Journal of Cranio-Maxillo-Facial Surgery 51 (2023) 393e398

Contents lists available at ScienceDirect

Journal of Cranio-Maxillo-Facial Surgery

journal homepage: www.jcmfs.com

Risk of bleeding in anticoagulated patients undergoing dental

extraction treated with topical tranexamic acid compared to collagen-
gelatin sponge: Randomized clinical trial
Sara Juliana de Abreu de Vasconcellos a, b, Raquel Souza dos Santos Marques c,
Elisama Gomes Magalha ~es de Melo c, Camila Silva de Almeida b,
~o Victor de Almeida Go
Joa es Silva b, Liane Maciel de Almeida Souza c,
Paulo Ricardo Martins-Filho a, c, *
a
Graduate Program in Health Sciences, Federal University of Sergipe, Sergipe, Brazil
b
Department of Dentistry, Tiradentes University, Sergipe, Brazil
c
Graduate Program in Dentistry, Federal University of Sergipe, Sergipe, Brazil

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

Article history: This two-arm, parallel-group, double-blind, randomized clinical trial design evaluated the risk of post-
Paper received 24 February 2023 operative bleeding in anticoagulated patients undergoing dental extraction treated with topical TXA in
Received in revised form comparison to collagen-gelatin sponge. Forty patients were randomly included in one of the study
5 May 2023
groups: (1) topical use of 4.8% TXA solution; and (2) resorbable hydrolyzed collagen-gelatin sponge
Accepted 25 June 2023
Available online 28 June 2023
applied to the surgical alveolus. Primary outcomes were postoperative bleeding episodes and secondary
outcomes were thromboembolic events and postoperative INR values. The relative risk (RR), the absolute
Handling Editor: Prof. Emeka Nkenke risk reduction (RAR) and the number needed to treat (NNT) were used as effect estimates and calculated
from the counting of bleeding episodes observed during the first postoperative week. The bleeding rate
Keywords: under the TXA treatment was 22.2%, while in the collagen-gelatin sponge group it was 45.7%, resulting in
Tranexamic acid a RR of 0.49 (95% CI 0.24e099; p ¼ 0.046), RAR 23.5% and NNT 4.3. TXA was more effective in reducing
Oral surgery bleeding in surgical sites located in the mandible (RR ¼ 0.10; 95% CI 0.01e0.71; p ¼ 0.021) and the
Bleeding posterior region (RR ¼ 0.39; 95% CI 0.18e0.84; p ¼ 0.016). Within the limitations of the study it seems
that topical TXA is more effective in controlling bleeding after tooth extractions in anticoagulated pa-
tients than collagen-gelatin sponge.
Clinical trial registration: RBR-83qw93.
© 2023 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights
reserved.

1. Introduction biotechnology, various agents have become available for providing

The appropriate management of anticoagulated patients during
and after surgery, particularly those who have been on long-term
warfarin therapy, remains a topic of debate. However, the mainte-
nance of anticoagulant therapy has been widely recommended for
patients undergoing minor oral surgery with adequate local he-
mostasis (Al-Belasy and Amer 2004). With advances in
* Corresponding author. Universidade Federal de Sergipe, Hospital Universita rio,
 rio de Patologia Investigativa, Rua Cla
Laborato udio Batista, s/n. Sanato
 rio, Aracaju,
Sergipe, CEP: 49060-100, Brazil.
E-mail address: prmartinsfh@gmail.com (P.R. Martins-Filho).
local hemostasis in invasive procedures, including resorbable
agents (such as absorbable hemostatic sponge or gelatin and re-
generated oxidized cellulose) and biologically activated topical
solutions (such as tranexamic acid [TXA] and epsilon aminocaproic
acid) (Pereira et al., 2018).
Several studies have evaluated the TXA as a local hemostatic
agent to control postoperative bleeding in oral surgery, especially in
tooth extraction (Borea et al., 1993; Souto et al., 1996; Sacco et al.,
2007; Queiroz et al., 2018). However, most of these studies have
contrasting methods, unclear randomization, and distinct com-
parison groups, which may decrease the confidence of oral sur-
geons in the use of TXA in their clinical routine. TXA is a lysine

