Vol. - No.

- Month 2016

Management of dental extraction in patients undergoing

anticoagulant oral direct treatment: a pilot study
Cédric Mauprivez, DDS, PhD,a Roman Hossein Khonsari, MD, PhD,b Omar Razouk, DDS,b
Patrick Goudot, MD, PhD,b Philippe Lesclous, DDS, PhD,c and Vianney Descroix, DDS, PhDd

Objective. The main goal of this study was to compare the incidence of postoperative bleeding events after dental extractions
between patients treated with direct oral anticoagulants (DOACs) and those treated with vitamin K antagonists (VKAs) without
withdrawal of oral anticoagulant therapy (OAT). Our second objective was to evaluate the risk factors affecting postoperative
hemorrhage after tooth extraction in patients taking DOACs.
Study Design. This prospective observational study included 51 patients who were being treated with oral anticoagulants and
required dental extractions. They were divided into two groups: 31 patients receiving a DOAC and 20 control patients taking
VKA with an international normalized ratio between 2.0 and 3.0. In both groups, extractions were performed under continued
OAT, and the same local hemostatic measures were applied. All procedures were performed in an outpatient facility. A
bleeding event was defined as persistent oozing or marked hemorrhage over 20 minutes after tooth extraction despite local
hemostasis procedures or all bleeding episode occurring during the first postoperative week.
Results. Five patients taking DOACs had seven bleeding episodes, and four patients receiving VKAs had five bleeding
episodes during the postoperative follow-up period. The difference in the number of bleeding events between the two groups
was not statistically significant (adjusted odds ratio ¼ 0.77; 95% confidence interval 0.19-3.19; P ¼ .723). Eleven (91.67%)
bleeding events were mild and controlled by mechanical compression with gauzes, and one (8.33 %) was managed with a
revision of the wound, application of fibrin glue, and resuturing. No bleeding required hospitalization or blood transfusion. All
bleeding episodes occurred during the first 3 postoperative days.
Conclusions. According to our preliminary outcome data, dental extractions can be performed safely in an outpatient facility
in patients treated with DOAC by applying local hemostatic measures, without interrupting or modifying OAT. (Oral Surg Oral
Med Oral Pathol Oral Radiol 2016;-:e1-e10)

For many decades, vitamin K antagonists (VKAs) have
been the only oral anticoagulant drugs available for the
prevention and treatment of thromboembolic diseases.
Anticoagulant therapy research has focused on target-
ing single enzymes in the coagulation cascade, hoping
to reduce the disadvantages of the traditional antico-
agulant drugs.1 Four new oral anticoagulants, also
called direct oral anticoagulants (DOACs), are
currently available in North America and in the
countries of the European Union.2 Dabigatran
etexilate (Pradaxa; Boehringer Ingelheim International
GmbH) is a direct thrombin inhibitor and a key
coagulation enzyme that converts fibrinogen into
a others drugs and food.1,3
AP-HP, Service d’Odontologie, Groupe Hospitalier Pitié Salpêtrière
Charles Foix, Paris, France; Service d’Odontologie, Hôpital Maison
Blanche, Centre Hospitalier Universitaire, Reims, France; Laboratoire
E.A., 4691 Biomateriaux et Inflammation en Site Osseux, Université
Reims Champagne-Ardennes, Reims, France.
b
AP-HP, Service de chirurgie maxillo-faciale, Paris, France; UPMC
Université Paris 06, Paris, France.
c
Consultant, INSERM 791, LIOAD; Université de Nantes, UMRS-S
791, LIOAD, UFR d’Odontologie; ONIRIS, UMR-S 791, LIOAD;
CHU Nantes, PHU 4 OTONN, Nantes, France.
d
AP-HP, Service d’Odontologie, Groupe Hospitalier Pitié Salpêtrière
Charles Foix, Paris, France.
Received for publication Apr 26, 2016; accepted for publication Jun
5, 2016.
Ó 2016 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
http://dx.doi.org/10.1016/j.oooo.2016.06.003
fibrin. The oral direct factor Xa inhibitor group is
often referred to as the -xaban group and contains
three molecules: rivaroxaban (Xarelto; Bayer Pharma
AG, and Jansen Pharmaceuticals, Inc.,), apixaban
(Eliquis; Bristol-Myers Squibb, and Pfizer EEIG), and
the more recent edoxaban (Lixiana, Savaysa; Daiichi
Sankyo Co.). These drugs block the enzymatic function
of factor Xada component of the prothrombinase
complex that catalyzes the generation of thrombindin
a reversible way.
Unlike VKAs, DOACs are administrated on the basis
of a fixed-dose regimen without the need for regular
laboratory monitoring. DOACs also have a relatively
rapid onset, a short half-life, and fewer interactions with
DOACs are used for the prevention of stroke and
systemic embolism in patients with nonvalvular atrial
fibrillation, as well as for the prevention and treatment
of recurrent venous thromboembolism. DOACs can be
Statement of Clinical Relevance
Patients currently taking direct oral anticoagulants
should wait at least 4 to 6 hours after the last dose
before dental extractions. Local hemostasis seems to
be sufficient to prevent postoperative bleeding.

