
[28] Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the manage-
ment of atrial fibrillation: the Task Force for the Management of
Atrial Fibrillation of the European Society of Cardiology (ESC).
Eur Heart J 2010; 31(19): 2369-429.
[29] Huang D, Anguo L, Yue WS, Yin L, Tse HF, Siu CW. Refinement
of ischemic stroke risk in patients with atrial fibrillation and CHA2
DS2 -VASc score of 1. Pacing Clin Electrophysiol 2014; 37(11):
1442-7.
[30] Lip GY, Skjoth F, Rasmussen LH, Larsen TB. Oral anticoagula-
tion, aspirin, or no therapy in patients with nonvalvular AF with 0
or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am
Coll Cardiol 2015; 65(14): 1385-94.
[31] Proietti M, Lip GY. Major Outcomes in Atrial Fibrillation Patients
with One Risk Factor: Impact of Time in Therapeutic Range Ob-
servations from the SPORTIF Trials. Am J Med 2016 Apr 15. pii:
S0002-9343(16)30352-7. doi: 10.1016/j.amjmed.2016.03.024.
[Epub ahead of print]
[32] Fauchier L, Lecoq C, Clementy N, et al. Oral Anticoagulation and
the Risk of Stroke or Death in Patients With Atrial Fibrillation and
One Additional Stroke Risk Factor: The Loire Valley Atrial Fibril-
lation Project. Chest 2016; 149(4): 960-8.
[33] Zhang E, Liu T, Li Z, Zhao J, Li G. H igh CHA2DS2-VASc score
predicts left atrial thrombus or spontaneous echo contrast detected
by transesophageal echocardiography. Int J Cardiol 2015; 184:
540-542.
[34] Sjalander S, Svensson PJ, Friberg L. Atrial fibrillation patients with
CHA2DS2-VASc >1 benefit from oral anticoagulation prior to car-
dioversion. Int J Cardiol 2016; 215: 360-3.
[35] Apiyasawat S, Tangcharoen T, Wisaratapong T, Yamwong S,
Wiboonpolprasert S, Sritara P. CHA(2)DS(2)-VASc scores predict
mortality after hospitalization for atrial fibrillation. Int J Cardiol
2015; 185: 293-6.
[36] Chao TF, Liu CJ, Wang KL, et al. Using the CHA2DS2-VASc
score for refining stroke risk stratification in 'low-risk' Asian pa-
tients with atrial fibrillation. J Am Coll Cardiol 2014; 64(16):
1658-65.
[37] Huisman MV. Patients with atrial fibrillation and a CHA2DS2-
VASc score of 1: are they at low or high stroke risk? J Am Coll
Cardiol 2015; 65(14): 1395-7.
[38] Chao TF, Liu CJ, Chen SJ, et al. Atrial fibrillation and the risk of
ischemic stroke: does it still matter in patients with a CHA2DS2-
VASc score of 0 o r 1? Stro ke 20 12; 43(10): 2551-5.
[39] Avgil Tsadok M, Jackevicius CA, Rahme E, Humphries KH,
Behlouli H, Pilote L. Sex differences in stroke risk among older pa-
tients with recently diagnosed atrial fibrillation. JAMA 2012;
307(18): 1952-8.
[40] Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovas-
cular events in initially healthy women with new-onset atrial fibril-
lation. JAMA 2011; 305(20): 2080-7.
[41] Friberg L, Benson L, Rosenqvist M, Lip GY. Assessment of female
sex as a risk factor in atrial fibrillation in Sweden: nationwide ret-
rospective cohort study. BMJ 2012; 344: e3522.
[42] Poli D, Lip GY, Antonucci E, Grifoni E , Lane D. Stroke risk strati-
fication in a "real-world" elderly anticoagulated atrial fibrillation
population. J Cardiovasc Electrophysiol 2011; 22(1): 25-30.
[43] Friberg L, Rosen qvist M, Lip GY. Net clinical benefit of warfarin
in patients with atrial fibrillation: a report from the Swedish atrial
fibrillation cohort study. Circulation 2012; 125(19): 2298-307.
[44] Singer DE, Chang Y, Borowsky LH, et al. A new risk scheme to
predict ischemic stroke and other thromboembolism in atrial fibril-
lation: the ATRIA study stroke risk score. J Am Heart Assoc 2013;
2(3): e000250.
