REVIEW ARTICLE

Anita Aminoshariae, DDS, MS,*

Perioperative Antiplatelet and Mark Donaldson, BSP,
PHARMDACPR, FASJP,
Anticoagulant Management FACHE,†‡ Michael Horan, MD,
DDS, PhD, FACS,§
with Endodontic Microsurgical James C. Kulild, DDS, MS,ǁ and
Dale Baur, DDS§
Techniques

ABSTRACT
SIGNIFICANCE
Introduction: The purpose of this study was to review evidence-based recommendations
for the safe perioperative management of patients undergoing endodontic microsurgery who Surgeons should be aware of
are currently taking antiplatelet or anticoagulant medications. Using the PICO (Population, the best available evidence
Intervention, Comparison, Outcome) format, the following scientific question was asked: In when treating patients who are
patients taking anticoagulant or antiplatelet agents, what is the available evidence in the on anticoagulant or antiplatelet
management of endodontic microsurgery? Methods: MEDLINE, Scopus, Cochrane Library, agents. Guidelines from an
and ClinicalTrials.gov databases were searched to identify current recommendations expert panel for endodontic
regarding the management of antiplatelet and anticoagulant medications in the context of surgery might be warranted to
outpatient dental surgical procedures. Additionally, the authors hand searched the mitigate risks while maximizing
bibliographies of all relevant articles, the gray literature, and textbooks. Because of the lack of hemostasis for these patients.
clinical studies and evidence on this subject, articles and guidelines from other organizations
and association position statements were included. Results: Because any minor surgery can
become a major surgery, the treating doctor needs to best assess the risk of bleeding,
especially if the surgery is anticipated to take longer than 45 minutes. Every patient should be
stratified on a case-by-case basis. Consultation with the patient’s physician is highly rec-
ommended. Conclusions: In order to maximize the effects of these medications (to prevent
thrombosis) while minimizing the potential risks (procedural hemorrhage), clinicians should
be aware of the best available evidence when considering continuation or discontinuation
of antiplatelet and anticoagulant agents perioperatively for endodontic microsurgery.
Ideally, a joint effort from an expert panel for microsurgery would be warranted. (J Endod
2021;-:1–9.)

KEY WORDS
Anticoagulant agents; antiplatelet agents; endodontic microsurgery; evidence-based
dentistry; guidelines

From the *Departments of Endodontics

The term blood thinners is a common misnomer used by laypersons to describe antiplatelet and and §Oral and Maxillofacial Surgery, Case
anticoagulant medications. In fact, these medications do not actually “thin” blood, but rather they aid in Western Reserve University, School of
the prevention of blood clot formation and propagation. Antiplatelet and anticoagulant medications are Dental Medicine, Cleveland, Ohio;
†
commonly used in the long-term treatment and prevention of thrombosis in the context of preexisting School of Pharmacy, University of
Montana, Missoula, Montana; ‡School of
cardiovascular pathology including deep venous thrombosis, pulmonary embolus, atrial fibrillation,
Dentistry, Oregon Health and Sciences
myocardial infarction with percutaneous intervention and endovascular stent placement, and a cerebral University, Portland, Oregon; and kUKMC
vascular accident (stroke). On the other hand, fibrinolytic medications are used acutely via localized Dental School, University of Missouri-
intravascular administration to ameliorate thrombi or clots during surgery or in emergency situations such Kansas City, Kansas City, Missouri
as a myocardial infarction, pulmonary embolism, or stroke1. To help minimize risks associated with these Address requests for reprints to Dr Anita
medications, it is further important to understand the 4 phases of hemostasis: the vascular phase, which Aminoshariae, 10900 Euclid Avenue,
is often associated with vasoconstriction; the platelet phase (primary hemostasis) and the formation of a Roomm 239C, Cleveland, OH 44106.
E-mail address: Axa53@case.edu
temporary “platelet plug”; the coagulation phase (secondary hemostasis) and activation of the 0099-2399/$ - see front matter
coagulation cascade with fibrin clot formation; and the fibrinolytic phase, which results in enzymatic
Copyright © 2021 American Association
breakdown and dissolution of the clot when no longer needed2. of Endodontists.
US Census Bureau estimates show the nation’s 65 and older population has grown rapidly since https://doi.org/10.1016/
2010 and suggest that this is primarily driven by aging baby boomers born between 1946 and 19643. Per j.joen.2021.07.006

JOE  Volume -, Number -, - 2021 Perioperative Antiplatelet and Anticoagulant Management 1