e1
ORAL AND MAXILLOFACIAL SURGERY
e2 Mauprivez et al.
used in combination with antiplatelet agents for the
prevention of atherothrombotic events in patients pre-
senting with acute coronary syndromes and elevated
cardiac biomarkers.
The management of anticoagulation in patients un-
dergoing surgical procedures is a clinical challenge.
Interruption of oral anticoagulant therapy (OAT)
temporarily increases the risk of thromboembolism, and
not interrupting OAT potentially increases the risk of
bleeding during and after surgical procedures.
Dental and skin surgical procedures are generally
associated with a low risk of bleeding. Postoperative
bleeding rates after dental surgery, including simple
and surgical tooth extractions, are below 1% in patients
without OAT.4,5 In patients taking VKAs with a stable
international normalized ratio (INR) in the therapeutic
range (i.e., <4) the risk of postoperative bleeding when
undergoing tooth extraction is below 7%.5 The oral
surgical sites are accessible, and bleeding is easily
controlled by using local hemostatic measures (e.g.,
gelatin sponge, oxidized cellulose, fibrin glue,
sutures, pressure application with gauze, and
tranexamic acid). The reported risk of severe bleeding
requiring more than local hemostatic measures is only
about 0.6%.5 No fatal hemorrhagic complications of
oral surgery have been reported in the literature.
Conversely, with OAT interruption, the risk of
thromboembolism is estimated to be 0.8%, including
0.2% fatal events.5 According to the literature, OAT
should not be interrupted when patients need dental
extractions.4-9
Current guidelines recommend not stopping oral
antithrombotic treatments for simple dental procedures
(e.g., dental extraction, dental implant surgery, peri-
odontal surgery).6-9 In brief, keeping patients under
OAT when a dental extraction has to be performed is
the gold standard in the perioperative management of
anticoagulation.
The primary objective of this prospective study was
to compare the incidence of postoperative bleeding after
tooth extractions between a group of patients treated
with DOACs and a group of patients using conven-
tional oral anticoagulant (VKAs) without any pause or
modification in their antithrombotic treatment. The
secondary objective of this study was to evaluate the
risk factors for postoperative bleeding after tooth ex-
tractions in patients under DOACs.
MATERIAL AND METHODS
Ethical guidelines
The study protocol was approved by the ethics com-
mittee “Comité de Protection des Personnes Ile de
France VI” (No. 020314), and the guidelines estab-
lished in the Declaration of Helsinki (revised 2002
version) for research involving human patients were
OOOO
Month 2016
followed. Each patient gave informed consent to take
part in the study.
Patients
We included patients admitted at the Oral Surgery
Department of the Pitié-Salpêtrière Hospital in Paris,
France, between January 2014 and December 2015; 31
patients (14 males and 17 females) treated with DOACs
were included. The control group consisted in 20 pa-
tients treated with VKAs. Indications were similar in
both the DOAC and VKA groups, with target INR
values between 2.0 and 3.0. Patients with a prosthetic
valve or valvulopathy with a target INR ranging from
3.0 to 4.0 and those with hematologic diseases or liver
dysfunction were excluded. Complete medical histories
were collected. Patients with an out-of-range INR value
(>4 on extraction day) or fluctuating INR values were
excluded.
Tooth extractions and local hemostatic measures
All tooth extractions were performed with the patients
under local anesthesia, without interrupting or modi-
fying OAT; the procedures were performed in an
outpatient facility, early in the morning, by four quali-
fied oral surgeons. Patients in both the DAOC and
VKA groups had similar indications for dental
extractions.
Local anesthesia was provided by using submucosal
infiltration of articaine hypochloride 4% with epineph-
rine (Septanest 1:200,000; Septodont, Saint-Maur des
Fossés, France) and/or inferior alveolar nerve block
with 3% mepivacaine hydrochloride without vasocon-
strictors (Scandicaïne, Septodont, Saint-Maur des
Fossés, France).
“Simple extraction” was defined as an extraction
using forceps and/or elevator, and “surgical extraction”
was defined as a procedure requiring the elevation of a
mucoperiosteal flap and/or an osteotomy. The dental
extractions were carried out in the least traumatic way
possible, and a meticulous curettage of the extraction
socket was performed. Local hemostasis was achieved
by applying a 10  10  10-mm absorbable gelatin
sponge (Gelitaspon, Gelita Medical GmbH, Eberbach,
Germany) in all dental extraction sockets. The wound
was closed with 4.0 polyglactin 910 sutures (Vicryl,
Johnson & Johnson/Ethicon, Somerville, NJ).
After surgery, patients were asked to bite on a piece
of sterile gauze for 10 minutes to compress the operated
area. Patients were then examined to ensure that he-
mostasis was obtained. When postoperative bleeding
was observed, patients were asked to bite on a piece of
sterile gauze for 10 more minutes. When the bleeding
stopped, patients were instructed to apply external ice
packs on the operated area for 6 to 8 hours
OOOO ORIGINAL ARTICLE
Volume -, Number - Mauprivez et al. e3

