Review

Journal of Pharmacy Practice

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Management of Direct-Acting Oral ª The Author(s) 2017
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Anticoagulants Surrounding Dental Procedures DOI: 10.1177/0897190017707126
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With Low-to-Moderate Risk of Bleeding

Kathleen A. Lusk, PharmD, BCPS1, Jenna L. Snoga, PharmD1,

Rebekah M. Benitez, PharmD1, and G. Blair Sarbacker, PharmD, BCACP1

Abstract
The purpose of this article is to review the available evidence regarding how to safely manage direct-acting oral anticoagulant
(DOAC) therapy in patients requiring dental procedures with low-to-moderate risk of bleeding. A literature search was
performed using MEDLINE and PubMed. Each author performed an independent search to ensure all pertinent articles were
identified. The reference sections of each article were also reviewed. Pertinent articles were evaluated by each author for
inclusion. Articles were eligible for inclusion if the participants were taking DOAC therapy surrounding a dental procedure known
to have low-to-moderate risk of bleeding. Studies could be prospective or retrospective and included case reports, case series,
and clinical trials. Articles were excluded if they assessed dental procedures known to carry a high risk of bleeding or were review
articles. Twenty-five articles were identified, 5 of which met inclusion criteria including 2 case series, 1 retrospective study, and 2
prospective trials. Variation in the management of DOAC therapy surrounding these procedures was found. Among patients
undergoing low-to-moderate risk dental procedures while receiving DOAC therapy, bleeding rates were low regardless of
whether the DOAC was held or continued surrounding the procedure. Documented bleeding was mild and easily controlled by
local hemostatic measures. Patients can safely continue DOAC therapy surrounding these dental procedures.

Keywords
anticoagulation, cardiology, medication safety, direct-acting oral anticoagulant

Introduction thromboplastin time. In contrast to warfarin, international nor-

malized ratio (INR) is relatively insensitive to dabigatran expo-
Starting in 2010, direct-acting oral anticoagulants (DOACs)
sure.21 Edoxaban is indicated for stroke prevention in patients
began emerging as an anticoagulant option. These newer
with nonvalvular atrial fibrillation and treatment of both DVT
agents fall into 2 pharmacologic categories. Dabigatran is a and PE.22 Rivaroxaban and apixaban are indicated for treating
direct thrombin inhibitor, while, rivaroxaban, apixaban, and
and preventing recurrence of DVT and PE, prophylaxis of
edoxaban are factor Xa inhibitors. The advantages of these
DVT and PE following hip or knee replacement surgery, and
agents over warfarin are their fixed dosing and the lack of
stroke prevention in patients with nonvalvular atrial fibrilla-
routine laboratory monitoring of anticoagulation. One major
tion. Table 2 outlines the indications for each DOAC. Similar
disadvantage of these agents includes the lack of well-
to dabigatran, these agents may prolong coagulation markers,
established reversal protocols. In addition, due to their recent
but the effects are variable and dose-dependent.23,24 The effects
emergence onto the market, less postmarket trial data are avail-
of DOACs on coagulation markers are not indicators of the
able. Table 1 provides an overview of the pharmacokinetic and extent of anticoagulation occurring due to the medication.
pharmacodynamic principles of these agents. From the existing
Although routine anticoagulation monitoring is not necessary,
trials, it has been noted that these agents have a major bleeding
hemoglobin, hematocrit, and renal function (serum creatinine
risk of approximately 0.3% to 5.6% and a minor bleeding risk
of up to 14% per year.1-20
Dabigatran is indicated in treatment and prevention of recur-
1
rence of deep vein thrombosis (DVT) and pulmonary embolism Feik School of Pharmacy, University of the Incarnate Word, San Antonio,
(PE), stroke prevention in nonvalvular atrial fibrillation, and TX, USA
prophylaxis of DVT and PE following hip replacement surgery.
Corresponding Author:
While routine laboratory monitoring is not required for dabiga- Kathleen A. Lusk, Feik School of Pharmacy, University of the Incarnate Word,
tran, it may prolong coagulation markers such as activated 4301 Broadway, CPO 99, San Antonio, TX 78209, USA.
partial thromboplastin time, ecarin clotting time, and Email: lusk@uiwtx.edu
2 Journal of Pharmacy Practice XX(X)