the Centers for Disease Control and
Prevention, heart disease continues to be the
leading cause of death in the United States,
with stroke not far behind as the fifth leading
cause of death4. With an increasing aged
population and prevalent cardiovascular and
neurovascular disease, the use of antiplatelet
and anticoagulant medications is steadily
growing1. Although excellent guidelines are in
place to safely manage patients who continue
to receive older anticoagulants and antiplatelet
medications, such as warfarin, aspirin, and
clopidogrel, there is limited guidance on how to
safely manage dental patients who are
receiving the newer direct-acting oral
anticoagulants (DOACs)5.
DOACs are also known as direct factor
Xa inhibitors and direct thrombin (IIa) inhibitors,
and they offer significant advantages over
warfarin to include fewer drug and nutrient
interactions and a more predictable efficacy
with fixed, standardized doses6. Against the
backdrop of good practice and the lack of
evidence-based guidelines7, clinicians are left
with the dilemma of whether to continue or
discontinue these medications before minor
outpatient dental surgeries, such as
endodontic microsurgery.
The challenge faced by oral health care
providers is having to constantly weigh the risk
of procedural hemorrhage versus the risk of
thrombosis due to the discontinuation of
antiplatelet and anticoagulant medications8.
For many decades, the American Dental
Association (ADA) has stated that for routine
dental treatment there is no need to
discontinue warfarin or aspirin9,10. However,
bleeding complications of antithrombotic
therapy might not always be controlled
sufficiently by local measures during
endodontic microsurgery and biopsy11.
Patients with inherited (eg, hemophilia A or
hemophilia B) or acquired coagulopathies (eg,
thrombocytopenia or cirrhosis) as well as those
with iatrogenically induced coagulopathies (eg,
antiplatelet and anticoagulant medications)
may be at risk of severe blood loss or potential
death subsequent to surgical interventions if
not managed properly12. Furthermore, there
are few randomized trials that have assessed
the optimal timing for the discontinuation of
these DOACs before surgery13. Thus, current
practice involves consultation with the
patient’s prescribing physician and is based
heavily on the perioperative risk of a
thromboembolic event versus a postoperative
hemorrhage when performing surgery2. In
addition, guidelines are often “fluid” and
complicated given a lack of consensus for
what could be construed as “major
bleeding”14. The Australian Clinical Excellence
Commission 2018 classified any surgery
2 Aminoshariae et al.
longer than 45 minutes as a major surgery
requiring medication adjustment15.
With an increasing number of patients
taking antiplatelet and anticoagulant
medications, the safety concern in relation to
the potential risk of thrombosis or bleeding
complications after dental surgery remains a
constant dilemma7The aim of this review was
to discuss the management of patients taking
antiplatelet and anticoagulant medications in
the context of endodontic microsurgery and to
explore the various drug classifications and
their mechanisms of action.
MATERIALS AND METHODS
The scientific question was formed using the
PICO (Population, Intervention, Comparison,
Outcome) approach as follows:
 Population: patients undergoing
endodontic microsurgery
 Intervention: patients on antiplatelet or
anticoagulant agents
 Comparison: not indicated
 Outcome: outcome would be measured in
terms of thrombosis and/or bleeding
events
Thus, the following question was asked:
What is the endodontic management for
microsurgery in patients who are taking
anticoagulant or antiplatelet agents?
Search Methodology
MEDLINE, Scopus, Cochrane Library, and
ClinicalTrials.gov databases were searched to
identify current recommendations regarding
the management of antiplatelet and
anticoagulant medications in the context of
outpatient dental surgical procedures.
Additionally, the authors hand searched the
bibliographies of all relevant articles, the gray
literature, and textbooks.
In trying to discover the best current
clinical evidence, an exhaustive search failed to
locate any clinical endodontic studies on this
subject. Another challenge that the authors
encountered was the lack of consensus in the
available literature to consider endodontic
microsurgery a minor surgery or a major
surgery specifically because of the intricate
performance of root-end resection and root-
end filling using a dental microscope16,17. The
authors believe that an expert panel would be
best suited to address this dilemma (see the
Discussion section). Because of the paucity of
evidence-based publications in the endodontic
literature on this subject, the authors included
studies from the medical and dental literature
and association position statements.
RESULTS
Class: Antiplatelet Agents
Adenosine Diphosphate Receptor/
P2Y12 Inhibitors
Mechanism of action. The thienopyridines
clopidogrel (Plavix; Bristol-Myers Squibb, New
York, NY) and prasugrel (Effient; Bristol-Myers
Squibb) are antiplatelet medications that are
often coprescribed with aspirin as dual
antiplatelet therapy to prevent thrombotic
complications after stent placement for
myocardial infarction or stroke18. P2Y12
receptors are activated by adenosine
diphosphate, which results in platelet
aggregation and activation of P13 kinase,
leading to fibrinogen formation19. The
thienopyridines were designed as antagonists
of the P2Y12 receptor, resulting in the
inhibition of platelet activation and
aggregation 20 (Table 1).
Recommendations for minor
surgeries. For dental surgeries, the alteration
of these drugs is not necessary before dental
intervention9.
Recommendations for major surgeries. A
systematic review that conducted a search on
patients undergoing an invasive dental
procedure on single or dual antiplatelet therapy
reported that there was no clinically significant
increased risk of postoperative bleeding
complications21. The interruption of these
medications poses risks of thrombosis;
however, with the lack of clinical randomized
trials, some authors have posed many
suggestions varying from interrupting 1 or
more medications22. There are many different
clinical recommendations largely based on
anecdotal evidence23. These
recommendations range from no change in
medication to discontinuing the medication 3
or 7 to 10 days before the surgery15,23,24.
Thromboxane Inhibitors
Mechanism of action. Aspirin irreversibly
binds to cyclooxygenase enzymes, which
leads to a reduction in thromboxane
production25. Thromboxane causes platelet
aggregation, vasoconstriction, and vascular
proliferation, with aspirin providing protection
against all of these. Ibuprofen and the other
nonsteroidal anti-inflammatory drugs (NSAIDs)
have a similar mechanism of action. However,
they bind reversibly to cyclooxygenase
enzymes2. This explains why patients who
take both aspirin and an NSAID should always
take their cardioprotective dose of aspirin at
least 30 minutes before their NSAID dose. If
they do the opposite, the NSAIDs will block the
platelet binding sites for aspirin, rendering it
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TABLE 1 - A Summary of the Medications and Reports