Table I. Patient characteristics (clinical and laboratory variables) and indications for oral anticoagulant therapy
(OAT)
DOACs VKAs
(n ¼ 31) (n ¼ 20) P value
Age (years) .892
Mean  SEM 70.26  2.07 70.60  2.80
Range [46-90] [44-94]
Gender .685
Male, n (%) 14 (45.17) 11 (55)
Female, n (%) 17 (54.83) 9 (45)
Drugs
Apixaban, n (%) 1 (1) -
Dabigatran, n (%) 9 (29) -
Rivaroxaban, n (%) 21 (70) -
Acenocoumarol, n (%) - 0 (0)
Fluindione, n (%) - 17 (85)
Warfarin, n (%) 3 (15)
Indication of OAT .935
Atrial fibrillation, n (%) 6 (19) 4 (20)
Venous thromboembolism, n (%) 22 (71) 13 (65)
Stroke, n (%) 3 (10) 2 (10)
Acute coronary syndrome, n (%) 3 (10) 4 (20)
Biologic data before intervention
INR, mean  SEM - 2.28  0.10
Range - [1.52-3.03]
Creatinine clearance (mL/min), mean  SEM 82.13  4.85 71.05  6.95 .482
Range [48-154] [23-126]
DOAC, direct oral anticoagulant; INR, international normalized ratio; SEM, standard error of mean; VKA, vitamin K antagonist; OAT, oral anti-
coagulant therapy; aPPT, activated partial thromboplastin time.

postoperatively. After at least 2 hours of monitoring and
a final clinical check-up, patients were sent back home.
They were handed a self-survey and written post-
operative instructions. To prevent postoperative
bleeding, each patient was prescribed passive mouth-
washes with acid tranexamic to be used three times a
day for 5 to 7 days. Postoperative pain was treated with
1 g acetaminophen every 8 hours for 3 days, or more if
necessary. Amoxicillin 1 g three times a day for 7 days
was prescribed, if required, for the management of
surgical site infections.
Assessment of postoperative bleeding
A “postoperative bleeding event” was defined as an
oozing or marked hemorrhage that could not be
controlled using local hemostasis measures followed by
a mechanical compression with gauze for over 20 mi-
nutes. Bleeding risk was monitored from the day of
surgery up to 1 week after the tooth extractions with a
self-administered survey. Patients from both groups had
to complete the survey to help assess the incidence and
severity of bleeding events. The oral surgeon’s cell
phone number was given to patients so that they could
reach him in case of problems.
During follow-up, all patients were called on post-
operative day 3 to confirm the absence of oozing or
major bleeding. Patients were seen in the clinic 7 days
after surgery to remove the stitches, evaluate the heal-
ing, and collect the survey answers. The number of
postoperative bleeding events and the number of pa-
tients with postoperative bleeding were recorded for
each group and compared. Furthermore, in patients with
postoperative bleeding, the time of onset of the post-
operative bleeding (24 hours, >24 hours and
48 hours, >48 hours, 72 hours, >72 hours, and
7 days), the description of the bleeding episode (site,
date/time, severity: mild, moderate, severe), and man-
agement of the bleeding (site compression, local he-
mostatic measures, hospital readmission, length of
hospital stay) were collected.
Risk factors for bleeding associated with direct
treatment with oral anticoagulants
The collected parameters were patient characteristics (age,
gender, weight, tobacco use), oral anticoagulant therapy
(dabigatran, rivaroxaban, apixaban, fluindione, warfarin,
acenocoumarol), total and mean number of extracted teeth,
type of tooth extraction (single or multiple, simple or
surgical), surgical procedure duration, and acute inflam-
matory findings in connection with extracted teeth. Acute
inflammatory findings were defined as pus discharge,
swelling and redness of soft tissue around the tooth to be
extracted (gingivitis), or strong percussion pain on the
tooth to be extracted (periapical infection); patients with at
ORAL AND MAXILLOFACIAL SURGERY OOOO
e4 Mauprivez et al. Month 2016

