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European Annals of Otorhinolaryngology, Head and Neck diseases xxx (2017) xxx–xxx

Available online at

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Original article

Epistaxis complicating treatment by anti-vitamin K and new oral

anticoagulants
V. L’Huillier ∗ , C. Badet , L. Tavernier
Service d’oto-rhino-laryngologie et chirurgie cervico-faciale, CHRU de Besançon, 2, boulevard Fleming, 25030 Besançon, France

a r t i c l e i n f o a b s t r a c t

Keywords: Objectives: To assess any differences in severity and management of epistaxis when complicating treat-
Epistaxis ment by anti-vitamin K (AVK) or by new oral anticoagulants (NOAC).
Rivaroxaban Materials and method: All patients admitted to the ENT department of a University Hospital Center for
Dabigatran
epistaxis under oral anticoagulation therapy between January 2010 and June 2015 were included in a
Oral anticoagulants
retrospective study. Severity was assessed in terms of management and of hemoglobin level at admission.
Two groups were distinguished: treatment by AVK or by NOAC.
Results: One hundred and thirty-four patients were included: 126 under AVK and 8 under NOAC. There
was a significant difference in mean hospital stay: 4.5 days for AVK versus 3.5 days for NOAC (P = 0.019;
95% CI [0.1921; 0.8907]). There were no significant differences for the other severity criteria. None of the
patients died.
Conclusion: Admission rates for epistaxis complicating NOAC therapy was low, and much lower than in
case of AVK. Bleeding severity was equivalent with both treatments. NOACs significantly reduce hospi-
tal stay. Contrary to the study hypothesis, epistaxis is less serious when complicating NOAC than AVK
therapy.
© 2018 Elsevier Masson SAS. All rights reserved.

1. Introduction
Treatment and prevention of thromboembolic events are major
public health issues in view of the risk of excess mortality, the
medical and socioeconomic impact and the increasing number of
patients concerned by such pathology [1]. Anti-vitamin K (AVK) is
the reference treatment, especially in case of non-valvular atrial
fibrillation [2].
Since 2008, there has been an alternative to AVK: new oral anti-
coagulants (NOAC). These are direct coagulation inhibitors, acting
on thrombin (anti-factor IIa) or factor X. The first class comprises
®
only dabigatran etexilate (Pradaxa ), and the second rivaroxaban
® ®
(Xarelto ) and apixaban (Eliquis ), marketed since 2008, 2009 and
2012, respectively. French national health insurance statistics show
that almost half (48%) of patients beginning oral anticoagulation
therapy between October 2012 and September 2013 were pre-
scribed a NOAC; the study revealed prescription beyond the Health
Authority guidelines [3]. Sales have soared since their introduction,
∗ Corresponding author.
E-mail address: virginie.lhuillier@yahoo.fr (V. L’Huillier).
with 1 million defined daily doses (DDD) in 2009 and 117 million
in 2013 [1]. This increase and overprescription can be explained by
the ease of use for patients: unlike AVK, no biological monitoring
or dose adaption is required [4]. Nor do NOACs display the numer-
ous drug and food interactions complicating treatment found with
AVKs [5,6].
The French National Drug Safety Agency (Agence nationale de
sécurité du médicament: ANSM), however, warned physicians of the
bleeding risks associated with all classes of anticoagulant. Epistaxis
is one such hemorrhagic complication, consisting in frequent and
potentially dangerous bleeding, and was the second most frequent
cause of minor hemorrhage in a study by the French National Health
Insurance Scheme (Caisse nationale d’assurance maladie) [3].
Given the increase in the number of NOAC prescriptions, it can
be assumed that the rate of epistaxis under NOAC is also rising. The
absence of biological monitoring, with dose modulation according
to clinical context, lack of antagonists and of guidelines in case of
hemorrhage suggest that epistaxis may be more serious than under
AVK. To our knowledge, since NOACs received market authoriza-
tion, there have been no French studies assessing their impact on
the rate and severity of epistaxis complicating oral anticoagulation
treatment.

