European Journal of Internal Medicine 24 (2013) 318323

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Original article

Hospitalized patients with atrial brillation compared to those included in recent

trials on novel oral anticoagulants: A population-based study
R. Joppi a,, E. Cinconze b, L. Mezzalira a, D. Pase a, C. Poggiani a, E. Rossi b,
V. Pengo c, on behalf of the Italian Horizon Scanning Project
a
b
c

Pharmaceutical Department, Local Health Unit of Verona, Via Salvo D'Acquisto 7, 37122 Verona, Italy
Health Care Systems Department, CINECA Consortium of Universities, Via Magnanelli 6/3, 40033 Casalecchio di Reno (BO), Italy
Department of Cardiac Thoracic and Vascular Sciences, University of Padova, School of Medicine, Via Giustiniani 2, 35128 Padova, Italy

a r t i c l e

i n f o

Article history:
Received 27 December 2012
Received in revised form 22 February 2013
Accepted 26 February 2013
Available online 23 March 2013
Keywords:
Atrial brillation
Stroke prevention
Oral anticoagulants
Antithrombotic therapy
Prescription

a b s t r a c t
Background: Nonvalvular atrial brillation is associated with a substantial risk of stroke. Novel oral anticoagulants
(NOACs) with predictable anticoagulant effect and no need for routine coagulation monitoring have recently
shown good results when compared with warfarin in phase III clinical trials.
Objective: To describe clinical features and pharmacological treatments of a population-based cohort of patients
with nonvalvular atrial brillation and ascertain whether they are comparable with those included in the three
main phase III clinical trials on NOACs.
Results: Of the 2,862,264 subjects considered for this study 13,360 patients (0.47%) were recently discharged from
the hospital with a diagnosis of nonvalvular atrial brillation. Mean age was 76.3 (SD 10.7), 49.8% were men and
64.6% were 75 years of age. 50% of patients were treated with warfarin and 44.1% with antiplatelet agents. The
proportion of patients on antiplatelet therapy increased with age up to a rate of 54.3% in subjects 85 years.
92.9% of the studied cohort was on polypharmacy (mean 8 drugs/patient). Around 20% of the entire cohort was
treated with amiodarone, a drug potentially interfering with NOACs, and 3.6% from a subgroup analysis had
renal failure, which is an exclusion criterion in trials on NOACs.
Conclusion: In patients recently discharged from the hospital with the diagnosis of nonvalvular AF, warfarin use
decreases and aspirin treatment increases with patients' age. These patients are older, more frequently female,
and on multiple medications. The benet of NOACs in these subjects needs to be conrmed in phase IV clinical
studies.
2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction
Atrial brillation (AF), the most frequently observed sustained
arrhythmia in clinical practice, affects 0.41.0% of the general
population with a lower prevalence among subjects below the age of
60, increasing to 8% in those aged over 80 years [1]. AF is an
independent risk factor for stroke: patients with AF have a four to ve
fold higher risk for stroke than unaffected subjects [2,3].
The annual risk of stroke in untreated patients with AF is age
dependent, being 1% in the 5059 age group, 3% in the 6069 age
group, 10% in the 7079 age group, and 24% in patients aged 80 to
89 [2,4,5].
In a meta-analysis on vitamin K antagonists (VKAs) and aspirin for
stroke prevention in patients with AF the occurrence of stroke
decreased by 60% and 20%, respectively, compared to placebo or no
treatment [6,7]. The magnitude of warfarin benet increased with
inherent risk of stroke. Despite the well-documented efcacy, VKAs
Corresponding author. Tel.: +39 045 8076056; fax: +39 045 8076098.
E-mail address: roberta.joppi@ulss20.verona.it (R. Joppi).