Table II. Dentoalveolar surgery

DOACs (n ¼ 31) VKAs (n ¼ 20) P value
Local anesthesia
Inferior alveolar nerve block, n (%) 4 (14.3) 4 (20) .441
Submucosal infiltration,n (%) 31 (100) 20 (100) .999
Vasoconstrictor, n (%) 25 (82.1) 19 (95) .548
Without vasoconstrictor, n (%) 8 (28.6) 5 (25) .755
Dental extractions
Total number of extracted teeth 73 53 .131
Simple extraction, n (%) 64 (87.67) 43 (81.13) .528
Surgical extraction, n (%) 9 (12.33) 10 (18.87) .139
Single extraction, n (%) 12 (38.71) 4 (20) .169
Multiple extractions, n (%) 19 (61.29) 16 (80) .169
Surgical duration (min), mean  SEM 35.00  2.47 32.28  2.17 .721
Range [13-60] [15-60]
Time to obtain complete hemostasis .237
<10 min, n (%) 23 (74.19) 11 (57.9)
>10 min and <15 min, n (%) 7 (22.58) 8 (36.8)
<20 min, n (%) 1 (3.22) 1 (5.3)
DOAC, direct oral anticoagulant; SEM, standard error of mean; VKA, vitamin K antagonist.

least one of these findings were considered as having acute
inflammation.10
Additional collected parameters were diabetes mel-
litus, concomitant medications affecting hemostasis
(e.g., antiplatelet agents, nonsteroidal anti-inflammatory
drugs, P-glycoprotein inhibitors), estimated creatinine
clearance (Modification of the Diet in Renal Disease
formula), activated partial thromboplastin time (aPTT),
prothrombin time (PT), and time of last dose of DOACs
before surgery.
Statistical analysis
For the primary objective, a c2 test was conducted to
compare bleeding events between the DOAC group and
the VKA group. Odds ratio and confidence intervals
were calculated for the 95% interval using the Miettinen
method. For all other analyses, a c2 test was used for
qualitative variables and a Mann-Whiney U test was
used for continuous variables.
In all analyses, differences were considered
significant for P  .05. Data were expressed as
mean  standard error of the mean. All analyses were
performed using StatView 5.0 (SAS Institute Inc., Cary,
NC).
RESULTS
Patients characteristics
The main clinical and biologic characteristics of the
patients enrolled in this study are reported in Table I.
In the DOAC group, 21 patients were taking
rivaroxaban, 9 were taking dabigatran, and 1 was
taking apixaban. In the VKA group, 17 patients
were taking fluindione and 3 patients were taking
warfarin. There was no significant difference
between the groups with regard to gender
(P ¼ .685), age (P ¼ .892), and the indications for
anticoagulant therapy (P ¼ .935).
Dental extraction characteristics
A total of 126 dental extractions were performed: 73 in
the case group and 53 in the control group. Data on the
number and the type of extractions are summarized in
Table II. There were no impacted wisdom teeth. No
surgery lasted for more than 1 hour. There was no
difference between the groups with regard to the type
of dental extraction, surgery duration (P ¼ .721), and
time required to control immediate postoperative
bleeding (P ¼ .237). Local hemostatic measures were
effective within 10 minutes for controlling the
bleeding in 74.19 % in patients of the DOAC group
and 55% of the VKA group. All bleeding events
could be controlled within 20 minutes for all patients
in this study.
Postoperative bleeding characteristics
Data on bleeding complications are summarized in
Table III. In the case group (DOAC group), we
encountered five episodes of mild bleeding the day of
surgery, one episode of mild bleeding, and one
episode of moderate bleeding on day 3 after surgery.
Two patients had two events so that a total of five
patients were reviewed. Two bleeding events occurred
with dabigatran (110 mg and 150 mg twice daily),
three events occurred with rivaroxaban (15 mg and
20 mg once daily), and two events occurred with
apixaban (5 mg twice daily). All DOACs had been
prescribed for the treatment of nonvalvular atrial
fibrillation.
OOOO ORIGINAL ARTICLE
Volume -, Number - Mauprivez et al. e5