Class Medication
Antiplatelet Clopidogrel (Plavix)
agents and prasugrel (Effient)
Aspirin and nonsteroidal Thromboxane inhibitors
anti-inflammatory drugs
Ticagrelor (Brilinta)
Cilostazol (Pletal) and
anagrelide (Agrylin)
Anticoagulants Warfarin (Coumadin)
agents
Heparin
Rivaroxaban (Xarelto;
Johnson & Johnson,
New Brunswick, NY)
Apixaban (Eliquis;
Bristol-Myers Squibb)
Edoxaban (Savaysa;
Daiichi Sankyo, Inc,
Tokyo, Japan)
Dabigatran etexilate
(Pradaxa; Boehringer
Ingelheim, Ingelheim
am Rhein, Germany)
Mechanism
of action Minor surgery recommendation Major surgery recommendation*
Adenosine diphosphate No modification; local
receptor/P2Y12 measures for hemostasis
inhibitors
No modification; local
measures for hemostasis
P2 receptor antagonist No modification; local measures
for hemostasis
Phosphodiesterase No modification; local measures
inhibitors for hemostasis
Vitamin K antagonists INR ranging from 2.0–3.5,
no modification; local measures
Factor Xa inhibitors Partial thromboplastin
time between 25 and 35),
no modification; local measures
No modification; local measures
for hemostasis
No modification; local measures f
Direct Xa inhibitors
or hemostasis
No modification; local measures
for hemostasis
Direct factor IIa inhibitors No modification; local measures
for hemostasis
Not much information available
and varied from no modifications
to interrupting 1 or more
medication(s) 3–10 days
before the surgery
Vast and different information
available (no change to
discontinuation 5–7 days
before surgery)
Not much information and
varied (no modification to
discontinuation 5 days
before surgery)
Not much information available
and varied (no modification
to discontinuation 3 days
before surgery)
Consultation with the physician
to adjust the INR as close
to the low range of
therapeutic (~2.0–2.5)
Consultation with the physician
and stop medication 1 day
before the surgery
Consultation with the physician
and stop medication 24 hours
before the surgery
Consultation with the physician
and stop medication 24–48 hours
before the surgery
Consultation with the physician
and stop medication 24–72 hours
before the surgery
Consultation with the physician and
stop medication 24–48 hours
before the surgery

*Any modification should be in consultation with the physician.

ineffective, and it will be metabolized and
excreted by the body. Later, as the NSAIDs
give up their enzyme blockade (because they
only bind reversibly for several hours), many
platelets are now left unaffected by either
aspirin or NSAIDs, which creates a
thrombogenic opportunity in these high-risk
cardiac patients25.
Recommendations for minor
surgeries. Low-dose aspirin (75–85 mg daily)
remains a popular beneficial drug for its
reduced all-cause mortality26. Patients on
long-term low-dose aspirin may be at higher
risk of bleeding during surgical procedures27.
However, both the ADA and the American
College of Chest Physicians do not
recommend stopping aspirin before dental
surgery9,13.
Recommendations for postoperative
medications. For these patients on low-dose
aspirin, the postoperative combination of
ibuprofen and diclofenac augments the
irreversible platelet inhibition produced by
aspirin25. In a meta-analysis comparing
preoperative continuation with cessation of
aspirin, it was reported that 0.6% of patients
developed acute vascular events28. Also,
ibuprofen taken before surgery resulted in
intraoperative bleeding, and its benefits should
be weighed when administering it before
dental surgery29.
Recommendations for major
surgeries. The bottom line is that there is
more evidence supporting the continuation of
aspirin than discontinuing it during the surgery
to prevent the risk of thrombosis without
increasing bleeding complications, and this is
specifically true for high-risk cardiovascular
patients30–34. However, concerns of increased
bleeding during endodontic microsurgery have
led many colleagues to consult with the
physician to discontinue concomitant low-
dose aspirin 1 week before the surgery for low-
risk patients with no history of myocardial
infarction2. When it comes to continuing or
discontinuing aspirin in low-risk patients,
perhaps updates by an expert panel would be
necessary regarding preoperative
discontinuation versus continuation of aspirin
in stable patients on dual antiplatelet therapy13.
P2 Receptor Antagonist
Mechanism of action. Ticagrelor (Brilinta;
AstraZeneca, Cambridge, UK) blocks platelet