are difcult to use for several reasons, including a narrow therapeutic

window, the multiple food and drug interactions, the need for
frequent monitoring, and the difculty in maintaining a stable
therapeutic INR and therefore for the bleeding complications, which
are more common in elderly patients [811]. For all these reasons
vitamin K antagonists are too often not given when indicated, despite
the fact that international guidelines recommend their use, as a class I
indication, in the large majority of patients with AF [1].
The promising results of the three phase III clinical trials (RE-LY,
ROCKET AF and ARISTOTLE) on novel oral anticoagulants (dabigatran,
rivaroxaban, apixaban, respectively) [1214] as compared with
warfarin challenge the use of classic oral anticoagulants as the new
drugs are less likely to induce intracranial bleeding and need no
routine laboratory testing. The apparently better safety prole
and ease of use of NOACs will probably induce a wider use of
antithrombotic agents in patients with AF. The question is whether
the results obtained in clinical trials on NOACs are generalizable to
hospitalized patients with AF.
The present study aims to describe clinical features and pharmacological treatments of a population-based cohort of Italian patients

0953-6205/$ see front matter 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ejim.2013.02.018

R. Joppi et al. / European Journal of Internal Medicine 24 (2013) 318323

discharged from the hospital with a diagnosis of AF and to compare

them with the patients included in the RE-LY, ROCKET AF and
ARISTOTLE studies [1214].
2. Materials and methods
2.1. Prescription database

319

of nonvalvular AF. Fig. 1 shows the prevalence of antithrombotic

treatments according to age. Half of the overall ARNO cohort received
warfarin, 44.1% antiplatelet agents, and 17.3% no antithrombotic
treatment. The highest prevalence of VKAs was among subjects
aged 6574 years and the lowest after 85 years. The prevalence of
antiplatelet agent use increased with age and nearly half of the
patients aged 85 years received this therapy.

The ARNO database is a population-oriented database for drug

use in Italy [15]. The system has been active since 1988 and run by
Centro Universitario di Calcolo dell'Italia Nord-Orientale, a National
interuniversity consortium, with the purpose of providing a friendly
and efcient database that collects and monitors the prescriptions
for nearly 11 million inhabitants (as of November 2012). The
database stores all prescriptions reimbursed by the National Health
Service to individuals living in the area covered by the local health
units. The system merges information regarding prescriptions,
population, geographical areas, and hospital admissions into a single
database. For hospital admissions, it stores International Classication
of Diseases, Ninth Revision (ICD-9) codes for all admissions to public
and private hospitals located in the areas covered by the local health
units. It is updated monthly and available through the Internet, and
accessible to authorized users with different levels of information.
The present analysis used data from 11 Italian local health units
in four regions (Abruzzo, Puglia, Toscana, Veneto), covering a
population of 3,428,000 inhabitants, of whom 2,862,264 aged
18 years.

3.1. Characteristics of patients in the ARNO cohort as compared to those

of patients randomized in the RE-LY, ROCKET AF and ARISTOTLE trials

2.2. Study participants

3.1.2. Drug treatments other than antithrombotic drugs

The use of amiodarone, statins and proton pump inhibitors
somehow differs between patients discharged from the hospital
with a diagnosis of AF and those randomized in the NOAC clinical
trials. The use of amiodarone in the main ARNO cohort nearly doubled
that in the RE-LY and ARISTOTLE studies (20.2% in the overall ARNO
cohort vs. 10.7% in RE-LY and 11.3% in ARISTOTLE).
Statin use among hospitalized patients with AF was roughly half
that seen in the trials (24.3% in the overall ARNO cohort vs. 44.4% in
RE-LY, 43.1% in ROCKET-AF, and 45.0% in ARISTOTLE).
Approximately two thirds of the cohort were given proton-pump
inhibitors as compared with one fth in the RCTs (65.3% in the overall
ARNO cohort vs. 17.7% in RE-LY, and 18.4% in ARISTOTLE).
Nearly all patients in the overall ARNO cohort were on multiple
medications, as 92.9% of them were treated with 3 drugs (mean 8
drugs per patient; range 128).