Table III. Delayed bleeding characteristics in the both groups

DOACs (n ¼ 31) VKAs (n ¼ 20) P value
Number patients who suffered bleeding event, n (%) 5 (17.8) 4 (20) .723
Total postoperative bleeding episodes, n (%) 7 (22.58) 5 (25) .962
Onset of delayed bleeding .583
>20 minutes and 120 minutes postoperative 3 (42.86) 1 (20)
>120 minutes and 12 hours 0 (0) 2 (40)
>12 hours and 24 hours postoperative 2 (28.57) 2 (40)
>24 hours and 48 hours postoperative 0 (0) 0 (0)
>48 hours and 72 hours postoperative 2 (28.57) 0 (0)
>72 hours and 7 days after tooth extraction(s) 0 (0) 0 (0)
Management of bleeding .999
Local compression 6 (85.7) 5 (100)
Require reoperation under local anesthesia 1 (14.3) 0 (0)
Hospitalization 0 (0) 0 (0)
DOAC, direct oral anticoagulant; VKA, vitamin K antagonist.

Table IV. Risk factors associated with bleeding events in patients on dabigatran
Dabigatran
No bleeding (n ¼ 7) Bleeding (n ¼ 2) P value
Age (years), mean  SEM 68.86  5.28 67.50  2.50 .768
Range [46-88] [65-70]
Gender (male/female), n 2/5 1/1 .593
Total number of extracted teeth 21 2 .313
Number of extraction per patient, mean  SEM 3.00  0.0 1.00  0.0
Range [1-9] [1]
Type of tooth extraction
Single/multiple, n/n 2/5 2/0
Simple/surgical, n/n 19/2 2/0
Surgical duration (min), mean  SEM 35.36  3.10 27.50  2.50 .613
Range [13-60] [25-30]
Smokers, n (%) 1 (14.28) 1 (50) .312
Acute inflammatory findings, n (%) 6 (85.71) 1 (50) .464
aPTT (patient/control), mean  SEM 1.35  0.13 1.80  0.01 <.05
Prothrombin time (seconds), mean  SEM 56.57  7.67 57.00  8.00 .317
Creatinine clearance (mL/min), mean  SEM 74.33  8.12 87.73  6.27 .317
Range [52-111] [81-94]
Last dose prior surgery (hours), mean  SEM 5.74  1.89 2.25  0.75 <.05
Range [3.08-17.00] [1.5-3.0]
SEM, standard error of mean.

In the control group (VKA group), five bleeding
events were reported; one patient had two bleeding
events, so we considered a total of four patients. All
postoperative bleeding episodes were mild and
occurred on the day of surgery, two in fluindione users
and two in warfarin users. INR values measured at the
time of tooth extractions ranged from 1.93 to 2.77. The
indications included the following: two patients treated
for nonvalvular atrial fibrillation, two for prevention of
recurrent deep venous thrombosis and pulmonary
thrombosis, and one for the prevention of athero-
thrombotic events after a stroke.
In both groups, postoperative bleeding events were
observed in the molar region for over 50% of the
patients. All cases of postoperative bleeding were
easily controlled with local hemostatic measures. No
patients included in the study had severe bleeding
requiring systemic therapy or a hospitalization. Mild
bleeding was managed by digital compression with
gauze soaked in acid tranexamic (Exacyl, 1 g/10 mL,
drinking solution, Sanofi, Gentilly, France) for
30 minutes. For moderate bleeding, a surgical explo-
ration of the wound was performed, and additional
local hemostatic measures, including topical hemo-
static agents and sutures, were taken to control the
bleeding.
The difference in the number of bleeding events
between the two groups was not statistically significant
(odds ratio ¼ 0.77; 95% confidence interval 0.19-3.19;
P ¼ .723; see Table III). No thromboembolic
ORAL AND MAXILLOFACIAL SURGERY OOOO
e6 Mauprivez et al. Month 2016