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binding to arterial surfaces by reversibly
inhibiting a chemoreceptor for adenosine
diphosphate35. A meta-analysis of 4
randomized clinical trials reported on the
primary reasons for the discontinuation of
ticagrelor, which were bleeding and
dyspnea36. In accordance with many
guidelines and recommendations, patients on
ticagrelor who underwent minor oral surgical
procedures experienced controllable
postoperative bleeding37.
Recommendations for minor
surgeries. According to the ADA, there is no
need to make modifications for patients who
are undergoing dental surgeries9.
Recommendations for major surgeries. A
variety of options have been suggested38.
However, if needed to be discontinued when
undergoing high bleeding risk surgery or for
low-risk cardiovascular patients, in
consultation with the patient’s physician,
ticagrelor might be discontinued 5 days before
the procedure15,39.Perioperative
communications between the specialist and
the patient’s physician are critical to effectively
manage high-risk patients and prevent harm40.
Phosphodiesterase Inhibitors
Mechanism of action. Cilostazol (Pletal;
Otsuka America Pharmaceutical, Inc.,
Princeton, NJ) and anagrelide (Agrylin; Takeda
Pharmaceuticals America, Inc., Deerfield, IL)
are phosphodiesterase inhibitors with
antiplatelet and vasodilator properties13. These
drugs promote vascular relaxation by reducing
cyclic guanylate monophosphate breakdown,
resulting in vasodilation41,42.
Recommendations for minor surgeries. In
general, discontinuation of these drugs is not
necessary before dental surgery unless the risk
and severity of bleeding clearly outweigh the
risk of thrombosis.43 For this reason alone,
consultation with the patient’s physician is
highly recommended.
Recommendations for major
surgeries. There is not much information
available, but discontinuing the medication
3 days before the surgery has been
recommended in consultation with the
patient’s physician24.
Class: Anticoagulants
Anticoagulant agents include vitamin K
antagonists, factor Xa inhibitors, and direct
thrombin IIa inhibitors1. To understand
anticoagulation, one needs to first understand
the sequence of events that creates the blood
clots and coagulation cascade (Fig. 1).
4 Aminoshariae et al.
Vitamin K Antagonist
Mechanism of action. Warfarin (Coumadin;
Bristol-Myers Squibb) is the most prevalent
oral anticoagulant2. It inhibits the biosynthesis
of vitamin K–dependent clotting factors
(factors II, VII, IX, and X)44. Because it is
sensitive to factor VII deficiency, a partial
thromboplastin blood test was used for many
years to evaluate blood clotting potential44.
However, partial thromboplastin is imprecise,
with variable results depending on the
laboratory and reagents used; therefore, the
international normalized ratio (INR) test is now
used with better reliability and predictability45.
Recommendations for minor
surgeries. Most surgical procedures can be
effectively performed with an INR ranging from
2.0–3.5 for minor surgical procedures. For
major surgical interventions, the surgeon may
request consultation with the physician to
determine the safest range for a specific
patient45. It should be noted that warfarin has
many drug and food interactions46.
Recommendations for major
surgeries. Consultation with the patient’s
physician would be highly advised to adjust the
dosing regimen before surgery with a target
INR as close to the low range of therapeutic
(~2.0–2.5)13. This is usually done by the
prescribing doctor or anticoagulation clinic.
Factor Xa Inhibitors
Heparin
Mechanism of action. Heparins are divided
into 2 categories: unfractionated heparin and
low–molecular-weight heparin (LMWH)1.
Heparins bind to the enzyme inhibitor plasma
antithrombin III, and this activated antithrombin
then inactivates factor Xa and other proteases
such as thrombin-causing anticoagulation47.
Heparin and LMWH activate antithrombin III
and inhibit factor Xa and thrombin equally2.
LMWH preparations include enoxaparin
(Lovenox; Sanofi-Aventis, Paris, France),
tinzaparin (Innohep; Pharmion, Boulder, CO),
and dalteparin (Fragmin; Pfizer Medical, New
York, NY)2.
Recommendations for minor
surgeries. The most recent information
suggests that for simple surgery with a low
bleeding risk (activated partial thromboplastin
time between 25–35), no modification is
necessary, but for more invasive surgeries,
modification to the medication regimen in
consultation with the patient’s physician is
suggested9. Thrombin time alone only
evaluates the part of the hemostatic process in
which soluble fibrinogen is changed into fibrin
threads. This test is much more sensitive when
performed along with prothrombin time and
activated partial thromboplastin time tests to
allow for the identification of specific
coagulation disorders involving the last stage
of the coagulation sequence2.
Recommendations for major
surgeries. Because the half-life of heparin
and LMWH is short (1–2 hours and 2–4 hours,
respectively), if significant bleeding is
anticipated, the medication may be
discontinued for 1 day upon consultation with
the patient’s physician and restarted once
hemostasis is achieved44. Screening
laboratory tests should be ordered to better
identify and detect potential “bleeders” before
dental surgery.
Direct Xa Inhibitors
Rivaroxaban (Xarelto)
Mechanism of action. Rivaroxaban is an
oral anticoagulant that selectively and
reversibly prevents fibrin clot formation by
directly inhibiting factor Xa6. The antidote for
this drug is andexanet alfa (Andexxa; Portola
Pharmaceuticals, Inc., San Francisco, CA),
which the US Food and Drug Administration
approved in 2018 as the first specific factor Xa
inhibitor antidote48.
Recommendations for minor
surgeries. The most current information
related to minor surgeries and rivaroxaban
management suggests that interruption of the
medication is not warranted9.
Recommendations for major
surgeries. Sherwood et al49 first
demonstrated the risk of excessive bleeding
with rivaroxaban and surgical intervention was
2.3%. Skipping the morning dose of this
DOAC before the surgery might avoid
excessive bleeding during and after the
surgery50. For major surgery, discontinuation
of the medication 24 hours before the
intervention should be considered51. When
discontinued, rivaroxaban should not be
immediately started after the surgery but
delayed for 24–48 hours because it has a very
rapid onset of action51.
However, for major surgeries,
modification of the drug regimen would be
recommended, and given its short half-life,
only 1 day would be required52. Any
suggested modification before surgery should
be in consultation with the patient’s physician.
Rivaroxaban has many drug interactions, but
the most important ones to consider in
dentistry might include aspirin, NSAIDs,
steroids, and ketoconazole53.
JOE  Volume -, Number -, - 2021
 Intrinsic Pathway
Factor
XII
Factor
XI
Extrinsic Pathwayy
Tissue Thromboplas n
Factor VII
Calcium
FIGURE 1 – The anticoagulant cascade. Warfarin inhibits the vitamin K -dependent clotting factors (II, VII, IX, X), and the new direct-acting anticoagulants inhibit factor Xa and factor II
(thrombin). Heparin also interferes with factor Xa and enhances antithrombin II, which inactivates thrombin.
Apixaban (Eliquis)
Mechanism of action. This is another
reversible DOAC.
Recommendations for minor
surgeries. According to the ADA, no
modification is required for minor surgeries9.
Dental extractions on patients continuing
DOACs led to bleeding rates similar to patients
on warfarin with an INR between 2.0 and 4.0;
thus, the authors concluded that there was no
need to adjust DOAC dosing before dental
surgery54.
Recommendations for major
surgeries. Presently, apixaban is
recommended to be discontinued 24–48
hours before a major surgical intervention8.
Some authors suggested that there was no
excessive bleeding during and after the
surgery when skipping the morning dose of
apixaban50.
Edoxaban (Savaysa)
Mechanism of action. Edoxaban reduces