https://doi.org/10.1016/j.anorl.2018.04.006
1879-7296/© 2018 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: L’Huillier V, et al. Epistaxis complicating treatment by anti-vitamin K and new oral anticoagulants.
European Annals of Otorhinolaryngology, Head and Neck diseases (2017), https://doi.org/10.1016/j.anorl.2018.04.006
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ANORL-765; No. of Pages 5 ARTICLE IN PRESS
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Fig. 1. Progression of admissions for epistaxis during anticoagulation therapy in the ENT department of Besançon Regional University Hospital Center between 2010 and
2015. The curve shows a trend for admission for epistaxis during AVK therapy only. AVK: anti-vitamin K; NOAC: new oral anticoagulants.
The main aim of the present study was therefore to investigate
possible differences in the severity of epistaxis under AVK com-
pared to NOACs.
2. Materials and method
A retrospective descriptive study included all patients aged > 18
years admitted to the ENT department of a Regional University Hos-
pital Center for spontaneous epistaxis under oral anticoagulation
therapy by AVK or NOAC between January 1, 2010 And June 30,
2015.
Data comprised demographic variables (age and gender), type
of treatment and indication, biological work-up at admission
(hemostasis, urea and creatinemia), aggravating bleeding risk fac-
tors (high blood pressure and/or concomitant antiplatelet therapy),
and comorbidities such as known kidney or liver failure.
After clearing the nose and aspirating clots, first-line treatment
in our center consists in uni- or bilateral anterior packing with
calcium alginate. In case of failure, anteroposterior packing is per-
formed using double-balloon probes, in which case admission is
systematic. Other criteria for admission comprise duration and/or
abundance of bleeding, iterative epistaxis, and diathesis. Endo-
scopic surgical treatment is indicated for recurrence of bleeding,
whether during or on removal of packing. Embolization is indicated
in case of contraindications to surgery: local obstacle, or contraindi-
cations to general anesthesia. In case of AVK overdose, antagonists
are administered in line with Health Authority guidelines.
Severity was assessed on 4 criteria:
• hemoglobin concentration at admission;
• need for transfusion;
• type of treatment (need for heavy treatment such as surgical
hemostasis and/or embolization);
• in-hospital progression (hospital stay, transfer to continuous
surveillance or intensive care, death).
Two treatment groups were distinguished: AVK (fluindione,
warfarin or acenocoumarol), and NOAC (dabigatran etexilate,
rivaroxaban or apixaban).
Statistical analysis used the BiostaTGV application [Pierre-Louis
Epidemiology and Public Health Institute, affiliated to the National
Institute of Health and Medical Research (Inserm) and Pierre-and-
Marie-Curie University, Paris). Fisher or Student tests were used as
appropriate. The significance threshold was set at P = 0.05.
3. Results
Between January 1, 2010 and June 30, 2015, 134 patients
were admitted for spontaneous epistaxis complicating oral
Please cite this article in press as: L’Huillier V, et al. Epistaxis complicating treatment by anti-vitamin K and new oral anticoagulants.
European Annals of Otorhinolaryngology, Head and Neck diseases (2017), https://doi.org/10.1016/j.anorl.2018.04.006
anticoagulation therapy: 126 under AVK and 8 under NOAC.
Molecules comprised fluindione, 84.2% (n = 139); acenocoumarol,
6.1% (n = 10); warfarin, 4.9% (n = 8); rivaroxaban, 3% (n = 5); and
dabigatran, 1.8% (n = 3). None of the NOAC patients received apixa-
ban.
Fig. 1 shows mean annual admission distributions: 26.1 for epis-
taxis under AVK, with a decreasing trend, and 2 for epistaxis under
NOAC (as of 2012). Admission for epistaxis under NOAC did not
increase over the study period.
Table 1 shows epidemiological data.
Results for severity of bleeding as endpoint are shown in Table 2.
Only mean hospital stay showed a significant inter-group differ-
ence, with 4.5 days for AVK versus 3.5 days for NOAC (P = 0.019;
95% CI [0.1921; 0.8907]).
4. Discussion
In almost 80% of the present series, oral anticoagulants were
prescribed for atrial fibrillation, with the objective of preventing
secondary stroke. According to European Society of Cardiology
guidelines, indications for effective anticoagulation are based on
the CHA2 DS2 -VASc score (Table 3) [7]. When anticoagulation ther-
apy is required, the choice between AVK and NOAC is left up to
the prescriber [7], although the French Health Authority (HAS)
systematically recommends AVK in first line [2]. Three major
studies assessed non-inferiority of NOACs to warfarin in this indi-
cation: RE-LY for dabigatran [8], ROCKET-AF for rivaroxaban [9]
and ARISTOTLE for apixaban [10]. The ROCKET-AF results were
later extrapolated to study treatment of major hemorrhage in
the two treatment arms [11]. Only severe epistaxis on the Inter-
national Society on Thrombosis and Haemostasis (ISTH) criteria
was included: i.e., epistaxis leading to death, with ≥ 2 g/dL fall in
hemoglobin concentration, or requiring transfusion of ≥ 2 PRBCs
[12]. There was no difference in epistaxis rate according to treat-
ment. Comparison of major hemorrhage rates under warfarin
versus apixaban was significantly in favor of the NOAC: 2.13%
per year for apixaban versus 3.09% for warfarin (P < 0.001). Com-
parison of rates of hemorrhage of whatever severity also favored
the NOAC: 28.5% per year for warfarin versus 18.1% for apixaban;
however, epistaxis rates per bleeding location were not specified
[13]. According to the literature, the risk of bleeding is equivalent
between AVK and NOACs, with a trend in favor of NOACs.
The data from the RE-LY study, which included 18,113 patients,
were used to study the interaction between age and bleeding risk.
Intra- and extracranial bleeding risk was equivalent between treat-
ments up to the age of 75 years; at more advanced age, the risk
of intracranial bleeding was less under dabigatran, but the risk
of extracranial bleeding was greater in certain locations. Data for
epistaxis were not analyzed specifically but rather included in a
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Table 1
Epidemiological data for patients admitted to the ENT department of Besançon Regional university Hospital with epistaxis during oral anticoagulation therapy: AVK group,
NOAC group and total population.