https://doi.org/10.1016/j.jcms.2023.06.003
1010-5182/© 2023 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
 ~es de Melo et al.
S.J. de Abreu de Vasconcellos, R. Souza dos Santos Marques, E. Gomes Magalha
analog that inhibits fibrinolysis by binding to plasminogen (Kim
et al., 2015). Therefore, this agent reduces bleeding by inhibiting
the enzymatic degradation of fibrin blood clots by the serine pro-
tease plasmin (Draxler et al., 2021). There is evidence that the
concentration of TXA in saliva after mouth rinsing in hemophilic
patients undergoing oral surgery is sufficient to decrease the
amount of lysed fibrin and postoperative bleeding (Sindet-
Pedersen et al., 1989; Borea et al., 1993; Sacco et al., 2007).
Despite the widespread use of TXA as a hemostatic agent in
various types of surgeries (Vasconcellos et al., 2018; Wong et al.,
2021), there is a lack of evidence regarding its efficacy in anti-
coagulated patients undergoing oral surgery compared to other
hemostatic agents commonly used in clinical practice. In a recent
systematic review with meta-analysis, we showed that local he-
mostasis with absorbable hemostatic materials (gelatin sponge,
fibrin glue or oxidized regenerated cellulose) was not more effec-
tive in preventing bleeding than TXA mouthwash in combination
with gelatin sponge or oxidized regenerated cellulose. Unfortu-
nately, no studies have compared the efficacy of the topical appli-
cation of TXA alone versus absorbable hemostatic materials
(Vasconcellos et al., 2017). Since TXA may be a better cost-effective
option to minimize bleeding risks after minor oral surgeries,
further studies are still necessary to support the superiority of TXA
over absorbable hemostatic materials. This study aimed to evaluate
the risk of postoperative bleeding in anticoagulated patients un-
dergoing dental extraction treated with topical TXA in comparison
to collagen-gelatin sponge.
2. Methods
2.1. Trial design
This study followed a two-arm, parallel-group, double-blind,
randomized clinical trial design, in accordance with the Consoli-
dated Standards of Reporting Trials (CONSORT) statement recom-
mendations (Schulz et al., 2010). The trial was registered at the
Brazilian Registry of Clinical Trials (ReBEC: RBR-83qw93), and the
study protocol was approved by the Research Ethics Committee at
the Federal University of Sergipe (UFS) (CAAE 60889416.
0.0000.5546).
2.2. Population, intervention, comparison, and outcome (PICO)
elements
The trial was based on the following PICO elements:
 Population (P): individuals over 18 years old using oral antico-
agulants (vitamin K dependent antagonists) and submitted to
tooth extraction;
 Intervention (I): topical use of 4.8% TXA solution;
 Comparison (C): resorbable hydrolyzed collagen-gelatin sponge
applied to the surgical alveolus;
 Outcome (O): postoperative bleeding episodes as the primary
outcome, and thromboembolic events and postoperative inter-
national normalized ratio (INR) values as secondary outcomes.
2.3. Participants
The sample consisted of patients recruited from the School of
Dentistry at the Federal University of Sergipe and the Center for
Dental Specialties, Sergipe state, Brazil. Patients using oral antico-
agulants who required extraction of at least one tooth and who had
an INR between 1.5 and 4.0 on the day before the procedure were
394
Journal of Cranio-Maxillo-Facial Surgery 51 (2023) 393e398
included. During each surgical procedure, only one dental unit was
extracted (Halfpenny et al., 2001).
We excluded patients with blood dyscrasia or other pathology
that interfered with blood clotting; smokers; diabetics; pregnant or
lactating women; patients with a history of allergy to TXA or
collagen-gelatin sponge; those using medications that could
interact with medications used in this study; those using anti-
platelet agents such as aspiring and clopidogrel; those with surgical
procedures with osteotomy of more than one alveolar bone wall;
and those with an INR above 4.0. Patients who did not return for re-
evaluation appointments, who did not respond to contact with the
researcher, or who did not follow postoperative recommendations
were also excluded.
2.4. Sample size and randomization
A sample size calculation was performed using the following
parameters: 80% power at a significance level of 5%; a reported 90%
and 60% efficacy in reducing postoperative bleeding for TXA and
collagen-gelatin sponge, respectively (Vasconcellos et al., 2017);