The study group consisted of male and female patients aged

18 years discharged from the hospital with a primary or secondary
diagnosis of nonvalvular AF (ICD-9 diagnostic code 427.31).
Hospitalizations due to ischemic stroke (ICD-9 diagnostic codes
434, 436), transient ischemic attack (ICD-9 diagnostic code: 435),
and renal failure (ICD-9 diagnostic codes: 403, 584, 585, 586) were
also evaluated.
Prescribed drugs were classied according to the Anatomical
Therapeutic Chemical (ATC) classication system and the following
groups were included: VKAs (ATC group B01AA), antiplatelet agents
and other antithrombotic drugs (ATC group B01AC), ARB-inhibitors
(ATC groups C09C and C09D), ACE-inhibitors (ATC groups C09A
and C09B), -blockers (ATC group C07), amiodarone (ATC group
C01BD01), verapamil (ATC group C08DA01), statins (ATC groups
C10AA and C10BA02), proton-pump inhibitors (ATC group A02BC),
H2-receptor antagonists (ATC group A02BA), and antidiabetics (ATC
group A10). All these agents are fully reimbursed by the Italian
National Health Service.
The study period was from January 1, 2007 to December 31, 2008.
The accrual period was from January 1, 2007 to December 31, 2007
with a follow-up period of one year.
3. Results
During 2007, out of the 2,862,264 screened subjects, 13,360
patients (0.47%) were discharged from the hospital with a diagnosis
of nonvalvular AF. The prevalence of AF in this cohort ranges from
0.03% among subjects aged b 55 years and reaches 3.52% after
85 years.
The prevalence of VKA use among the 2,862,264 screened subjects
is 1.5% and ranges from 0.15% among subjects aged b 55 years,
increases until 8.35% among patients aged 7584 and slightly
decreases among those aged > 85 years (6.77%). Considering that AF
affects 45% of naive patients taking VKAs [16] the prevalence of this
condition in the screened cohort is 0.68% and more than two thirds
of these subjects were discharged from the hospital with a diagnosis

3.1.1. Age and gender

The main ARNO cohort was fairly older compared to participants
in the RE-LY (mean age 76.3 10.7 vs. 71.5 8.7), ROCKET AF
(median age 79 [interquartile range 7184] vs. 73 [interquartile
range 6578]) and ARISTOTLE (median age 79 [interquartile range
7184] vs. 70 [interquartile range 6376]) trials.
Fig. 2 shows the prevalence of patients 75 years in the overall
ARNO cohort vs. RE-LY, ROCKET and ARISTOTLE studies. A total of
63.2% of the cohort was aged 75 years (21.7% of them 85 years),
while patients of this age hardly reached 40% in the trial setting.
Fig. 3 presents the gender distribution in the overall ARNO cohort
vs. the study population in the three randomized clinical trials (RCT).
The proportion of women in the study setting did not reach 40%,
while they accounted for half of the patients with nonvalvular AF in
daily practice (57.2% of patients 75 years were female).

3.1.3. Renal failure, previous cerebral ischemia, diabetes, and hypertension

For a sub-group of the overall ARNO cohort (i.e. 7994 subjects
belonging to seven of the 11 local health units participating in
the study and representing 59.8% of the overall ARNO cohort),
information on hospitalization due to severe stroke, and/or renal
failure within 12 months before accrual was also available.
Age and gender distribution of this sub-group was similar to the
overall ARNO cohort (mean age 77 10.6 in the sub-group vs.
76.3 10.7 in the overall ARNO cohort; female prevalence 49.2% vs.
50.2%, respectively).
A total of 3.6% of hospitalized patients with AF were hospitalized
for renal failure in the 12 months before hospitalization due to AF,
which means that 288 out of 7994 subjects hospitalized for AF
would not have been suitable for the therapy with the new
anticoagulants.
Similarly, 176 subjects from the same sub-group were hospitalized
for severe stroke in the same period. These patients would also meet
the exclusion criteria for both the RE-LY and ROCKET-AF studies.
For the same sub-group of the overall ARNO cohort information on
other co-morbidities such as diabetes and hypertension was also
available. The prevalence of diabetes (17.7%) is slightly lower than

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R. Joppi et al. / European Journal of Internal Medicine 24 (2013) 318323

100%

12.6

15.5

90%

14.8
25.5

32.1
80%

16.4

16.8

12.4
5.7

Users (%)

70%
60%

9.8
24.0

30.4

24.7
50%

21.4

48.6

40%
30%
20%

36.7

47.1

43.1

42.4
20.1

10%
0%
<55
N=523

55-64
N=1,168

65-74
N=3,221

75-84
N=5,551

>=85
N=2,897

Age (years)
Vitamin K Antagonist (%)

Antiplatelet agents (%)

Vitamin K Antagonist and Antiplatelet Agents (%)