AVK NOAC Total

n= % [95% CI] n= % [95% CI] n= % [95% CI]

Numbers 126 94 [90; 98] 8 6 [2; 10] 134 100

Age
< 65 years 16 12.7 [6.9; 18.5] 0 – 16 11.9 [6.4; 17.4]
65–74 years 14 11.1 [7.9; 20.1] 2 25 [−5; 55] 16 11.9 [6.4; 17.4]
75–79 years 24 19.1 [12.2; 26] 1 12.5 [−10.4; 35.4] 25 18.7 [12.1; 25.3]
≥ 80 years 72 57.1 [48.5; 65.7] 5 62.5 [29; 96] 77 57.5 [49.1; 65.9]
Gender
Male 77 61.1 [52.6; 69.6] 5 62.5 [29; 96] 82 61.2 [52.8; 69.4]
Female 49 38.9 [30.4; 47.4] 3 37.5 [4; 71] 52 38.8 [43.5; 60.5]
Risk factors
History of epistaxis 63 50 [41.3; 58.7] 5 62.5 [29; 96] 67 50 [41.5; 58.5]
Known HBP 85 67.5 [59.3; 75.7] 2 25 [−5; 55] 87 64.9 [56.8; 73]
Associated APA 50 39.7 [31.2; 48.2] 5 62.5 [29; 96] 55 41 [32.7; 49.3]
Kardegic only 43 34.1 [25.8; 42.4] 5 62.5 [29; 96] 48 35.8 [27.7; 43.9]
Other APA 7 5.6 [25.8; 42.4] 0 – 7 35.8 [27.7; 49.3]
Indication for anticoagulation
Emboligenic cardiopathy 94 74.6 [67; 82.2] 5 62.5 [29; 96] 99 73.9 [66.5; 81.3]
DVT and/or PE 19 15.1 [8.8; 21.4] 3 37.5 [4; 71] 22 16.4 [10.1; 22.7]
Prevention of MI complications 5 4.0 [0.6; 7.4] 0 – 5 3.8 [0.6; 7]
Valve replacement 25 19.8 [12.8; 26.8] 0 – 25 18.7 [12.1; 25.3]

AVK: anti-vitamin K; NOAC: new oral anticoagulants; HBP: high blood pressure; APA: antiplatelet agent; DVT: deep venous thrombosis; PE: pulmonary embolism; MI:
myocardial infarction.