Table 1. Pharmacokinetic and Pharmacodynamic Principles of Direct-Acting Oral Anticoagulants.21-24

Medication Mechanism Bioavailability Half-Life Elimination Time to Peak Excretion

Apixaban23 Selective inhibitor Doses up to 10 mg: 12 hours 3-4 hours 27% urine
of Factor Xa approximately 50%
Dabigatran21 Direct thrombin 3%-7% 12-17 hours 1 hour (fasting) Oral administration:
inhibitor Renal impairment: 2 hours (taken with 7% urine
Mild-moderate (CrCl 30-80 high-fat meal) 86% feces
mL/min): 15-18 hours
Severe (CrCl 15-30 mL/min):
27 hours
Edoxaban22 Selective inhibitor 62% 10-14 hours 1-2 hours 50% urine (unchanged)
of factor Xa 50% metabolism and biliary/
intestinal excretion
Rivaroxaban24 Selective Inhibitor Dose-dependent Age 20-45: 5-9 hours 2-4 hours 66% urine
of Factor Xa 10 mg dose: 80-100% Age  65: 11-13 hours 28% feces
(with or without food)
20 mg dose:
66% (fasting)

Abbreviation: CrCl, creatinine clearance.

Table 2. Indications of Direct-Acting Oral Anticoagulants.21-24

DVT/PE Stroke Prevention in Prophylaxis of DVT/PE Prophylaxis of DVT/PE

Treatment Nonvalvular Atrial Fibrillation Post-Hip Replacement Surgery Post-Knee Replacement Surgery

Apixaban Yes Yes Yes Yes

Dabigatran Yes Yes Yes No
Edoxaban Yes Yes No No
Rivaroxaban Yes Yes Yes Yes

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism.