No antithrombotic treatment

Fig. 1. Prevalence of antithrombotic treatments in the overall ARNO cohort according to age.

that in clinical trials and that of hypertension (76.9%) is close to that

reported for patients included in the RCTs.
4. Discussion
To the best of our knowledge this is the rst study comparing a
large cohort of patients discharged from the hospital with a diagnosis
of nonvalvular AF with patients included in the recent NOAC RCTs.
The study population does not represent the whole real world
setting. Many patients with AF are community patients receiving
treatment without need for hospitalization. However, the mean
prevalence in general population accounts for about 1%; data from
ATRIA study reported that AF prevalence accounts for 0.95% in
North America [17] and 0.87% in the study of Scottish Murphy [18].
In another more recent study in the United States of America, its
prevalence was 1.12% [19]. Thus hospitalized patients with AF
(0.47%) account for nearly half of patients with AF in the general
population.
Despite the fact that the use of VKAs is mandatory and that the
magnitude of benet increases with age [710,20], half of the ARNO
cohort did not receive VKA therapy and the same can be said for
patients aged 85 years, whose risk is higher due to age and
co-morbidities. The underutilization of VKAs in the elderly is partially

compensated by the use of aspirin, with nearly half of patients

85 years undergoing this treatment. These ndings seem in line
with other studies [8,9], which reect the reluctance of clinicians
in giving VKAs to elderly patients due to the potential bleeding
complications which are more common in this population. This
attitude is in contrast with the clear evidence that VKAs are superior
to aspirin in this setting too, with no difference in major bleeding
(or intracranial hemorrhage) in the elderly [2123]. Recently it was
reported that the benets in stroke prevention and cerebral bleeding
with dabigatran versus warfarin are preserved in those in the 9th
decade compared to those younger except for major bleeding
where, compared to warfarin, there is no difference using a lower
dosage of dabigatran (110 mg bid) and an increase bleeding rate
using 150 mg bid. of dabigatran [24]. Therefore a dose reduction
should be considered for dabigatran in the very old population and
this strategy might be applied to all the new oral anticoagulants.
As NOACs need no laboratory control and have caused signicantly
less intracranial bleeding as compared with warfarin, it is possible

Females

Males

70

60

% Study Population

70

% Study Population

60
50
40
30

50
40
30
20
10

20

10

RE-LY
ROCKET-AF

0
RE-LY

ROCKET-AF

ARISTOTLE

Main ARNO Cohort

Age >75
_ years
Fig. 2. Distribution of patients aged >75 years in the main ARNO cohort vs. RE-LY,
ROCKET or ARISTOTLE studies.

ARISTOTLE
Overall
ARNO Cohort

Fig. 3. Gender distribution of the main ARNO cohort vs. RE-LY or ROCKET or ARISTOTLE
participants.