and a 10% loss due to attrition. A total of 36 surgical sites were
needed for each group. A block randomization sequence was
created using the Sealed Envelope Ltda program (www.sealedenve
lope.com) to allocate treatment and ensure balance. Surgical sites
were randomized in a 1:1 ratio to TXA or collagen-gelatin sponge.
Allocations were made by the attending investigator using opaque
envelopes.
2.5. Interventions
Interventions were performed as follows: (1) TXA: intra-
operative irrigation to the surgical alveolus with 4.8% TXA (10 ml),
suture and local compression for 30 min with TXA-soaked gauze,
followed by mouthwash with the same solution (10 ml) for 2 min
every 6h for seven days; (2) Collagen-gelatin sponge: intra-
operative irrigation to the surgical alveolus with 0.9% saline solu-
tion (10 ml), insertion of resorbable hydrolyzed collagen-gelatin
sponge (Hemospon®; Maquira Indústria de Produtos Odon-
 gicos SA - Maring
tolo a/PR, Brasil) in the alveolus, suture and local
compression with dry gauze for 30 min, followed by mouthwash
with 0.9% saline solution (10 ml) for 2 min every 6h for seven days.
TXA and saline solution were delivered to patients in identical
packages and had the same color characteristics. Patients were
blinded to treatment assignment.
The patients underwent the surgical procedure by a single oral
surgeon with 10 years of experience (S.J.A.V.). All patients received
authorization from the assistant cardiologist to undergo the sur-
gical procedure while using oral anticoagulants. The procedures
were performed under local anesthesia without pharmacological
sedation, and the doses of oral anticoagulants were not suspended
or modified. In cases where antibiotic prophylaxis was necessary,
the American Heart Association protocol was used (https://www.
heart.org/-/media/files/health-topics/infective-endocarditis/infecti
ve-endocarditis-wallet-card.pdf). Blood pressure and heart rate
were measured prior to all interventions. In all cases, sutures were
performed on the surgical wound with 4e0 nylon (Shalon®; Fios
Cirúrgicos LTDA, Goia ^nia/GO, Brasil). The procedure time was
measured with a chronometer, beginning from the first incision for
gingival detachment until complete suture. Depending on the
group to which the patient was allocated, hemostasis was achieved
by local compression with TXA-soaked gauze in the TXA group and
by compression with a dry gauze in the collagen-gelatin sponge
group, as per the randomization protocol.
After the surgical procedure, analgesic medication was pre-
scribed (dipyrone 500 mg every 6 h for 2 days, or dexamethasone
 ~es de Melo et al.
S.J. de Abreu de Vasconcellos, R. Souza dos Santos Marques, E. Gomes Magalha
4 mg every 8 h for 2 days in surgeries with osteotomies). In case of
dipyrone allergy, paracetamol 750 mg was prescribed every 6 h for
2 days, and the postoperative guidelines were explained to the
patient in detail. Transparent bottles (240 ml) containing the sub-
stance to be used in the postoperative oral rinses, along with a
10 ml dosing syringe and instructions, were given to each patient.
In addition, we requested a repeat INR measurement on the 3rd
postoperative day and removed the sutures one week after the
procedure.
2.6. Postoperative data collection and outcome assessment
A single examiner, a dentist and specialist in oral and maxillo-
facial surgery (L.M.A.S.), who was blinded to the allocated groups,
performed examinations to assess outcome variables. The evalua-
tions regarding the presence of bleeding and clot formation were
performed 2 h after the procedure (visual inspection), on the 3rd
(patient self-report via telephone contact) and on the 7th (visual
inspection) days. In case of active bleeding, the event was charac-
terized as postoperative bleeding and additional measures for local
hemostasis were performed. Bleeding from the surgical wound was
classified as mild (bleeding that stopped spontaneously or with
local compression with gauze for 20 min) or severe (bleeding that
did not stop with the previous measures and required new inter-
vention by the researcher) (Souto et al., 1996).
In case of severe bleeding, the hemostatic measurement per-
formed during the surgery was repeated. In case of persistent
bleeding, patients would be referred for bleeding control measures
in the hospital setting. During the entire first postoperative week,
all patients were instructed to contact the researcher by telephone.
2.7. Statistical methods