blood coagulation by directly inhibiting Xa,
much like apixaban and rivaroxaban53.
Recommendations for minor
surgeries. According to the ADA, no
modifications are required9.
Recommendations for major
surgeries. The decision to discontinue the
medication, like the other DOACs, should be
closely juxtaposed against patients’ risk for
thrombosis and bleeding risk during the
procedure. In high bleeding risk procedures,
JOE  Volume -, Number -, - 2021
Factor
XIIa
Factor
XIa
Factor Factor
IX IXa
Factor
Factor
VIII
Phospholipid
Prothrombin
Calcium (Factor II)
the medication should be discontinued
72 hours before the treatment and 24 hours
before low bleeding risk procedures8. As
always, the decision to adjust the medications
should be in conjunction with the physician.
Direct Factor IIa Inhibitors
Dabigatran Etexilate (Pradaxa)
Mechanism of action. Dabigatran reduces
blood coagulation by binding with the active
site of factor IIa6. Idarucizumab (Praxbind;
Boehringer Ingelheim) is a monoclonal
antibody fragment that has been reported to
be a safe and effective antidote in reversing
potential overanticoagulation caused by this
medication55.
Recommendations for minor
surgeries. According to the ADA and many
authorities, no modifications are required9,56.
Recommendations for major
surgeries. Any adjustment of this dabigatran
should be in consultation with the physician,
and if discontinuation is necessary, dabigatran
should be restarted when a stable clot has
formed, usually within 24–48 hours after
surgery51. NSAIDs should be prescribed with
caution51,57. Dexamethasone and
carbamazepine have been reported to
decrease plasma concentrations of
dabigatran, whereas coadministration with
ketoconazole, itraconazole, erythromycin, and
clarithromycin increases the plasma
concentration of dabigatran51,57.
There are little data on the management
and outcomes of patients on DOACs
Perioperative Antiplatelet and Anticoagulant Management
X
Fibrinogen
Factor
Xa Thrombin
(Factor IIa)
Fibrin Clot
undergoing surgical interventions58. Although
the ADA and many authorities suggest most
dental treatment may be performed without
complications on DOAC patients56,
microsurgical endodontic techniques require a
dry field of operation; therefore, modifications
with insight from the medical practitioner might
be considered before performing endodontic
surgery. The management of hemostasis in
patients with dabigatran should be performed
according to the severity of the bleeding59.
Local hemostatic measures should be
considered in mild bleeding, but in moderate to
serious bleeding cases, hospitalization should
be considered with platelet transfusion,
parenteral administration of antifibrinolytics, or
recombinant factor VIIa.14 Dental extractions
on patients continuing DOACs led to bleeding
rates similar to patients on warfarin with an INR
between 2.0 and 4.0. There is no need to
adjust DOAC dosing before dental
extractions54.
Local Hemostatic Agents
Bleeding control is an imperative part of a
successful endodontic surgery. Jang et al60
reported a comprehensive review on local
hemostatic agents. The authors reported that
epinephrine, calcium sulfate, and ferric sulfate
with or without carrier materials like collagen or
cotton pellet, while applying pressure for a few
minutes, were vastly used by endodontists.
Polytetrafluoroethylene strips as an adjunct to
epinephrine gauze were compared with
aluminum chloride in a randomized controlled
trial, and no difference in the hemostatic
efficacy was noted61.
5
 Other authors have used aluminum
chloride with greater success with ferric
sulfatecompared with bone wax62. Aluminum
chloride has been reported to perform similar
to electrocauterization63, and other hemostatic
agents like Gelfoam (Pharmacia & Upjohn
Company LLC., New York, NY) and Surgicel
(Ethicon, Raritan, NJ) have also been used with
varying success rates64.
In medicine, tranexamic acid, which is
an antifibrinolytic agent, has been used alone
or with other carrier materials with clinical
success65. Other agents that have yet to be
used in endodontics include bismuth
subgallate, fibrin tissue adhesive, and
microfibrillar collagen66.
DISCUSSION
Need for an Expert Panel
The current DOACs have brought new issues
to light that require addressing with
endodontic microsurgery. The question as to
whether endodontic microsurgery is a minor or
major surgery deserves much attention and
further discussion. On one hand, microsurgery
may be perceived as an atraumatic surgery,
particularly with the advent of static or dynamic
navigation with ease and efficiency67, but on
the other hand endodontic microsurgery
required flap reflection, performing osteotomy,
and requiring visualization with a microscope,
which indicates having a completely dry field to
perform root-end preparation and retrofill
placement.17 Because any minor surgery can
become a major surgery, the treating doctor
needs to best assess the risk of bleeding or
withholding the medication and risking
thromboembolic complications7.
It is important to note that per the
Cochrane Handbook (GRADE handbook
[gradepro.org]), “Going from evidence to
recommendation deals with a series of criteria
that are outlined in the GRADE framework.”
Although systematic reviews are a key element
(and, in particular, systematic reviews with
randomized controlled trials are the desirable
source of evidence to address the effects of an
intervention), in order to accomplish this task of
clinical recommendations, systematic reviews
of effects by themselves alone do not allow
making any clinical recommendation. A
recommendation is created by considering at
least 4 important factors: the effects of an
intervention and a balance between benefits
and harms, the quality of the evidence, the
patient’s values and preferences, and
resources. As observed, only the first 2 factors
are addressed with a systematic review of
randomized controlled trials. However, these 2
factors are not enough to make a
recommendation. The other 2 factors ideally
have to also be addressed with other type(s) of
systematic reviews. In addition, a panel of
experts needs to interpret the results of all these
systematic reviews considering the context in
which the recommendation is targeted.
Two panels can arrive at 2 different
recommendations because of the context.
Based on this information, the development of
meaningful clinical practice guidelines
represents a critical but necessary step in
improving clinical decision making and
optimizing patient outcomes68.
After much research and exploration in
this area, the current authors remained divided
as to whether microsurgery is considered a
minor surgery or a major surgery15–17,24,69,70.
Although 3 sources considered any
periradicular and periosteal flap surgery a
major surgery15,17,69, 2 other sources
considered any dental surgery a minor
surgery16,70. Although any minor surgery can
become a major surgery, consultation with the
patient’s physician would be highly
recommended. The Australian Guidelines on
Perioperative Management of Anticoagulant
and Antiplatelet Agents suggested that any
surgery longer than 45 minutes should be
considered as a risk factor for excessive
bleeding15. Thus, an expert panel including
those specialized in endodontics, medicine,
and pharmacology should address this
question.
CONCLUSIONS
The number of patients being prescribed
antiplatelet and anticoagulant agents
continues to rise, as does the number of new
medications in these drug classes.
Additionally, there is controversy and
misinformation in how to safely manage these
patients who may be scheduled for
endodontic microsurgery. In order to maximize
the effects of these medications (to prevent
thrombosis) while minimizing the potential risks
(procedural hemorrhage), clinicians should be
aware of the best available evidence when
considering care. Guidelines from an expert
panel for endodontic surgery might be
warranted to mitigate risks while maximizing
hemostasis for these patients.
ACKNOWLEDGMENTS
The authors deny any conflicts of interest
related to this study.