R. Joppi et al. / European Journal of Internal Medicine 24 (2013) 318323

that physicians will be more condent in treating their patients

with NOACs instead of aspirin.
Are the results of the phase III NOAC trials applicable to the entire
population of patients with nonvalvular AF? The answer is difcult, as
features of hospitalized patients with AF are quite different from those
presented by the subjects included in the clinical studies [1214].
With nearly two thirds of subjects aged 75 years, hospitalized
patients are much older than those included in the RE-LY, ROCKET AF
and ARISTOTLE trials [1214]. The under-representation of elderly in
clinical trials is a matter of concern. An elderly patient with AF
differs considerably from younger patients due to the fragile
condition, multiple co-morbidities, including cardiovascular and noncardiovascular diseases, and decreased renal and hepatic function. Of
the individual components of the CHADS2 score, age 75 carries a
worse prognosis for stroke and mortality than hypertension, diabetes,
and heart failure [25].
Women are also underrepresented in the NOAC studies, although
women and men are equally affected with AF in daily hospital practice
and female are even predominant among hospitalized patients with AF
aged 75 years. AF is associated with an increased risk of stroke, heart
failure, and all-cause mortality, especially among women [26,27]. A
report from the Euro Heart Survey on AF [28] documented that
women with AF in European countries had more co-morbidities, a
lower quality of life, and a higher risk of stroke than men. In addition,
women have a greater risk of developing adverse drug reactions
than men. In the Sportif V trial women were more prone to
anticoagulant-related bleeding and to higher rate of thromboembolism due to more frequent interruption of anticoagulant therapy
[29].
In spite of documented age- and gender-related differences,
elderly patients and women are still underrepresented in RCTs and
no analysis of the results by gender is reported.
Another important issue to be considered is the impact of
polypharmacy in elderly patients with AF, as hypothetical interactions with drugs are likely to occur, based on the main mechanisms
by which NOACs are metabolized and eliminated. The long term
use of drugs for chronic disorders is common in the elderly and
polypharmacy increases with age, particularly after the age of 70
and in women [30]. Thus, possible drug interactions increase in
the patients described in this study as they are signicantly older
than those of NOAC clinical trials and women are largely more
represented.
Looking at the treatments prescribed to the overall ARNO cohort, a
matter of concern is the use of amiodarone in these patients, the
prevalence of which doubled that seen in the phase III NOAC studies.
Amiodarone is a P-glycoprotein inhibitor and, a single dose of 600 mg
increases dabigatran AUC and Cmax by about 50% and 60%,
respectively. The bioavailability of the other NOACs (rivaroxaban
and apixaban) is also inuenced by P-glycoprotein. In view of the
long half-life of amiodarone the potential for drug interaction and
the risk of bleeding may persist for weeks after its discontinuation.
The European product monograph states that a reduction in the
dose of dabigatran is recommended when it is co-administered with
amiodarone [31,32].
Concerning possible drugdrug interactions verapamil, another
P-glycoprotein inhibitor, should also be taken into consideration. Within
the overall ARNO cohort, 1008 patients (8.3%) were treated with this
active principle. When dabigatran (150 mg) is co-administered with
oral verapamil, the Cmax and AUC of dabigatran increased (increase of
Cmax by about 180% and AUC by about 150% in the case of an immediate
release formulation of verapamil administered 1 h prior to dabigatran
intake) but the magnitude of this change differs depending on timing
of administration and formulation of verapamil. The European product
monograph reports that no meaningful interaction is observed when
the antihypertensive drug is given 2 h after dabigatran [31]. The
over-prescription of proton-pump inhibitors among hospitalized patients

321

with AF vs. the use reported in the NOAC trials could possibly be reduced
with the use of the new anticoagulants as it can be explained with the
large utilization of aspirin in these patients (nearly half of the overall
ARNO cohort). On the other hand, the lower use of proton pump
inhibitors in the phase III studies may account for the excess of dyspepsia
(RE-LY) and gastro-intestinal bleeding (RE-LY and Rocket-AF) as
compared to warfarin.
The use of statins is quite low in this study: this may reect the
unproven benet in primary cardiovascular prevention in elderly
patients and/or restrictions in getting these drugs free from the
national health system.
Patients with severe renal failure were excluded from all the three
trials on new anticoagulants. According to our data 3.6% of hospitalized
patients with AF cannot be treated with the new medications. Severe
impairment of renal function is an important issue in the elderly,
particularly in patients aged over 80 years, half of whom show a
creatinine clearance 50 mL/min [33]. These frail patients should be
carefully monitored for renal function over time if treated with NOACs
with prevalent renal excretion.
The prevalence of diabetes in the sub-group of the overall ARNO
cohort was assessed looking at the prescription data on antidiabetics.
Each subject who received at least one package of glucose-lowering
medications was considered a diabetic patient. This assumption
is commonly utilized in pharmacoepidemiological studies using
prescription databases [34]. Since no details concerning the disease
were available, a slight underestimation of the disease prevalence in
the ARNO cohort could be possible. However, this gure is consistent
with previous national and international observational studies
[33,3537] and a randomized clinical trial performed among Italian
ambulatory patients with AF [38]. The magnitude of the difference
in the prevalence of diabetes between patients seen in the daily
practice and those included into the three trials is unlikely to be
explained by this potential limitation.
The prevalence of hypertension in the sub-group of the overall
ARNO cohort was identied through analysis of therapies with at
least four packs during 12 months of the following ATC codes:
C02A, C02C, C03A, C03B, C03D, C03E, C07, C08C, C09A, C09B, C09C,
and C09D (alone or combined). This assumption was previously
utilized and validated [39] and is in line with the data reported in
other observational studies performed on Italian patients with AF
[33,36].
4.1. Strengths and limitations of the study
This population-based study includes data from a large cohort of
subjects discharged from the hospital with a diagnosis of nonvalvular
AF. The study dataset includes all the reimbursable prescriptions that
were issued in 2008 by general practitioners and specialists to these
patients and were subsequently collected by the patients in local
pharmacies. Thus, the major strengths of the present study are the
representativeness of the cohort and the reliability of the dispensing
data.
This analysis is limited by its observational retrospective design,
its focus on the hospital setting (while the majority of these subjects
are outpatients, this study includes recently hospitalized patients,
probably older in comparison with outpatients, with a higher number
of drugs prescribed, and affected by conditions contraindicating
the use of anticoagulants) and the incomplete clinical information
on the included patients.
5. Conclusion
This study documents that patients discharged from the hospital
with the diagnosis of nonvalvular AF are elderly people, with a higher
prevalence of women among patients > 75 years. Warfarin use
decreases, aspirin treatment increases with age and nearly all