Categorical variables were expressed as absolute frequencies
and percentages, and groups were compared using the Chi-Square
test. Continuous variables were expressed as median and quartiles
(Q1 and Q3) and groups were compared using the Mann-Whitney
test. The effect estimates used to compare the efficacy of TXA
versus collagen-gelatin sponge were the relative risk (RR) with 95%
confidence interval (CI) and the absolute risk reduction (ARR) with
standard error, calculated from the number of bleeding episodes
recorded during the first postoperative week. Additionally, we
calculated the number needed to treat (NNT) and the RR (95% CI) for
immediate and late postoperative bleeding according to the INR.
We performed the analyses using the statistical package R (version
3.2.3) and considered P-values less than 0.05 as statistically
significant.
3. Results
Initially, 46 patients were recruited, and six were excluded due
to the use of antiplatelet agents or no need for dental extraction. A
total of 72 surgical procedures were performed on 40 patients, 36 in
the TXA group, and 36 in the collagen-gelatin sponge group. One
patient in the collagen-gelatin sponge group was excluded for not
returning for postoperative evaluation (Fig. 1).
All patients in both groups were under the use of warfarin. There
were no significant differences between groups in systolic and
diastolic blood pressure, heart rate, prothrombin time, partial
thromboplastin time, or preoperative INR. Most surgical proced-
ures were performed in the mandible (53.5%) in the posterior re-
gion (74.7%), and over 80% of extractions were due to dental caries
(Table 1).
Table 2 described all 17 sites with 24 episodes of postoperative
bleeding. Four bleeding sites had INR values above 4.0, one being
395
Journal of Cranio-Maxillo-Facial Surgery 51 (2023) 393e398
Fig. 1. Flow diagram of the patient selection process.
treated with TXA and three with collagen-gelatin sponge. Only two
sites required postoperative intervention due to bleeding, both in
the collagen-gelatin sponge group. No patient had thromboembolic
events or required hospital admission.
We observed a bleeding rate of 22.2% during the first post-
operative week in the surgical sites treated with TXA, compared to
45.7% in those treated with collagen-gelatin sponge. The calculated
ARR was 23.5%, and the NNT was 4.3. A 51% reduction in the risk of
bleeding with TXA compared to collagen-gelatin sponge was
observed (RR ¼ 0.49; 95% CI 0.24e0.99; p ¼ 0.046). TXA was more
effective in reducing bleeding in surgical sites located in the
mandible (RR ¼ 0.10; 95% CI 0.01e0.71; p ¼ 0.021) and the posterior
region (RR ¼ 0.39; 95% CI 0.18e0.84; p ¼ 0.016), but no significant
differences were observed between groups regarding the use
(RR ¼ 1.33; 95% CI 0.07e26.15; p ¼ 0.850) or non-use (RR ¼ 0.50;
95% CI 0.24e1.04; p ¼ 0.062) of the flap during the procedure
(Fig. 2). Furthermore, no statistically significant effect was observed
between groups in reducing the risk of bleeding based on INR
values during the immediate and late postoperative periods
(Table 3).
4. Discussion
In recent years, an increasing number of patients with diverse
systemic conditions requiring continuous anticoagulant therapy
have been observed in dental clinics. Anticoagulants are used to
prevent thrombus formation and discontinuing them before a
surgical procedure is generally contraindicated due to the risks to
the patient's health (Wahl 2000; Queiroz et al., 2018). However,
anticoagulated patients undergoing oral surgical procedures are at
a high risk of bleeding, and the management approach should
consider the risks of bleeding if anticoagulant therapy is main-
tained, or the chances of thromboembolic complications if it is
discontinued (Balevi 2010). Many authors assert that tooth ex-
tractions can be performed safely in anticoagulated patients with
therapeutic INR values (up to 4.0) without altering their anti-
coagulation therapy (Morimoto et al., 2008; Bajkin et al., 2009;
Bacci et al., 2010; Galinde and Sidana 2011; Svensson et al., 2013;
Mingarro-de-Leon et al., 2014).
This study aimed to evaluate the risk of postoperative bleeding
in patients using oral anticoagulants who underwent tooth
extraction and to compare two local hemostatic agents: TXA and
collagen-gelatin sponge. To our knowledge, there are no head-to-
 ~es de Melo et al.
S.J. de Abreu de Vasconcellos, R. Souza dos Santos Marques, E. Gomes Magalha Journal of Cranio-Maxillo-Facial Surgery 51 (2023) 393e398