and creatinine clearance) still remain important in terms of
safety monitoring.21-24
A concern regarding patients taking any oral anticoagulant
is how to adjust therapy surrounding procedures that increase
the risk of bleeding. Dental procedures are among the most
common, with data estimating that around 548 million dental
procedures were completed in 2009 alone.25 The type of dental
procedure planned affects the risk of bleeding and the manage-
ment of anticoagulation. Low-risk procedures include local
anesthetic administration, simple restorations, supragingival
scaling, and single tooth extraction. Moderate risk procedures
include extractions of 2 to 4 teeth and local gingival surgery of
5 or fewer teeth. High-risk procedures include extractions of 6
or more teeth, osseous biopsy, placement of multiple implants,
and generalized gingival surgery of 6 or more teeth.26 Bleed
risk in dental procedures is dependent upon the procedure being
completed, with higher risk procedures bringing a higher risk
of bleeding. To put this in perspective, tooth extractions come
with a 1% bleed risk in patients not receiving anticoagula-
tion.26,27 A 2005 article assessed patients undergoing tooth
extraction while receiving oral anticoagulation with warfarin.
In this population, 9% of patients experienced delayed post-
operative bleeding, 3.5% of these being considered serious.26
Before assessing the data in the periprocedural management
of DOACs surrounding low-to-moderate risk dental proce-
dures, it is helpful to first review where the large bulk of the
data lies. Data assessing the management of warfarin therapy in
patients undergoing dental procedures are plentiful. In 2007,
the British Committee for Standards in Haematology published
a guideline stating that significant bleeding risk is small in
patients on warfarin with a stable INR of 2 to 4. The thrombosis
risk is increased if anticoagulation is held, so it is recom-
mended to continue warfarin therapy in most patients.28 To
decrease the bleed risk, use of oxidized cellulose or collagen
sponges and sutures as well as tranexamic acid 5% mouthwash
is recommended in patients undergoing a dental procedure.28
Unfortunately, a newer guideline that includes the management
of DOACs in this setting is not currently available.
A 2009 systematic review and meta-analysis found no
increased bleeding risk associated with continuing regular
doses of warfarin in comparison to discontinuing or modifying
the dose for patients undergoing single and multiple tooth
extractions.29 In addition, a 1998 systematic review found that
in patients undergoing dental procedures where anticoagulation
with warfarin was held, 1% of patients experienced serious
embolic complications, 4 of which were fatal.30 When antic-
oagulants were continued, over 98% of patients had no serious
bleeding events. Less than 2% of the patients had postoperative
bleeding complications that could not be controlled using local
measures. Notably, three-quarters of the patients that experi-
enced postoperative bleeding had supratherapeutic INRs.30
With a similar or even lower risk of bleeding associated with
Lusk et al
the DOACs when compared to warfarin, it can be postulated
that continuation of DOAC therapy may be reasonable in a
similar situation.
While the American College of Chest Physicians guideline
for the perioperative management of antithrombotic therapy
have recommendations concerning warfarin management in
patients undergoing dental procedures, they lack recommenda-
tions for DOAC therapy. This guideline recommends continu-
ing warfarin therapy surrounding low and moderate risk
procedures if oral prohemostatic agents, such as tranexamic
acid, are given or stopping warfarin therapy for 2 to 3 days
before the procedure.31 The purpose of this article is to review
the available evidence regarding how to safely manage DOAC
therapy in patients requiring low-to-moderate bleed risk dental
procedures.
Material and Methods
MEDLINE and PubMed literature searches were performed
using the search terms apixaban, dabigatran, edoxaban, rivar-
oxaban, bleeding, novel anticoagulants, direct-acting oral
anticoagulant, target-specific oral anticoagulant, dentistry, and
dental procedure in January 2016. The search was repeated in
October 2016 and January 2017 to ensure no articles were
missed and to determine whether new literature had been pub-
lished on the topic. No time cutoff or limitation was used.
Limits included English language and human subjects. Each
author performed an independent search to ensure all pertinent
articles were found. The articles reviewed were those assessing
the use of DOACs surrounding dental procedures. Studies
using any DOAC dose were included. The reference sections
of each included article were also reviewed for additional arti-
cles. Pertinent articles were evaluated by each author for inclu-
sion in the review. Articles were eligible for inclusion if the
participants were taking DOAC therapy surrounding a low or
moderate risk dental procedure. Studies could be prospective or
retrospective in nature and included case reports, case series,
and clinical trials. Articles were excluded if they assessed high