[45] Lip GY, Nielsen PB, Skjoth F, Lane DA, Rasmussen LH, Larsen
TB. The value of the European society of cardiology guidelines for
refining stroke risk stratification in patients with atrial fibrillation
categorized as low risk using the anticoagulation and risk factors in
atrial fibrillation stroke score: a nationwide cohort study. Chest
2014; 146(5): 1337-46.
[46] van den Ham HA, Klungel OH, Singer DE, Leufkens HG, van Staa
TP. Comparative Performance of ATRIA, CHADS2, and
CHA2DS2-VASc Risk Scores Predicting Stroke in Patients With
Atrial Fibrillation: Results From a National Primary Care Database.
J Am Coll Cardiol 2015; 66(17): 1851-9.
[47] Lip GY, Nielsen PB, Skjoth F, Rasmussen LH, Larsen TB. Atrial
fibrillation patients categorized as "not for anticoagulation" accord-
ing to the 2014 Canadian Cardiovascular Society algorithm are not
"low risk". Can J Cardiol 2015; 31(1): 24-8.
[48] Friberg L, Skeppholm M, Teren t A. Benefit of anticoagu lation
unlikely in patients with atrial fibrillation and a CHA2DS2-VASc
score of 1. J Am Coll Cardiol 2015; 65(3): 225-32.
[49] Chan YH, Wu LS, Chang SH, et al. Young Male Patients with
Atrial Fibrillation and CHA2DS2-VASc Score of 1 May Not Need
Anticoagulants: A Nationwide Population-Based Study. PLoS One
2016; 11(3): e0151485.
[50] Banerjee A, Lane DA, Torp-Pe dersen C, Lip GY. Net clinical
benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixa-
ban) versus no treatment in a 'real world' atrial fibrillation popula-
tion: a modelling analy sis based on a nationwid e cohort study.
Thromb Haemost 2012; 107(3): 584-9.
[51] Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a sys-
tematic review. JAMA 2015; 313(19): 1950-62.
Dispensing with the Risk Stratification Schemes in AF? Current Drug Targets, 2017, Vol. 18, No. 5 13
[52] van Walraven C, Hart RG, Connolly S, et al. Effect of age on
stroke prevention therapy in patients with atrial fibrillation: the
atrial fibrillation investigators. Stroke 2009; 40(4): 1410-6.
[53] Stroke Risk in Atrial Fibrillation Working Group. Independent
predictors of stroke in patients with atrial fibrillation: a systematic
review. Neurology 2007; 69(6): 546-54.
[54] Eckman MH, Singer DE, Rosand J, Greenberg SM. Moving the
tipping point: the decision to anticoagulate patients with atrial fib-
rillation. Circ Cardiovasc Qual Outcomes 2011; 4(1): 14-21.
[55] Taillandier S, Olesen JB, Clementy N, et al. Prognosis in patients
with atrial fibrillation and CHA2DS2-VASc Score = 0 in a com-
munity-based cohort study. J Cardiovasc Electrophysiol 2012;
23(7): 708-13.
[56] Pisters R, Nieuwlaat R, Lane DA, Crijns HJ, Lip GY. Potential net
clinical benefit of population-wide implementation of apixaban and
dabigatran among European patients with atrial fibrillation. A
modelling analysis from the Euro Heart Survey. Thromb Haemost
2013; 109(2): 328-36.
[57] Jahangir A, Lee V, Friedman PA, et al. Long-term progression and
outcomes with aging in patients with lone atrial fibrillation: a 30-
year follow-up study. Circulation 2007; 115(24): 3050-6.
[58] Potpara TS, Stankovic GR, Beleslin BD, et al. A 12-year follow-up
study of patients with newly diagnosed lone atrial fibrillation: im-
plications of arrhythmia progression on prognosis: the Belgrade
Atrial Fibrillation study. Chest 2012; 141(2): 339-47.
[59] Potpara TS, Lip GY. Lone atrial fibrillation - an overview. Int J
Clin Pract 2014; 68(4): 418-33.