Table 1
General characteristics of the study sample.

Variables Sample (%) Tranexamic acid (n ¼ 36) Collagen-gelatin sponge (n ¼ 35) p-value

Gender
Male 23 (32.4%) 16 (44.4%) 7 (20.0%) 0.052
Female 48 (67.6%) 20 (55.6%) 28 (80.0%)
Age (years) ¥ 48.0 (35.0e64.3) 48.0 (35.0e60.5) 48.5 (35.0e64.5) 0.908
Race/ethnicity
Brown 21 (29.6%) 10 (27.8%) 12 (34.3%)
White 23 (32.4%) 14 (38.9%) 9 (25.7%) 0.494
Black 27 (38.0%) 12 (33.3%) 14 (40.0%)
Education
Primary school 42 (59.2%) 25 (69.4%) 17 (48.6%)
High school 26 (36.6%) 10 (27.8%) 16 (45.7%) 0.199
Higher education 3 (4.2%) 1 (2.8%) 2 (5.7%)
Reason for the use of anticoagulant therapy
Cardiac arrhythmia 20 (28.2%) 12 (33.3%) 8 (22.9%)
Stroke 18 (25.4%) 9 (25.5%) 9 (25.7%)
Cardiac valvopathy 15 (21.1%) 9 (25.5%) 6 (17.1%) 0.479
Pulmonary hypertension 7 (9.9%) 2 (5.6%) 5 (14.3%)
Others 11 (15.4%) 4 (27.7%) 7 (20.0%)
Anticoagulant therapy
Warfarin 72 (100%) 36 (100.0%) 35 (100.0%) 1.000
SBP (mm/Hg) ¥ 120.0 (110.0e133.3) 120.0 (110.0e130.8) 120.0 (111.5e136.5) 0.853
DBP (mmHg) ¥ 79.0 (70.0e89.3) 75.5 (70.0e90.0) 80.0 (70.0e84.3) 0.937
HR (bpm) ¥ 80.0 (70.0e85.0) 80.0 (71.5e85.0) 75.0 (80.0e85.0) 0.353
PT (sec) ¥ 27.9 (22.6e29.3) 27.9 (22.6e33.2) 27.1 (20.0e28.4) 0.180
PTTa (sec) ¥ 38.7 (34.6e42.6) 39.8 (35.0e42.8) 37.5 (34.4e40.3) 0.342
¥
INR 2.4 (2.2e2.9) 2.4 (2.0e2.7) 2.7 (2.2e2.9) 0.100
Surgical site
Maxilla 33 (46.5%) 17 (47.2%) 16 (45.7%) 0.912
Mandible 38 (53.5%) 19 (52.8%) 19 (54.3%)
Type of teeth
Anterior 18 (25.3%) 8 (22.2%) 10 (28.6%) 0.732
Posterior 53 (74.7%) 28 (77.8%) 25 (71.4%)
Reason for extraction
Dental caries 59 (83.1%) 32 (89.0%) 27 (77.1%)
Periodontal disease 5 (7.0%) 2 (5.5%) 3 (8.6%) 0.388
Others 7 (9.9%) 2 (5.5%) 5 (14.3%)
Surgical procedure
Without flap elevation 60 (84.5%) 28 (77.8%) 32 (91.4%) 0.207
With flap elevation 11 (15.5%) 8 (22.2%) 3 (8.6%)
¥
Time of surgery (min) 8.0 (5.0e12.0) 9.5 (5.0e13.5) 8.0 (5.0e10.5) 0.337

SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; PT, prothrombin time; PTTa, partial thromboplastin time; INR, international normalized ratio. ¥ Data
expressed in median (Q1 e Q3).

Table 2
Description of surgical sites with postoperative bleeding.

Case Age Dental Dental Disease Antithrombotic Hemorrhage (24 INR Group Local Hemostatic Management
(yr) unit therapy episodes)
Extraction Pos- Compression Suture TXA Collagen-gelatin
operative sponge

1 66 26 Dental caries Warfarin 02h 1.51 2.01 Sponge X

2 65 26 Dental caries Warfarin 02h, 3d, 7d 2.43 3.70 Sponge X X X
3 57 43, 44 Dental caries Warfarin 02h 1.62 2.20 Sponge X
4 49 16 Dental caries Warfarin 02h, 3d 2.18 2.61 TXA X
5 48 28 Prosthetic Warfarin 02h 3.36 2.08 Sponge X
surgery
6 75 11, 12 Abfraction Warfarin 02h 2.72 2.22 TXA X
7 75 21 Abfraction Warfarin 02h 2.72 2.22 TXA X
8 35 14, 16 Dental caries Warfarin 02h 3.25 4.54 TXA X
9 65 46 Dental caries Warfarin 02h, 7d 3.93 4.29 Sponge X
10 65 45 Dental caries Warfarin 02h, 7d 2.93 4.29 Sponge X
11 65 44 Dental caries Warfarin 02h, 7d 2.93 4.29 Sponge X
12 65 41 Dental caries Warfarin 02h 2.87 2.87 Sponge X
13 65 36 Dental caries Warfarin 02h 2.71 2.87 Sponge X
14 65 24 Dental caries Warfarin 02h, 7d 2.97 3.47 TXA X
15 44 44 Dental caries Warfarin 02h 2.09 1.68 Sponge X
16 41 45 Dental caries Warfarin 02h 2.37 2.20 TXA X
17 64 31 Periodontal Warfarin 7d 2.17 2.60 Sponge X X X
disease