bleeding risk dental procedures or if they were review articles.
Twenty-five articles were found using these search criteria; 5
met the search criteria and were reviewed (Figure 1). Of the
articles included, 2 were case series,32,33 1 was a retrospective
study,34 and 2 were prospective trials.35,36
Results
In 2014, Breik and colleagues published a case series including
reviews of 5 case reports of patients undergoing tooth extrac-
tion while taking dabigatran. The primary outcome was bleed-
ing. In 4 cases, the dabigatran was continued. In 3 of these
cases, no significant bleeding occurred. In the fourth case, the
patient experienced significant bleeding. However, this bleed-
ing can be attributed to the type of procedure the patient
required. The patient had multiple dental caries and underwent
a high-risk, 18-tooth extraction and abscess drainage. Because
this patient would not be classified as a low or moderate risk
3
Figure 1. Summary of evidence search and selection.
dental procedure due to the large number of teeth extracted, this
case was excluded from our final conclusion. The final patient
included in this case series had the dabigatran discontinued 48
hours prior to the procedure. The patient had a successful
extraction of 3 teeth without bleeding. Based on these findings,
the authors concluded that dabigatran should be continued for
standard procedures including scaling, restorative treatment,
endodontic treatment, or single uncomplicated tooth extrac-
tions. If bleeding does occur, it should be managed with
mechanical pressure and other local hemostatic measures.32
In 2016, Morimoto and colleagues published a cases series
assessing 19 patients taking DOAC therapy while undergoing
tooth extractions. In all patients, the DOAC was continued and
local hemostatic measures, such as oxidized cellulose, atelo-
collagen sponges, and sutures, were used to control bleeding.
Patient age ranged from 43 to 86 years, and no patients had
renal or hepatic dysfunction. Of the patients included, 9 were
taking rivaroxaban, 6 were taking apixaban, and 4 were taking
dabigatran. Eighteen patients underwent uncomplicated tooth
extractions and 1 required surgical extraction. The DOAC dose
was taken 4 to 9 hours before the procedure in most patients.
Following simple extraction, mild bleeding in the form of ooz-
ing occurred in 5 patients, 2 on rivaroxaban and 3 on apixaban.
Adequate hemostasis was achieved in all but 1 patient postpro-
cedure. This patient underwent a surgical extraction, a high-
risk procedure, and thus is excluded from our conclusion.
Based on these findings, the authors recommend that DOAC
therapy be continued surrounding tooth extraction. However,
tooth extraction should be avoided immediately following
administration of the DOAC dose, when the plasma concentra-
tion of the medication is at its highest. Surgical extraction
carries a higher bleed risk; however, local hemostatic measures
can be used to control bleeding that may occur.33
In 2015, a retrospective, observational trial was conducted
in Scotland. Patients were included if they had a planned inva-
sive or noninvasive dental procedure and were taking prasu-
grel, ticagrelor, dabigatran, rivaroxaban, or apixaban. An
outcome assessed was adverse bleeding events. Of the 95
patients included, 13 were taking dabigatran, 43 were taking
rivaroxaban, and 7 were taking apixaban. No patients were tak-
ing a DOAC in combination with prasugrel or ticagrelor. Forty-
four patients attended 156 dental appointments. The average
patient age was 64 years, and the number of dental visits per
patient ranged from 1 to 12. Thirteen (8.3%) dental encounters
4 Journal of Pharmacy Practice XX(X)
were invasive of which 11 were extractions, 1 was an apicect-
omy of an upper incisor, and 1 was an incisional biopsy of the
tongue. There were 2 cases of perioperative bleeding, both of
which occurred in a patient taking dabigatran. The bleeding
occurred immediately post-tooth extraction and was controlled
using a hemostatic sponge. In this study, the management of
anticoagulation surrounding dental procedures was highly var-
ied, but the incidence of significant bleeding was low.34
In 2016, Gómez-Moreno and colleagues assessed bleeding
complications occurring after dental implant placement in
patients on rivaroxaban without interrupting the anticoagulant
therapy. Fifty-seven patients were included in the study, 18 of
whom were taking rivaroxaban. Tranexamic acid–soaked gauzes
were used following the procedure. One rivaroxaban patient and
2 control patients experienced moderate bleeding following the
dental procedure. No statistical difference was found between
the groups (relative risk: 0.919, 0.078-10.844; P ¼ 0.688). In all
cases, the bleeding was controlled with tranexamic acid–soaked
gauzes.35
Similarly, a 2016 study by Gómez-Moreno and colleagues
assessed bleeding complications occurring after dental implant
placement in patients on dabigatran. Seventy-one patients were
included in this study, 29 of whom were taking dabigatran. The
last dabigatran dose had to be given no later than 12 hours
before the dental procedure. Sutures and tranexamic acid–