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R. Joppi et al. / European Journal of Internal Medicine 24 (2013) 318323

subjects are on multiple medications. These subjects are fairly

different from those included in recent clinical trials [1214] and as
many efforts as possible should be done to include real-world
patients in RCTs, particularly women and elderly people.
Furthermore, potentially dangerous interactions in these patients,
together with the high prevalence of renal failure, might be a relevant
issue in daily practice, which is similar to the drugdrug interaction
associated to the VKAs but with two important differences: 1) the
lack of a lab test (INR) that, though extremely imprecise and not
always sensible, can be a ringing bell and anyway a reason to monitor
the patient; and 2) as far as we know, the absence of an antidote.
For all these reasons, while suggesting a role for NOACs in satisfying
patients' needs that are still unmet so far, our study indicates that
further phase IV studies are required to conrm the benet and clarify
the safety prole of NOACs in daily practice.
Learning points
Patients discharged from the hospital with the diagnosis of
nonvalvular AF are fairly different from those included into recent
clinical trials on novel oral anticoagulants (NOACs): they are
older, more frequently female and on multiple medications.
Warfarin use decreases, aspirin treatment increases with patients'
age and nearly all subjects are on multiple medications.
Potentially dangerous drugdrug interactions in the treatment of
these patients with NOACs, together with the high prevalence of
renal failure, might be a relevant issue in daily practice, considering
the lack of a lab test (INR) to monitor the patients and the current
absence of an antidote.
The results of this survey advise once more that as many efforts as
possible should be done to include women and elderly people in
randomized clinical trials.
While suggesting a role for NOACs in satisfying patients' needs that
are still unmet so far, this study suggests that further phase IV studies are required to conrm the benet and clarify the safety prole
of novel oral anticoagulants in daily practice.
Italian horizon scanning group
Scientic Committee
Fabio Benedetti, Vittorio Bertele, Luigi Bozzini, Emanuele
Carbonieri, Claudio Graiff, Anna Maria Grion, Roberta Joppi, Luigi
Mezzalira, Vittorio Pengo, and Anna Maria Stanzial.
ScienticSecretariat
Laura Agnoletto, Elisa Cinconze, Luca Dematt, Marisa De Rosa,
Daniela Pase, Chiara Poggiani, and Elisa Rossi.
We thank the ARNO Working Group for providing the data
Roberta Callegari, Asolo; Mirano Luisa Cordella; Chioggia Bianca
Pari; Alta Padovana Antonella Pedrini; Monselice Maria Gabriella
Zogno; Adria Grazia Rizzotti; Verona Margherita Andretta; Legnago
Silvia Brasola; Firenze Paolo Batacchi; Teramo Antonio Orsini; and
Taranto Rossella Moscogiuri.

[2]
[3]
[4]
[5]
[6]

[7]

[8]

[9]

[10]
[11]

[12]

[13]
[14]

[15]
[16]

[17]

[18]
[19]
[20]

[21]

[22]

[23]

[24]

[25]

Funding
This study was supported by internal institutional funds.

[26]

Conict of interests
The authors state that they have no conicts of interests.
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