Table V. Risk factors associated with bleeding events in patients on -xabans*

-xabans
No bleeding (n ¼ 19) Bleeding (n ¼ 3) P value
Age (years), mean  SEM 71.16  2.82 69.67  1.76 .701
Range [48-90] [67-73]
Gender (male/female), n 2/5 1/2 .544
Total number of extracted teeth 21 8 .211
Number of extraction per patient, mean  SEM 3.00  0.0 2.67  0.57
Range [1-9] [2-3]
Type of tooth extraction
Single/multiple, n/n 2/5 0/3
Simple/surgical, n/n 19/2 8/0
Surgical duration (min), mean  SEM 34.84  3.06 38.33  11.67 .691
Range [17-60] [20-60]
Smokers, n (%) 2 (11.76) 1 (33.33) .296
Acute inflammatory findings, n (%) 13 (68.42) 2 (66.66) .645
aPTT (patient/control), mean  SEM 1.17  0.04 1.31  0.09 .165
Prothrombin time (seconds), mean  SEM 56.51  4.36 56.00  4.73 .632
Creatinine clearance (mL/min), mean  SEM 85.70  7.07 68  3.79 .315
Range [48-154] [61-74]
Last dose prior surgery (hours), mean  SEM 7.68  1.36 2.19  0.43 <.05
Range [1.83-18] [1.5-3.75]
SEM, standard error of mean.
*Because of the low number of patients treated by apixaban, patients on rivaroxaban and on apixaban were consolidated in a single class, i.e.,
-xabans.