[60] Potpara TS, Polovina MM, Licina MM, Marinkovic JM, Prostran
MS, Lip GY. Reliable iden tificatio n of "truly low" thromboembolic
risk in patients initially diagnosed with "lone" atrial fibrillation: the
Belgrade atrial fibrillation study. Circ Arrhythm Electrophysiol
2012; 5(2): 319-26.
[61] Jouven X, Desnos M, Guerot C, Ducimetiere P. Idiopathic atrial
fibrillation as a risk factor for mortality. The Paris Prospective
Study I. Eur Heart J 1999; 20(12): 896-9.
[62] Andersson T, Magnuson A, Bryngelsson IL, et al. Gender-related
differences in risk of cardiovascular morbidity and all-cause mor-
tality in patients hospitalized with incident atrial fibri llation wi thout
concomitant diseases: a nationwide cohort study of 9519 patients.
Int J Cardiol 2014; 177(1): 91-9.
[63] Kim EJ, Yin X, Fontes JD, et al. Atrial fibrillation without comor-
bidities: Prevalence, incidence and prognosis (from the
Framingham He art Study). Am Heart J 2016 ; 177: 138-44.
[64] Wyse DG, Van Gelder IC, Ellinor PT, et al. Lone atrial fibrillation:
does it exist? J Am Coll Cardiol 2014; 63(17): 1715-23.
[65] Wang HJ, Si QJ, Shan ZL, et al. Effects of body mass index on
risks for ischemic stroke, thromboembolism, and mortality in Chi-
nese atrial fibrillation patients: a single-center experience. PLoS
One 2015; 10(4): e0123516.
[66] Manolis AS, Manolis AA. Exercise and Arrhythmias: A Double-
Edged Sword. Pacing Clin Electrophysiol 2016; 39(7): 748-62.
[67] Tello-Mon toliu A, Hernandez-Romero D, Sanchez-Martinez M,
Valdes M, Marin F. Lone atrial fibrillation - a diagnosis of exclu-
sion. Curr Pharm Des 2015; 21(5): 544-50.
[68] Kozlowski D, Budrejko S, Lip GY, et al. Lone atrial fibrillation:
what do we know? Heart 2010; 96(7): 498-503.
[69] Ceresnak SR, Liberman L, Silver ES, et al. Lone atrial fibrillation
in the young - perhaps not so "lone"? J Pediatr 2013; 162(4): 827-
31.
[70] Daccarett M, Badger TJ, Akoum N, et al. Association of left atrial
fibrosis detected by delayed-en hanc ement magnetic resonance im-
aging and the risk of stroke in patients with atrial fibrillation. J Am
Coll Cardiol 2011; 57(7): 831-8.
[71] McManus DD, Rie nstra M, Benjamin EJ. An update on the prog-
nosis of patients with atrial fibrillation. Circulation 2012; 126(10):
e143-146.
[72] Chao TF, Wang KL, Liu CJ, et al. Age Threshold for Increased
Stroke Risk Among Patients With Atrial Fibrillation: A Nationwide
Cohort Study From Taiwan. J Am Coll Cardiol 2015; 66(12):
1339-47.
[73] Berkovitch A, Kivity S, Klempfner R, et al. Body mass index and
the risk of new-onset atrial fibrillation in middle-aged adults. Am
Heart J 2016; 173: 41-8.
[74] Overvad TF, Rasmussen LH, Skjoth F, Overvad K, Lip GY, Larsen
TB. Body mass index and adverse events in patients with incident
atrial fibrillation. Am J Med 2013; 126(7): 640.e649-17.
[75] Sandhu RK, Ezekowitz J, Andersson U, et al. The 'obesity paradox'
in atrial fibrillation: observations from the ARISTOTLE (Apixaban
for Reduction in Stroke and Other Thromboembolic Events in
Atrial Fibrillation) trial. Eur Heart J 2016 Apr 12. pii: ehw124.
[Epub ahead of print]
[76] Yaranov DM, Smyrlis A, Usatii N, et al. Effect of obstructive sleep
apnea on frequency of stroke in patients with atrial fibrillation. Am
J Cardiol 2015; 115(4): 461-5.
[77] Aspberg S, Chang Y, Atterman A, Bottai M, Go AS, Singer DE.