REFERENCES
1. Yang JH, Chen HM, Kuo YS, Chiang CP. Management of patients taking antithrombotic drugs
before dental surgery. J Dent Sci 2020;15:222–4.

2. Little JM, Rhodus N. Dental Management of the Medically Compromised Patients. 9th ed. St
Louis, MO: Elsevier; 2018.
3. Bureau UC. 65 and older population grows rapidly as baby boomers age. Available at: https://
www.census.gov/newsroom/press-releases/2020/65-older-population-grows.html; 2020.
Accessed February 22, 2021.
4. Centers for Disease Control and Prevention. Leading causes of death. Available at: https://www.
cdc.gov/nchs/fastats/leading-causes-of-death.htm; 2020. Accessed February 22, 2021.

5. Fortier K, Shroff D, Reebye UN. Review: an overview and analysis of novel oral anticoagulants
and their dental implications. Gerodontology 2018;35:78–86.

6. Levy JH, Key NS, Azran MS. Novel oral anticoagulants: implications in the perioperative setting.
Anesthesiology 2010;113:726–45.

6 Aminoshariae et al. JOE  Volume -, Number -, - 2021

 7. Mahmood H, Siddique I, McKechnie A. Antiplatelet drugs: a review of pharmacology and the
perioperative management of patients in oral and maxillofacial surgery. Ann R Coll Surg Engl
2020;102:9–13.