complication was reported by the physicians in the
30 days following surgery.
Risk factors for bleeding associated with direct
treatment with oral anticoagulants
Among the nine patients taking dabigatran, two pa-
tients (22.22%) developed a bleeding complication.
With regard to factors affecting postoperative bleeding,
significant differences were seen in relation to the
prolongation of aPTT and delay between the last drug
administration and the surgical procedure (P < .05).
All bleeding occurred with aPTT 1.80 and taking
medication within 3 hours before the surgery
(Table IV).
Among the 22 patients receiving oral direct factor Xa
inhibitor, three patients (13.63%) experienced bleeding
events. For these three patients, surgery was performed
less than 4 hours after the last dose of drug (P < .05;
Table V).
DISCUSSION
To date, few studies have investigated the perioperative
dental management of patients under DOAC therapy.
Some authors supported withholding the DOAC dose
before performing invasive dental procedures.11,12
These authors preferred stopping DOACs temporarily
at least 24 hours before the elective surgery and
restarting the following day. These initial studies were
based on speculative expert opinions and on pharma-
cologic profile of DOACs.
Others authors suggested that interrupting DOACs
was not necessary and that the bleeding risk for
dentoalveolar surgery, such as tooth extractions or
dental implant placement, were overstimated.13-17
This approach is supported by data obtained from
safety profiles in the phase III clinical trials comparing
patients using dabigatran, rivaroxaban, or apixaban
compared with (1) patients using warfarin, for the
treatment of atrial fibrillation or (2) patients using
enoxaparin (40 mg) for the prevention of venous
thromboembolism after major orthopedic procedures
(hip or knee replacement). In all these trials, the rates
of minor bleeding in patients using DOACs were
similar todor lower thandthose in patients using
warfarin or enoxaparin.18 These authors thus
recommended not interrupting DOACs in patients
requiring dental extraction or minor oral surgical
procedures and considering them in the same
manner as patients taking VKAs with an INR value
less than 3. The bleeding risk could be reduced
using topical hemostatic agents. These authors
suggested that continuing DOACs was safe for tooth
extractions when local hemostatic measures were
applied.
Various hemostatic agents (oxidized cellulose,
gelatin sponge, fibrin glue, and tranexamic acid) have
been used without real difference in efficiency.19 The
main factors involved in controlling local hemostasis
OOOO
Volume -, Number - Mauprivez et al. e7
are sutures and digital mechanical compression of the
wound with gauze by the surgeon for at least
10 minutes. In this study, the local hemostatic
measures with gelatin sponge, suture, and gauze
soaked with tranexamic acid helped achieve
hemostasis within 20 minutes in all patients, without
modifying their anticoagulant treatments.
Elective invasive surgery, such as autologous bone
grafts, sinus-lift, or maxillofacial procedures, require a
higher control of bleeding. In patients with a high
bleeding risk, DOACs can be stopped on the basis of
the half-life of the drug. One advantage of DOACs is
their short-half-lives (dabigatran: 12-17 hours; rivar-
oxaban: 5-13 hours; apixaban: 12-18 hours), similar to
low-molecular-weight heparin (LMWH) (e.g., 4-
7 hours for enoxaparin), but unlike VKAs (acenocou-
marol: 8-11 hours; fluindione: approximately 31 hours;
warfarin: 36-42 hours).1 Using an oral anticoagulant
drug with a short half-life allows reduction of the
interval without anticoagulation and possibly avoidance
of heparin bridging, and the rapid offset and onset of
DOACs may not require preoperative bridging with
LMWH. Furthermore, data from the Outcomes Registry
for Better Informed Treatment of Atrial Fibrillation
(ORBIT-AF) registry showed that heparin bridging
during anticoagulation interruption in patients with
atrial fibrillation increased the incidence of myocardial
infarction, stroke, systemic embolism, hospitalization,
and/or death within the first month after an invasive
procedure but reduced the bleeding incidence down to
5%.20 Finally, unlike warfarin and LMWH, DOACs
do not induce rebound thrombin generation when
withdrawn.18
Oral surgical procedures associated with a low
bleeding risk (e.g., dental extractions) are often per-
formed without interrupting anticoagulation. When oral
and maxillofacial surgical procedures with a higher risk
are required, DOAC therapy can be discontinued after
an agreement with the prescribing physicians of these
drugs. The plasmatic half-lives of DOACs range be-
tween 7 and 17 hours, and are shorter than the plasmatic
half-lives of VKAs. This indicates that the impact of
stopping these treatments will be observed within a day
or two.18 Thus, for surgeries with a high bleeding risk,
the patient has to skip two or three doses of DOACs and
will not receive any doses for the last 2 days before
surgery and on the day of surgery. After the surgery,
the patient can restart DOACs when hemostasis is
secured. This brief withdrawal protocol is associated
with a 48-72-hour period without anticoagulation. The
last DOAC dose depends on the patient’s kidney
function. For patients with a very high risk of throm-
boembolism (>10% annual risk; e.g., stroke, systemic
embolic event within the previous 3 months, non-
valvular atrial fibrillation with CHADS2 [Congestive
ORIGINAL ARTICLE
heart failure, Hypertension, Age 75 years, Diabetes
mellitus, Stroke (double weight)] score >5), elective
surgery may be delayed.21
In the present study, the numbers of bleeding
complications in the test group and in the control
group were not statistically different. These data
suggest that the local hemostatic measures used after
dental extractions in patients taking VKAs were
effective in patients treated with DOACs. These local
hemostatic measures (gelatin sponge, sutures, and
mouthwash with tranexamic acid) were reliable for
preventing postoperative bleeding. In case of severe
bleeding, when local hemostasis is not sufficient, the
DAOCs should be temporarily stopped in collabora-
tion with the patient’s physician. Withholding or
delaying a dose of DOAC is possible in the majority
of patients, except in those with a high risk of
thromboembolism.
In the absence of a specific antidote for DOACs,
prothrombin complex concentrates may be used, when
necessary. Recently, idarucizumab, a monoclonal anti-
body fragment, was developed to neutralize the activity
of dabigatran.22 However, there is very limited clinical
experience with the use of these products in conjunction
with DOACs.
We investigated risk factors influencing post-
operative hemorrhage after tooth extractions in patients
undergoing DOAC therapy. There is heterogeneity in
the definition of bleeding complications. According to
Lockhart et al.,23 “significant bleeding” is defined as
bleeding which (1) is continuous for over 12 hours;