Comparison of the ATRIA, CHADS2, and CHA2DS2-VASc
stroke risk scores in predicting ischaemic stroke in a large Swedish
cohort of patients with atrial fibrillation. Eur Heart J 2016 Mar 3.
pii: ehw077. [Epub ahead of print]
[78] Bautista J, Bella A, Chaudhari A, et al. Advanced chronic kidney
disease in non-valvular atrial fibrillation: extending the utility of
R2CHADS2 to patients with advanced renal failure. Clin Kidney J
2015; 8(2): 226-31.
[79] Potpara TS, Olesen JB. Compa ring the ATRIA, CHADS2, and
CHA2DS2-VASc Scores for Stroke Prediction in Atrial Fibrilla-
tion. J Am Coll Cardiol 2016; 67(19): 2316-7.
[80] Tsang TS, Barnes ME, Bailey KR, et al. Left atrial volume: impor-
tant risk marker of incident atrial fibrillation in 1655 older men and
women. Mayo Clin Proc 2001; 76(5): 467-75.
[81] Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk
factors for atrial fibrillation in older adults. Circulation 1997; 96(7):
2455-61.
[82] Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic
predictors of nonrheumatic atrial fibrillation. Th e Framingham
Heart Study. Circulation 1994; 89(2): 724-30.
[83] Barnes ME, Miyasaka Y, Seward JB, et al. Left atrial volume in the
prediction of first ischemic stroke in an elderly cohort without atrial
fibrillation. Mayo Clin Proc 2004; 79(8): 1008-14.
[84] Benjamin EJ, D'Agostino RB, Belanger AJ, Wolf PA, Levy D. Left
atrial size and the risk of stroke and death. The Framingham Heart
Study. Circulation 1995; 92(4): 835-41.
[85] Shin HY, Jeong IH, Kang CK, et al. Relation between left atrial
enlargement and stroke subtypes in acute ischemic stroke patients.
J Cerebrovasc Endovasc Neurosurg 2013; 15(3): 131-6.
[86] Takemoto Y, Barnes ME, Seward JB, et al. Usefulness of left atrial
volume in predicting first congestive heart failure in patients > or =
65 years of age with well-preserved left ventricular systolic func-
tion. Am J Cardiol 2005; 96(6): 832-6.
[87] Laukkanen JA, Kurl S, Eranen J, Huttunen M, Salonen JT. Left
atrium size and the risk of cardiovascular death in middle-aged
men. Arch Intern Med 2005; 165(15): 1788-93.
[88] Di Biase L, Santangeli P, Anselmino M, et al. Does the left atrial
appendage morphology correlate with the risk of stroke in patients
with atrial fibrillation? Results from a multicenter study. J Am Coll
Cardiol 2012; 60(6): 531-8.
[89] Friberg L, Hammar N, Ro senqvist M. Stroke in paroxysmal atrial
fibrillation: report from the Stockholm Cohort of Atrial Fibrillation.
Eur Heart J 2010; 31(8): 967-75.
[90] Inoue H, Atarashi H, Okumura K, Yamashita T, Kumagai N, Ori-
gasa H. Thromboembolic events in paroxysmal vs. permanent non-
valvular atrial fibrillation. Subanalysis of the J-RHYTHM Registry.
Circ J 2014; 78(10): 2388-93.
[91] Lip GY, Frison L, Grind M. Stroke event rates in anticoagulated
patients with paroxysmal atrial fibrillation. J Intern Med 2008;
264(1): 50-61.
[92] Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixa-
ban vs. warfarin by type and duration of atrial fibrillation: results
from the ARISTOTLE trial. Eur Heart J 2013; 34(31): 2464-71.
[93] Chen LY, Agarwal SK, Norby FL, et al. Persistent but not Parox-
ysmal Atrial Fibrillation Is Independently Associated With Lower
Cognitive Function: ARIC Study. J Am Coll Cardiol 2016; 67(11):
1379-80.
[94] Vidal-Perez R, Otero-Ravina F, Lado-Lopez M, et al. The change
in the atrial fibrillation type as a prognosis marker in a community
study: long-term data from AFBAR (Atrial Fibrillation in the
BARbanza) study. Int J Cardiol 2013; 168(3): 2146-52.
[95] Walters TE, Nisbet A, Morris GM, et al. Progression of atrial re-
modeling in patients with high-burden atrial fibrillation: Implica-
tions for early ablative intervention. Heart Rhythm 2016; 13(2):
331-9.