396
 ~es de Melo et al.
S.J. de Abreu de Vasconcellos, R. Souza dos Santos Marques, E. Gomes Magalha
Fig. 2. Risk of bleeding according to the surgical procedure, surgical site, and type of teeth.
Table 3
Assessment of the influence of the INR on the risk of immediate and late postoperative bleeding within each group.
INR Tranexamic acid (n ¼ 36) Collagen-gelatin sponge (n ¼ 35)
Events/n (%) Events/n (%)
Immediate postoperative bleeding
<3.0 5/29 (17.2%) 8/27 (29.6%)
3.0 1/7 (14.3%) 2/8 (25.0%)
Late postoperative bleeding
<3.0 1/29 (3.5%) 1/23 (4.4%)
3.0 1/7 (14.3%) 5/12 (41.7%)
Total 8/36 (22.2%) 16/35 (45.7%)
RR, relative risk; CI, confidence interval; RAR, absolute risk reduction; NNT, number needed to treat.
head clinical trials comparing the effects of these two hemostatic
agents on postoperative bleeding in anticoagulated patients.
Available evidence shows a reduced risk of bleeding from TXA in
placebo-controlled studies (Sindet-Pedersen et al., 1989; Ramstro €m
et al., 1993) or when compared to the topical use of epsilon ami-
nocaproic acid (Souto et al., 1996).
All patients included in the present trial were using sodium
warfarin, and the median INR was 2.4, which is within the thera-
peutic range for coagulation control in oral surgical procedures. The
results of the study showed a 51% reduction in the risk of bleeding
with the use of TXA compared to collagen-gelatin sponge and a
NNT of 4.3, reflecting the significant benefit of TXA for anti-
coagulated patients undergoing dental extraction. Furthermore, the
use of TXA was effective in reducing bleeding in posterior jaw ex-
tractions, which are considered more traumatic due to the pre-
dominance of very thick cortical bone.
Although numerous treatment regimens and concentrations
have been proposed, topical TXA within the first two days after
surgery has proven to be effective and safe in controlling bleeding
(Carter and Goss 2003). The local inhibition of fibrinolysis when
using TXA as a mouthwash provides several advantages, including
simple administration and reduced systemic absorption, which
minimizes adverse events such as deep vein thrombosis, pulmo-
nary embolism, and myocardial infarction. This drug maintains
high concentrations in saliva and has an action that lasts up to 8 h,
with almost undetectable serum concentration when used for
rinsing (Silva et al., 2018).
In the current study, no thromboembolic events were reported
in patients treated with TXA or collagen-gelatin sponge, indicating
that these hemostatic agents are safe to use in anticoagulated pa-
tients undergoing minor oral surgery. However, while no adverse
effects were observed with the use of collagen-gelatin sponge, this
hemostatic agent was found to be less effective than TXA in
reducing the risk of postoperative bleeding. Two sites treated with
collagen-gelatin sponge required postoperative intervention due to
severe bleeding. Nevertheless, local hemostatic measures were
sufficient to control postoperative hemorrhage, with no need for
hospital intervention.
397
Journal of Cranio-Maxillo-Facial Surgery 51 (2023) 393e398
RR (CI 95%) p-value RAR NNT
0.58 (0.22e1.56) 0.282 12.4% 8.1
0.57 (0.06e5.03) 0.614 10.7% 9.3
0.79 (0.05e12.0) 0.867 0.9% 111.2
0.34 (0.05e2.37) 0.278 27.4% 3.6
0.49 (0.24e0.99) 0.046 23.5% 4.3
There have been few clinical trials evaluating the influence of
INR on postoperative bleeding in anticoagulated patients under-
going oral surgery. Blinder et al. found no differences in bleeding
rates for different INR ranges analyzed (Blinder et al., 2001).
However, in the present study, all patients were evaluated for INR
preoperatively and on the 3rd day of follow-up, and the operated
sites were categorized into two subgroups (INR <3.0 and INR 3.0)
for each follow-up period, which may have generated a type II error
and an insignificant reduction in the risk of bleeding among the
hemostatic agents analyzed within the INR ranges. Despite these