8. Acosta RD, Abraham NS, Chandrasekhara V, et al. The management of antithrombotic agents for
patients undergoing GI endoscopy. Gastrointest Endosc 2016;83:3–16.

9. ADA. Oral anticoagulant and antiplatelet medications and dental procedures. Available at: https://
www.ada.org/en/member-center/oral-health-topics/oral-anticoagulant-and-antiplatelet-
medications-and-dental-procedures. Accessed January 26, 2021.

10. Brennan MT, Valerin MA, Noll JL, et al. Aspirin use and post-operative bleeding from dental
extractions. J Dent Res 2008;87:740–4.
11. van Diermen DE, Bruers JJ, Hoogstraten J, et al. Treating dental patients who use oral
antithrombotic medication: a survey of dentists in the Netherlands. J Am Dent Assoc
2011;142:1376–82.
12. Malamed SF. The medically compromised patient in the dental office. CDS Rev 1985;78:31–7.

13. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic
therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e326S–50S.

14. Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel
therapeutic agents. J Thromb Haemost 2009;7(Suppl 1):107–10.
15. Clinical Excellence Commission. Guidelines on perioperative management of anticoagulant and
antiplatelet agents. Available at: https://www.cec.health.nsw.gov.au/__data/assets/pdf_file/
0006/458988/Guidelines-on-perioperative-management-of-anticoagulant-and-antiplatelet-
agents.pdf; 2018. Accessed June 8, 2021.
16. Cho YW, Kim E. Is stopping of anticoagulant therapy really required in a minor dental surgery? -
How about in an endodontic microsurgery? Restor Dent Endod 2013;38:113–8.
17. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective
procedure or surgery. Blood 2012;120:2954–62.

18. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med 2007;357:2001–15.

19. Zhang Y, Zhang S, Ding Z. Role of P2Y(12) receptor in thrombosis. Adv Exp Med Biol
2017;906:307–24.
20. Niitsu Y, Jakubowski JA, Sugidachi A, Asai F. Pharmacology of CS-747 (prasugrel, LY640315), a
novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb
Hemost 2005;31:184–94.
21. Napen~as JJ, Oost FC, DeGroot A, et al. Review of postoperative bleeding risk in dental patients
on antiplatelet therapy. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:491–9.

22. Banerjee S, Angiolillo DJ, Boden WE, et al. Use of antiplatelet therapy/DAPT for post-PCI patients
undergoing noncardiac surgery. J Am Coll Cardiol 2017;69:1861–70.
23. Inman DS, Michla Y, Partington PF. Perioperative management of trauma patients admitted on
clopidogrel (Plavix). A survey of orthopaedic departments across the United Kingdom. Injury
2007;38:625–30.
24. Family Practice Notebook. Available at: https://fpnotebook.com/legacy/Surgery/Pharm/
PrprtvGdlnsFrMdctnsPrTSrgry.htm; 2021. Accessed June 8, 2021.
25. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet
effects of aspirin. N Engl J Med 2001;345:1809–17.

26. Zhao Y, Jeyaraman K, Burgess P, et al. All-cause mortality following low-dose aspirin treatment
for patients with high cardiovascular risk in remote Australian Aboriginal communities: an
observational study. BMJ Open 2020;10:e030034.

27. Gupta R, Dugal A, Sane VD, et al. Effect of low-dose aspirin on bleeding following exodontia: a
prospective clinical study. J Maxillofac Oral Surg 2018;17:350–5.
28. Burger W, Chemnitius JM, Kneissl GD, Ru €cker G. Low-dose aspirin for secondary cardiovascular
prevention - cardiovascular risks after its perioperative withdrawal versus bleeding risks with its
continuation - review and meta-analysis. J Intern Med 2005;257:399–414.
29. Shiva Prasad BM, Vijaya M, Reddy SB, et al. The effect of ibuprofen on bleeding during
periodontal surgery. Indian J Dent Res 2008;19:22–5.

JOE  Volume -, Number -, - 2021 Perioperative Antiplatelet and Anticoagulant Management 7

30. Oscarsson A, Gupta A, Fredrikson M, et al. To continue or discontinue aspirin in the perioperative
period: a randomized, controlled clinical trial. Br J Anaesth 2010;104:305–12.

31. Ong W, Shen T, Tan WB, Lomanto D. Is preoperative withdrawal of aspirin necessary in patients
undergoing elective inguinal hernia repair? Surg Endosc 2016;30:5542–9.
32. Yan Z, Liu Y, Ruze R, et al. Continuation of low-dose acetylsalicylic acid during perioperative
period of laparoscopic inguinal hernia repair is safe: results of a prospective clinical trial. Hernia
2019;23:1141–8.
33. Rossini R, Musumeci G, Visconti LO, et al. Perioperative management of antiplatelet therapy in
patients with coronary stents undergoing cardiac and non-cardiac surgery: a consensus
document from Italian cardiological, surgical and anaesthesiological societies. EuroIntervention
2014;10:38–46.

34. Llau JV, Kamphuisen P, Albaladejo P. European guidelines on perioperative venous

thromboembolism prophylaxis: chronic treatments with antiplatelet agents. Eur J Anaesthesiol
2018;35:139–41.