[96] Anter E. Paroxysmal atrial fibrillation: A window of opportunity to
modify disease progression. Heart Rhythm 2016; 13(2): 340-1.
14 Current Drug Targets, 2017, Vol. 18, No. 5 Manolis et al.
[97] Palomaki A, Mustonen P, Hartikainen JE, et al. Strokes after car-
dioversion of atrial fibrillation--The FibStroke study. Int J Cardiol
2016; 203: 269-73.
[98] Gronberg T, Hartikainen JE, Nuotio I, Biancari F, Ylitalo A, Airak-
sinen KE. Anticoagulation, CHA2DS2VASc Score, and
Thromboembolic Risk of Cardioversion of Acute Atrial Fibrillation
(from the FinCV Study). Am J Cardiol 2016; 117(8): 1294-8.
[99] Nuotio I, Hartikainen JE, Gronberg T, Biancari F, Airaksinen KE.
Time to cardioversion for acute atrial fibrillation and thromboem-
bolic complications. JAMA 2014; 312(6): 647-9.
[100] Gallagher MM, Henn essy BJ, Edvardsson N, et al. Embolic com-
plications of direct current cardioversion of atrial arrhythmias: as-
sociation with low intensity of anticoagulation at the time of car-
dioversion. J Am Coll Cardiol 2002; 40(5): 926-33.
[101] Waldo AL, Becker RC, Tapson VF, Colgan KJ. Hospitalized pa-
tients with atrial fibrillatio n and a high risk of stroke are not being
provided with adequate anticoagulation. J Am Coll Cardiol 2005;
46(9): 1729-36.
[102] Arts DL, Visscher S, Opstelten W, Korevaar JC, Abu-Hanna A,
van Weert HC. Frequency and risk factors for under- and over-
treatment in stroke prevention for patients with non-valv ular atrial
fibrillation in general practice. PLoS One 2013; 8(7): e67806.
[103] Aronis KN, Thigpen JL, Tripodis Y, et al. Paroxysmal atrial fibril-
lation and the hazards of under-treatment. Int J Cardiol 2016; 202:
214-20.
[104] Kakkar AK, Mueller I, Bassand JP, et al. Risk profiles and anti-
thrombotic treatment of patients newly diagnosed with atrial fibril-
lation at risk of stroke: perspectives from the international, observ a-
tional, prospective GARFIELD registry. PLoS One 2013; 8(5):
e63479.
[105] Chen CH, Chen MC, Gibbs H, et al. Antithrombotic treatment for
stroke prevention in atrial fibrillation: The Asian agenda. Int J Car-
diol 2015; 191: 244-53.
[106] Mochalina N, Joud A, Carlsson M, et al. Antithrombotic therapy in
patients with non-valvular atrial fibrillation in Southern Sweden: A
population-based cohort study. Thromb Res 2016; 140: 94-9.
[107] Hsu JC, Chan PS, Tang F, Maddox TM, Marcus GM. Oral Antico-
agulant Prescription in Patients With Atrial Fibrillation and a Low
Risk of Thromboembolism: Insights From the NCDR PINNACLE
Registry. JAMA Intern Med 2015; 175(6): 1062-5.
[108] Bell AD, Gross P, Heffernan M, et al. Appropriate Use of Anti-
thrombotic Medication in Canadian Patients With Nonvalvular
Atrial Fibrillation. Am J Cardiol 2016; 117(7): 1107-11.
[109] Wong CX, Lee SW, Gan SW , et al. Underuse and overuse of anti-
coagulation for atrial fibrillation: A study in Indigenous and non-
Indigenous Australians. Int J Cardiol 2015; 191: 20-4.
[110] De Caterina R, Andersson U, Alexander JH, et al. History of bleed-
ing and outcomes with apixaban versus warfarin in patients with
atrial fibrillation in the Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibril lation trial. Am Heart J
2016; 175: 175-83.
[111] Lip GY, Lane DA. Matching the NOAC to the Patient: Remember
the Modifiable Bleeding Risk Factors. J Am Coll Cardiol 2015;
66(21): 2282-4.