results, it is plausible to support the clinically relevant benefit of
TXA, as it showed an ARR of bleeding of 27.4% compared to
collagen-gelatin sponge in the late postoperative period and cases
where INR was out of the safety range. Furthermore, the calculated
NNT demonstrated a large magnitude of effect for sites treated with
TXA.
Several limitations of this study should be noted, including: (1)
the sample size was calculated based on surgical sites rather than
patients, which was challenging due to the complexity of selecting
eligible patients with comorbidities that may preclude the pro-
cedure; (2) data collection on the 3rd postoperative day relied on
self-reporting via telephone, which may have influenced the
reporting of bleeding episodes; (3) the assessment of postoperative
bleeding was based on visual analysis, which lacks a standardized
definition of severity and makes comparison between studies
difficult. Future studies should aim to validate bleeding assessment
methods for reproducibility, sensitivity, and specificity, as this area
of research is currently limited in the literature.
5. Conclusions
Within the limitations of the study it seems that topical
TXA is more effective in controlling bleeding after tooth extractions
in anticoagulated patients than collagen-gelatin sponge.
Funding source
None.
 ~es de Melo et al.
S.J. de Abreu de Vasconcellos, R. Souza dos Santos Marques, E. Gomes Magalha
Declaration of competing interest
None.
References
Al-Belasy, F., Amer, M., 2004. Hemostatic effect of n-butyl-2-cyanoacrylate (histo-
acryl) glue in warfarin-treated patients undergoing oral surgery. J. Oral Max-
illofac. Surg. 61, 1405e1409.
Bacci, C., Maglione, M., Favero, L., Perini, A., Lenarda, R Di, Berengo, M., et al., 2010.
Management of dental extraction in patients undergoing anticoagulant treat-
ment. Thromb. Haemostasis 104, 972e975.
Bajkin, B.V., Popovic, S.L., Selakovic, S.D.J., 2009. Randomized, prospective trial
comparing bridging therapy using low-molecular-weight heparin with main-
tenance of oral anticoagulation during extraction of teeth. J. Oral Maxillofac.
Surg. 67, 990e995. http://www.ncbi.nlm.nih.gov/pubmed/19375008. (Accessed
12 August 2014).
Balevi, B., 2010. Should warfarin be discontinued before a dental extraction? A
decision-tree analysis. Oral Surgery. Oral Med. Oral Pathol. Oral Radiol. Endo-
dontol. 110, 691e697.
Blinder, D., Manor, Y., Martinowitz, U., Taicher, S., 2001. Dental extractions in pa-
tients maintained on oral anticoagulant therapy: comparison of INR value with
occurrence of postoperative bleeding. Int. J. Oral Maxillofac. Surg. 30, 518e521.
Borea, G., Montebugnoli, L., Capuzzi, P., Magelli, C., 1993. Tranexamic acid as a
mouthwash in anticoagulant-treated patients undergoing oral surgery. Oral
Surgery. Oral Med. Oral Pathol. 75, 29e31.
Carter, G., Goss, A., 2003. Tranexamic acid mouthwash–a prospective randomized
study of a 2-day regimen vs 5-day regimen to prevent postoperative bleeding in
anticoagulated patients requiring dental extractions. Int. J. Oral Maxillofac. Surg.
32, 504e507. http://www.ncbi.nlm.nih.gov/pubmed/14759109. (Accessed 12
August 2014).
Draxler, D.F., Zahra, S., Goncalves, I., Tran, H., Hanafi, G., Ho, H., et al., 2021. Tra-
nexamic acid rapidly inhibits fibrinolysis, yet transiently enhances plasmin
generation in vivo. Blood Coagul. Fibrinolysis 32, 172e179. https://journals.lww.
com/10.1097/MBC.0000000000001008.
Galinde, J., Sidana, S., 2011. Contemporary management of patients on warfarin,
aspirin and clopidogrel requiring dentoalveolar surgery. J. Contemp. Dent. 1,
22e25.
Halfpenny, W., Fraser, J.S., Adlam, D.M., 2001. Comparison of 2 hemostatic agents for
the prevention of postextraction hemorrhage in patients on anticoagulants.
Oral Surgery. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 92, 257e259.
Kim, C., Park, S.S.-H., Davey, J.R., 2015. Tranexamic acid for the prevention and