Table 2
Epistaxis severity criteria per group and in total population.

AVK NOAC Total OR P-value

n= % [95% CI] n= % [95% CI] n= % [95% CI]

Treatment
Embolization 7 4.6 [1.3; 7.9] 1 12.5 [−10.4; 35.8] 8 4.8 [−10.4; 35.8] 4.6 0.2
Endonasal surgery 6 3.8 [0.8; 6.8] 0 6 3.6 [0.8; 6.4] 1
Antagonization 41 26.1 [19.2; 33] 1 12.5 [−10.4; 35.8] 42 25.5 [18.8; 32.2] 0.4 0.68
Transfusion 32 20.4 [14.1; 26.7] 2 25 [−5; 55] 34 20.6 [14.4; 26.8] 1.1 1
PRBCs: mean (SD) 0.41 (0.96) – 0.5 (0.87) – 0.41 (0.96) – – 0.79
Hospital admission
Number: mean (SD) 1.75 (1.43) – 1 (0) – 1.72 (1.40) – – 0.14
Stay (days): mean (SD) 4.54 (2.85) – 3.5 (0.87) – 4.49 (2.80) – – 0.02
Transfer to continuous surveillance 3 1.9 [−0.2; 4] 1 12.5 [−10.4; 35.8] 4 2.4 [0.1; 4.7] 6.1 0.21
Hemoglobin at admision (g/dL): mean (SD) 12.4 (2.3) – 13.1 (1.7) – 12.5 (2.3) – – 0.3

AVK: anti-vitamin K; NOAC: new oral anticoagulants; PRBC: packed red blood cells; SD: standard deviation.

Table 3
CHA2 DS2 -VASc score (from [7]).

Risk factors Definition Points

Congestive heart failure Symptoms of heart failure or objective reduction in LVEF +1

High blood pressure BP > 140/90 mmHg on ≥ 2 measurements, or antihypertensive treatment +1
Age ≥ 75 years +2
Diabetes Fasting glucose > 7 mmol/L or oral antidiabetes treatment +1
History of thromboembolism +2
Vascular pathology History of MI, LLAO or carotid atheroma +1
Age 65–74 years +1
Female gender +1

LVEF: left ventricle ejection fraction; BP: blood pressure; MI: myocardial infarction; LLAO: lower-limb arteriopathy obliterans.

“nose–throat–ear” category of hemorrhage locations, in which the
difference in bleeding risk between warfarin and dabigatran was
non-significant [14]. Atrial fibrillation is a pathology of the elderly,
two-thirds of patients being aged ≥ 75 years [15]. The present epi-
demiological data were coherent with this figure, with 76.1% of
patients aged > 75 years. Advanced age is thus a supplementary risk
factor for hemorrhagic complications in anticoagulation therapy.
However, elderly subjects also show increased risk of embolism,
and anticoagulation therapy has been demonstrated to provide net
benefit. The French Geriatrics and Gerontology Society and French
Cardiology Society jointly recommend applying the precautionary
principle in prescribing NOACs to patients aged > 80 years, given a
lack of relevant data in the literature [15]. However, in a subgroup
analysis of the 3 princeps NOAC studies by age, Barco et al. con-
cluded that the risk/benefit ratio was in favor of anticoagulation
therapy for elderly patients [16].
In the present series, the number of hospital admissions
for epistaxis complicating NOAC treatment was low, and much
lower than in case of AVK. This might suggest that epistaxis is
less severe under NOACs than under AVK, allowing outpatient
management; however, as prescription rates per molecule over
the study period and the geographical area concerned are not