[112] Manolis A. Adverse cardiovascular events with nonsteroidal anti-
inflammatory agents. Rhythmos 2015; 10(2): 21-7.
[113] Goodman SG. Prior bleeding, future bleeding and stroke risk with
oral anticoagulation in atrial fibrillation: What new lessons can
ARISTOTLE teach us? Am Heart J 2016; 175: 168 -71.
[114] Morais J, De Caterina R. Stroke Prevention in Atrial Fibrillation: A
Clinical Perspective on Trials of the Novel Oral Anticoagulants.
Cardiovasc Drugs Ther 2016; 30(2): 201-14.
[115] Manolis AS, Manolis TA, Melita H. Novel oral anticoagula nts for
stroke prophylaxis in non-valvula r atrial fibrillation: Agen t selec-
tion and patient monitoring. Hosp Chronicles 2013; 8(4): 151-63.
[116] Cohen AT, Hamilton M, Bird A, et al. Comparison of the Non-
VKA Oral Anticoagulants Apixaban, Dabigatran, and Rivaroxaban
in the Extended Treatment and Prevention of Venous Thromboem-
bolism: Systematic Review and Network Meta-Analysis. PLoS One
2016; 11(8): e0160064.
[117] Lip GY. Stroke and bleeding risk assessment in atrial fibrillation:
when, how, and why? Eur Heart J 2013; 34(14): 1041-9.
[118] Verheugt FW. Advances in stroke prevention in atrial fibrillation:
enhanced risk stratification combined with the newer oral antico-
agulants. Clin Cardiol 2013; 36(6): 312-22.
[119] Lip GY, Haguenoer K, Saint-Etienne C, Fauchier L. Relationship
of the SAMe-TT(2)R(2) score to poor-quality an ticoagulation,
stroke, clinically relevant bleeding, and mortality in patients with
atrial fibrillation. Chest 2014; 146(3): 719-26.
[120] Lane DA, Aguinaga L, Blomstrom-Lundqvist C, et al. Cardiac
tachyarrhythmias and patient values and preferences for their man-
agement: the European Heart Rhythm Association (EHRA) con-
sensus document endorsed by the Heart Rhythm Society (HRS),
Asia Pacific Heart Rhythm Society (APHRS), and Sociedad Lati-
noamericana de Estimulacion Cardiaca y Electrofisiologia
(SOLEACE). Europace 2015; 17(12): 1747-69.
[121] Joundi RA, Cipriano LE, Sposato LA, Saposnik G. Ischemic Stroke
Risk in Patients With Atrial Fibrillation and CHA2DS2-VASc
Score of 1: Systematic Review and Meta-Analysis. Stroke 2016;
47(5): 1364-7.
[122] Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus
warfarin in patients with atrial fibrillation. N Engl J Med 2009;
361(12): 1139-51.
[123] Patel MR, Mah affey KW, Garg J, et al. Rivaroxaban versus war-
farin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365(10):
883-91.
[124] Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus
warfarin in patients with atrial fibrillation. N Engl J Med 2011;
365(11): 981-92.
[125] Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus war-
farin in patients with atrial fibrillation. N Engl J Med 2013;
369(22): 2093-104.
[126] Alberts MJ, Peacock WF, Fields LE, et al. Association between
once- and twice-daily direct oral anticoagulant adherence in non-
valvular atrial fibrillation patients and rates of ischemic stroke. Int J
Cardiol 2016; 215: 11-3.
[127] Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an inde-
pendent risk factor for stroke: the Framingham Study. Stroke 1991;
22(8): 983-8.
[128] Fetsch T, Bauer P, Eng berding R, et al. Prevention of atrial fibrilla-
tion after cardioversion: results of the PAFAC trial. Eur Heart J
2004; 25(16): 1385-94.
[129] Verma A, Champagne J, Sapp J, et al. Discerning the incidence of
symptomatic and asymptomatic episodes of atrial fibrillation before
and after catheter ablation (DISCERN AF): a prospective, multi-
center study. JAMA Intern Med 2013; 173(2): 149-56.
[130] Manolis AS. Should all patien ts with atrial fibrillation receive an
oral anticoagulant in the era of non-vitamin K anticoagulants?
Rhythmos 2016; 11(3): 63-9.
!
!
!
!
!
PMID: 27593686