(2) requires the patient to reach his doctor or to return
to the surgery; or (3) requires admission to the
Emergency Department. For Fakhri et al.,12 the cutoff
between postoperative course and a bleeding
complication was 5 to 6 hours after dental extraction.
Morimoto et al.10 defined “postoperative bleeding
events” as oozing that cannot be stopped using
compression by biting down on gauze or bleeding that
requires hemostatic measures performed by an oral
surgeon. Finally, for Eichhorn et al.24 and Hanken
et al.,25 a bleeding complication was registered as an
event that required additional surgical intervention. In
our opinion, a clinically relevant bleeding event is
persistent oozing for over 20 minutes because it
requires a type of care and/or medical supervision that
is not compatible with office practice.
In this study, five out of 31 patients receiving DOAC
therapy had a least one bleeding event, which corre-
sponds to a postoperative bleeding incidence of 16.13%
(95% confidence interval 3.18-29.08; see Table III).
This is in accordance with newly published data by
Hanken et al.,25 reporting a postoperative bleeding
incidence of 11.5% after minor oral surgery in
patients under continued rivaroxaban anticoagulant
ORAL AND MAXILLOFACIAL SURGERY
e8 Mauprivez et al.
therapy. The incidence of postoperative bleeding in the
control group was 20% (4 of 20 patients). This is in
accordance with the literature: 1.55% to 26%
postoperative bleeding events are reported in patients
receiving warfarin therapy and undergoing tooth
extractions.4,11,26
Several patient-dependent or surgery-dependent
factors have to be taken into account when assessing
bleeding risk. An accurate medical history and phys-
ical examination, including intraoral examination, are
very important to assess bleeding risk. Patient-
dependent factors associated with DOAC-related
bleeding, as reported in the literature, are: >80 years
of age, weight less than 63 kg, severe (<30 mL/min)
or moderate (30-50 mL/min) impairment in creatinine
clearance, diabetes mellitus, and concomitant medi-
cations affecting hemostasis (e.g., antiplatelet agents,
nonsteroidal anti-inflammatory drugs, P-glycoprotein
inhibitors).27
Thrombin clotting time and ecarin clotting time are
the most sensitive assays to assess dabigatran effect,
and calibrated antifactor Xa chromogenic assays can
accurately give a quantitative measure of the rivar-
oxaban and apixaban activities.28 However, these
tests are not routinely available for monitoring
DOAC activity. Measurement of anticoagulant
activity or drug concentration might be potentially
necessary in some situations, such as urgent
invasive surgical procedures or major bleeding
complications, or when there is suspicion of acute
drug abuse with overdose.29
A growing amount of data indicates that the aPTT is
the most suitable assay for assessing dabigatran ac-
tivity in acute situations. The dose-response curve is
curvilineardthat is, this test is less reliable at higher
concentrations.30 Our findings showed that PT was not
influenced by dabigatran but that aPTT was longer in
patients treated with dabigatran and presenting with
bleeding complications (P ¼ .04; see Table IV).
Several studies have assessed the effect of
rivaroxaban and apixaban on PT.28,30 PT is pro-
longed with the -xabans, but the concentrationeeffect
relationship depends on the thromboplastin reagent
used. Hillarp et al.31 showed that aPTT was also
sensitive to the effect of rivaroxaban but with a large
variability in response to high drug concentrations.
No significant difference was found between PT and
aPTT in patients taking -xabans with postoperative
bleeding and those without hemorrhagic
complications. The present study confirms that PT
and aPTT are of little interest before a surgical
procedure. There is no correlation between the
prolongation of PT or aPTT and the postoperative
bleeding rate. Normal or subnormal aPTT and PT
only indicate that DOACs were properly cleared
OOOO
Month 2016
from the circulation prior to the surgery and are
evidence of low plasma concentrations of the drugs.
Data on the time of the last dose of DOAC appears to
be more reliable than conventional coagulation tests to
estimate bleeding risk in patients undergoing elective
procedures or surgery. This could help identify patients
with a minimal blood level of anticoagulants, depend-
ing on their kidney function. Dabigatran and rivarox-
aban, which have a predominantly renal elimination
(about 80%), should not be prescribed to patients with
chronic kidney failure (creatinine clearance below
30 mL/min) and avoided in the elderly (age >75 years).
Apixaban and endoxaban have a lower renal excretion
rate (about 30%).3,18 With kidney dysfunction, there is
a risk for drug accumulation.32 Clearly, the half-lives of
DOACs should be considered even more carefully in
severe renal failure,32,33 knowing that the risk of
bleeding is directly correlated with the severity of renal
failure.34
Our outcomes suggest that patients should not take
their medication at least 4 to 6 hours before tooth ex-
tractions. The surgical procedure could be timed to
coincide with a low plasma concentration of DOACs.
Peak plasma levels of the DOACs are observed about 2
to 4 hours after intake.3,18,35 Some authors suggest that
the surgical procedure should be performed just before
the next dose of DOAC or at least 10 hours after the last
dose of DOAC 18,32,33,35,36
In practice, for dabigatran and apixaban, which are
taken twice daily, this involves skipping the morning
dose. In the case of rivaroxaban, a once-daily drug, two
possibilities exist, depending on the timing of medica-
tion intake. If the drug is normally taken in the morning,
the dose should be delayed until 4 hours after the
procedure. If the drug is normally taken in the evening,
no adjustment is necessary. To assess bleeding risk,
surgery-dependent and local factors must be also
examined. In oral surgery, the variables most often
associated with bleeding events reported in the litera-
ture in patients receiving warfarin therapy are surgical
extraction, multiple extractions (>3 teeth), gingivitis,
periodontal disease, and tobacco use.10 Our findings did
not identify such local risk factors in patients taking
DOACs.
Limitations of this study
Outcomes of this preliminary study revealed that the
postoperative bleeding events after tooth extraction in
patients taking DOACs, without suspending DOA
therapy, is statically comparable with those in patients
under VKA therapy. All bleeding events were easily
controllable using local hemostatic measures. Other
studies with a larger sample size should be performed to
confirm ours results.
OOOO
Volume -, Number - Mauprivez et al. e9
CONCLUSIONS
Our data suggest that DOAC therapy can be continued
in patients undergoing tooth extractions and that the
application of local hemostatic measures is sufficient to
prevent postoperative bleeding.
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