Please cite this article in press as: L’Huillier V, et al. Epistaxis complicating treatment by anti-vitamin K and new oral anticoagulants.
European Annals of Otorhinolaryngology, Head and Neck diseases (2017), https://doi.org/10.1016/j.anorl.2018.04.006
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available, no conclusion can be reached. In a prospective study,
García Callejo et al. [17] compared emergency consultation rates
between acenocoumarol, dabigatran and no anticoagulation treat-
ment, in 222 patients (acenocoumarol, 27%; dabigatran, 9%; no
anticoagulation treatment, 64%); they also found lower epistaxis
rates under NOAC, but with less difference between groups than in
the present study. Transfusion rates, on the other hand, were higher
with dabigatran than with acenocoumarol (80% vs. 58%; P < 0.001),
as was the rate of invasive hemostasis (surgical or by emboliza-
tion): 80% vs. 35.2%; P < 0.001. The authors concluded that bleeding
risk was lower under dabigatran, but with more difficult control
[17]. In contrast, the present study found no significant difference
in invasive treatment rates between the 2 groups.
In the present series, hospital stay was shorter with NOACs than
with AVKs, and this was the only significant severity criterion. In the
ROCKET-AF study [11], median hospital stay was likewise shorter
in the rivaroxaban arm. In the study by García Callejo et al., on the
other hand, hospital stay was longer in the dabigatran group (5.9
vs. 4.3 days), although the difference was not significant [17].
Biologically, creatinemia and urea levels were above normal
in both groups, without significant difference. Whereas AVKs are
metabolized by the liver and eliminated in bile as inactive metabo-
lites [15], NOACs are eliminated mainly through the kidneys: 80%
for dabigatran [4,6,18], and 25–29% for apixaban [19]. There is thus
a risk of overdose by plasma accumulation that might induce bleed-
ing; dose should therefore be adjusted for each molecule in case of
kidney failure [13,18,19].
In the present study, several points might implicate anticoagu-
lants in onset of bleeding. Firstly, 55% of patients had concomitant
treatment including ≥ 1 antiplatelet agent, with aspirin in 48% of
cases. Antiplatelets are frequently associated with epistaxis [20,21]
and aggravate severity [21]. The risk/benefit ratio for associating
anticoagulants, whether AVK or NOAC, to 1 or 2 antiplatelet agents
has never been assessed in over 75-year-olds, although it has been
shown to increase the risk of hemorrhage [15]. Moreover, 64.9% of
the present patients had history of high blood pressure, without
significant inter-group difference. In a literature review seeking
to confirm a relation between epistaxis and high blood pressure,
Kikidis et al. [22] included 9 articles: 3 failed to take account of
confounding factors, 3 found a relation and 3 did not. The causal
relation between high blood pressure and epistaxis thus remains a
matter of debate.
The present study shows 2 main limitations. Firstly, the NOAC
group was small, hindering comparison. This was because NOACs
are still little prescribed compared to AVKs. It may also be that
they induce less epistaxis, or that the bleeding they induce is less
severe, allowing outpatient management. Secondly, and perhaps
more importantly, only hospital patients were included, and hospi-
tal admission is in itself a criterion of severity, indicated for failure
of emergency treatment, duration and/or abundance of bleeding,
iterative epistaxis, and/or comorbidity. The present series thus
presented a certain primary level of severity, within which we
identified sublevels.
5. Conclusion
New oral anticoagulants have shown equivalence or superiority
to AVKs as reference treatment in the indication of atrial fibrillation.
They are thus an alternative of choice, being notably easy to use for
the patient.
In our center, the number of patients admitted for epistaxis
complicating NOAC treatment is low, and much lower than for
the same complication under AVK. NOACs also induce less severe
bleeding, with significantly shorter hospital stay. Contradicting the
Please cite this article in press as: L’Huillier V, et al. Epistaxis complicating treatment by anti-vitamin K and new oral anticoagulants.
European Annals of Otorhinolaryngology, Head and Neck diseases (2017), https://doi.org/10.1016/j.anorl.2018.04.006
initial study hypothesis, epistaxis is less serious when complicating
treatment by NOACs than by AVK.
NOACs are indicated for elderly patients liable to show multiple
comorbidity. Prescription and monitoring should take account of
this, with dose adaption as needed. A prospective study of patients
presenting in emergency with epistaxis under oral anticoagulant
therapy would better determine whether the increasing number
of NOAC prescriptions affects the number and severity of cases
of iatrogenic epistaxis. Admission rates could then be taken into
account as a severity criterion. Such a study could have a larger
cohort and shorter inclusion period.
Disclosure of interest
The authors declare that they have no competing interest.
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European Annals of Otorhinolaryngology, Head and Neck diseases (2017), https://doi.org/10.1016/j.anorl.2018.04.006