soaked gauzes were used following the procedure. Dabigatran
was restarted 8 hours after the procedure. Two patients in each
group experienced bleeding. In all cases, the bleeding was
controlled with tranexamic acid–soaked gauzes. No statistical
difference in bleeding was found between the groups (hazard
ratio: 0.675, 0.090-5.088; P ¼ 0.542).36
Discussion
Based on the available evidence, DOAC therapy surrounding
low and moderate risk dental procedures can be safely continued
as the risk of bleeding is low. If bleeding occurs, local hemo-
static measures can be used to control the bleeding. It should be
noted that currently no data are available for the management of
edoxaban in this setting. Data for the management of DOAC
therapy surrounding these types of procedures are limited. Only
small trials and case reports are available. These data should be
interpreted with caution. The quantity of patients in the included
trials previously discussed is small, and the management of the
DOAC therapy varied. Direct comparisons of 1 DOAC to
another cannot be made. A larger, retrospective review or a
prospective, randomized trial would be helpful to better clarify
the risks and benefits of continuing or discontinuing DOAC
therapy surrounding low and moderate risk dental procedures.
It is vital to understand the pharmacologic properties of the
DOACs to determine whether and when the medication should
be held surrounding dental procedures. In addition, it is impor-
tant to have knowledge of the options available to manage any
minor bleeding that may occur. Currently, the manufacturers of
edoxaban and rivaroxaban recommend discontinuation 24
hours prior to invasive or surgical procedures where bleeding
is a risk.22,24 The manufacturer of apixaban recommends dis-
continuation 48 hours prior to elective surgery or invasive pro-
cedures with a moderate to high risk of bleeding. The package
insert does differentiate that procedures with a low bleeding
risk only warrant discontinuation 24 hours prior.23 Dabiga-
tran’s manufacturer recommends discontinuation 1 to 2 days
before an invasive or surgical procedure if creatinine clearance
is greater than or equal to 50 mL/min or 3 to 5 days before if the
creatinine clearance is less than 50 mL/min.21 There are no
specific manufacturer recommendations for any of these agents
regarding discontinuation prior to low and moderate risk dental
procedures for any of the DOACs.
A consensus document was released by the European Heart
Rhythm Society in 2015, suggesting that some dental proce-
dures do not require discontinuation of anticoagulation therapy
including extraction of 3 or fewer teeth, paradontal surgery,
abscess incision, or implant positioning. For interventions with
low bleed risk or procedures where local hemostasis is possi-
ble, it is reasonable to continue DOAC therapy if the procedure
is completed near the end of the dosing cycle. The authors
specifically recommend not performing these procedures dur-
ing peak concentrations of DOAC therapy.37 Dabigatran and
edoxaban reach peak concentration 1 to 2 hours after the dose is
taken, while apixaban and rivaroxaban reach peak concentra-
tion 3 to 4 after the dose is taken (Table 1).21-24
Available data have found low risk of bleeding complica-
tions following low and moderate risk dental procedures. Cur-
rently, the evidence for interruption of DOAC therapy is not
convincing in the setting of these types of dental procedures.
For low-to-moderate risk dental procedures, it is reasonable to
continue DOAC therapy as prescribed. If a concern for bleed-
ing exists, it is reasonable to schedule the DOAC dosing based
on the procedure time. An option is to administer the DOAC
dose after the procedure is completed rather than before. Poten-
tial DOAC administration surrounding these procedures could
be scheduling the procedure 12 to 24 hours after the DOAC
dose is taken and delaying the next dose until after the proce-
dure is completed. In addition to an assessment of the bleeding
risk of the procedure, specific details that may affect a patient’s
risk of bleeding and clotting should be considered before a
decision is made. Additional considerations that may affect
bleeding risk include renal function, age, history of bleeding
complications, and concomitant medications. If interruption of
therapy is deemed necessary, reinitiation of DOAC therapy
should occur the same day of the procedure.
The final decision of whether to continue or hold therapy,
and when to restart DOAC therapy, should be an interprofes-
sional decision including the dentist, DOAC prescriber, and a
pharmacist. Development of an institutional guideline and
practice policy concerning periprocedural anticoagulation
management in varying dental procedural settings is warranted.
Acknowledgments
We thank Dr. April Sousa, DDS, for prompting the research and
composition of this article.
Lusk et al
Authors’ Contribution
Kathleen A. Lusk, Jenna L. Snoga, Rebekah M. Benitez, and G. Blair
Sarbacker conceived and designed this article. All authors contributed
to research, composition, and manuscript preparation.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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