management of orthopedic surgical hemorrhage: current evidence. J. Blood
Med. 6, 239e244. http://www.ncbi.nlm.nih.gov/pubmed/26345147.
Mingarro-de-Leon, A., Chaveli-Lopez, B., Gavalda-Esteve, C., 2014. Dental manage-
ment of patients receiving anticoagulant and/or antiplatelet treatment. J. Clin.
Exp. Dent. e155ee161.
Morimoto, Y., Niwa, H., Minematsu, K., 2008. Hemostatic management of tooth
extractions in patients on oral antithrombotic therapy. J. Oral Maxillofac. Surg.
66, 51e57.
398
Journal of Cranio-Maxillo-Facial Surgery 51 (2023) 393e398
Pereira, B.M., Bortoto, J.B., Fraga, G.P., 2018. Agentes hemosta ticos to
 picos em cir-
urgia: revis~ ao e perspectivas. Rev. Col. Bras. Cir. 45.
Queiroz, S.I.M.L., Silvestre, V.D., Soares, R.M., Campos, G.B.P., Germano, A.R., da
Silva, J.S.P., 2018. Tranexamic acid as a local hemostasis method after dental
extraction in patients on warfarin: a randomized controlled clinical study. Clin.
Oral Invest. 22, 2281e2289.
Ramstro €m, G., Sindet-Pedersen, S., Hall, G., Blomb€ €
ack, M., Alander, U., 1993. Pre-
vention of postsurgical bleeding in oral surgery using tranexamic acid without
dose modification of oral anticoagulants. J. Oral Maxillofac. Surg. 51, 1211e1216.
http://linkinghub.elsevier.com/retrieve/pii/S0278239110802915. (Accessed 8
November 2015).
Sacco, R., Sacco, M., Carpenedo, M., Mannucci, P.M., 2007. Oral surgery in patients on
oral anticoagulant therapy: a randomized comparison of different intensity
targets. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 104, e18ee21.
http://www.ncbi.nlm.nih.gov/pubmed/17482846. (Accessed 8 November 2015).
Schulz, K.F., Altman, D.G., Moher, D., 2010. CONSORT 2010 Statement: updated
guidelines for reporting parallel group randomised trials. BMJ 340 c332ec332.
Silva, R.V., Gadelha, T.B., Luiz, R.R., Torres, S.R., 2018. Intra-alveolar epsilon-
aminocaproic acid for the control of post-extraction bleeding in anti-
coagulated patients: randomized clinical trial. Int. J. Oral Maxillofac. Surg. 47,
1138e1144.
Sindet-Pedersen, S., Ramstro €m, G., Bernvil, S., Blomba €ck, M., 1989. Hemostatic effect
of tranexamic acid mouthwash in anticoagulant-treated patients undergoing
oral surgery. N. Engl. J. Med. 320, 840e843. http://www.ncbi.nlm.nih.gov/pu
bmed/2648144. (Accessed 8 November 2015).
Souto, J.C., Oliver, A., Zuazu-Jausoro, I., Vives, A., Fontcuberta, J., 1996. Oral surgery in
anticoagulated patients without reducing the dose of oral anticoagulant: a
prospective randomized study. J. Oral Maxillofac. Surg. 54, 27e32 discussion
323. http://www.ncbi.nlm.nih.gov/pubmed/8530996. (Accessed 8 November
2015).
Svensson, R., Hallmer, F., Englesson, C.S., Svensson, P.J., Becktor, J.P., 2013. Treatment
with local hemostatic agents and primary closure after tooth extraction in
warfarin treated patients. Swed. Dent. J. 37, 71e77.
Vasconcellos, SJ. de A., do Nascimento-Júnior, E.M., de Aguiar Menezes, M.V.,
Tavares Mendes, M.L., de Souza Dantas, R., Martins-Filho, P.R.S., 2018. Preop-
erative tranexamic acid for treatment of bleeding, edema, and ecchymosis in
patients undergoing rhinoplasty: a systematic review and meta-analysis. JAMA
Otolaryngol. Head Neck Surg. 144, 816e823. http://www.ncbi.nlm.nih.gov/pu
bmed/30098161.
Vasconcellos, SJ. de A., de Santana Santos, T., Reinheimer, D.M., Faria-e-Silva, A.L., de
Melo, M. de FB., Martins-Filho, P.R.S., 2017. Topical application of tranexamic
acid in anticoagulated patients undergoing minor oral surgery: a systematic
review and meta-analysis of randomized clinical trials. J. Cranio-Maxillofacial
Surg. 45, 20e26.
Wahl, M.J., 2000. Myths of dental surgery in patients. J. Am. Dent. Assoc. 131, 77e81.
Wong, J., George, R.B., Hanley, C.M., Saliba, C., Yee, D.A., Jerath, A., 2021. Tranexamic
acid: current use in obstetrics, major orthopedic, and trauma surgery. Can. J.
Anaesth. 68, 894e917. http://www.ncbi.nlm.nih.gov/pubmed/33993459.