35. Hollopeter G, Jantzen HM, Vincent D, et al. Identification of the platelet ADP receptor targeted by
antithrombotic drugs. Nature 2001;409:202–7.
36. Arora S, Shemisa K, Vaduganathan M, et al. Premature ticagrelor discontinuation in secondary
prevention of atherosclerotic CVD: JACC review topic of the week. J Am Coll Cardiol
2019;73:2454–64.
37. Doganay O, Atalay B, Karadag E, et al. Bleeding frequency of patients taking ticagrelor, aspirin,
clopidogrel, and dual antiplatelet therapy after tooth extraction and minor oral surgery. J Am Dent
Assoc 2018;149:132–8.

38. Kremke M, Gissel MS, Jensen MJ, et al. The association between a three-day ticagrelor
discontinuation and perioperative bleeding complications. Eur J Cardiothorac Surg
2019;55:714–20.

39. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. [2018 ESC/EACTS Guidelines on myocardial
revascularization. The Task Force on myocardial revascularization of the European Society of
Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS)]. G Ital Cardiol
(Rome) 2019;20:1s–61s.
40. Rahman A, Latona J. New oral anticoagulants and perioperative management of anticoagulant/
antiplatelet agents. Aust Fam Physician 2014;43:861–6.

41. Ghiadoni L, Versari D, Taddei S. Phosphodiesterase 5 inhibition in essential hypertension. Curr

Hypertens Rep 2008;10:52–7.

42. Joseph EC. Arterial lesions induced by phosphodiesterase III (PDE III) inhibitors and DA(1)
agonists. Toxicol Lett 2000;112-113:537–46.
43. Weimar C, Cotton D, Sha N, et al. Discontinuation of antiplatelet study medication and risk of
recurrent stroke and cardiovascular events: results from the PRoFESS study. Cerebrovasc Dis
2013;35:538–43.
44. Little JW, Miller CS, Henry RG, McIntosh BA. Antithrombotic agents: implications in dentistry.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:544–51.

45. Sheth SB, DiCicco RA, Hursting MJ, et al. Interpreting the international normalized ratio (INR) in
individuals receiving argatroban and warfarin. Thromb Haemost 2001;85:435–40.

46. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food
interactions. Arch Intern Med 2005;165:1095–106.
47. Jackson CM. Mechanism of heparin action. Baillieres Clin Haematol 1990;3:483–504.

48. Andexxa–an antidote for apixaban and rivaroxaban. Med Lett Drugs Ther 2018;60:99–101.

49. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban
compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban
once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of
stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014;129:1850–9.
50. Miclotte I, Vanhaverbeke M, Agbaje JO, et al. Pragmatic approach to manage new oral
anticoagulants in patients undergoing dental extractions: a prospective case-control study. Clin
Oral Investig 2017;21:2183–8.
51. Firriolo FJ, Hupp WS. Beyond warfarin: the new generation of oral anticoagulants and their
implications for the management of dental patients. Oral Surg Oral Med Oral Pathol Oral Radiol
2012;113:431–41.

8 Aminoshariae et al. JOE  Volume -, Number -, - 2021

 52. Kvasnicka T, Malikova I, Zenahlikova Z, et al. Rivaroxaban - metabolism, pharmacologic
properties and drug interactions. Curr Drug Metab 2017;18:636–42.

53. Sunkara T, Ofori E, Zarubin V, et al. Perioperative management of direct oral anticoagulants
(DOACs): a systemic review. Health Serv Insights 2016;9:25–36.
54. Brennan Y, Gu Y, Schifter M, et al. Dental extractions on direct oral anticoagulants vs. warfarin:
The DENTST study. Res Pract Thromb Haemost 2020;4:278–84.
55. Thibault N, Morrill AM, Willett KC. Idarucizumab for reversing dabigatran-induced anticoagulation:
a systematic review. Am J Ther 2018;25:e333–8.

56. Kwak EJ, Nam S, Park KM, et al. Bleeding related to dental treatment in patients taking novel oral
anticoagulants (NOACs): a retrospective study. Clin Oral Investig 2019;23:477–84.
57. Costantinides F, Rizzo R, Pascazio L, Maglione M. Managing patients taking novel oral
anticoagulants (NOAs) in dentistry: a discussion paper on clinical implications. BMC Oral Health
2016;16:5.
58. Kawabata M, Goya M, Maeda S, et al. A survey of direct oral anticoagulant cessation in general
surgery and outcomes in patients with nonvalvular atrial fibrillation. Int Heart J 2020;61:905–12.

59. Curto A, Albaladejo A, Alvarado A. Dental management of patients taking novel oral
anticoagulants (NOAs): Dabigatran. J Clin Exp Dent 2017;9:e289–93.

60. Jang Y, Kim H, Roh BD, Kim E. Biologic response of local hemostatic agents used in endodontic
microsurgery. Restor Dent Endod 2014;39:79–88.
61. Pen~arrocha-Oltra D, Soto-Pen~aloza D, Pen~arrocha-Diago M, et al. Hemostatic agents in
endodontic surgery of maxillary molars: a randomized controlled pilot study of
polytetrafluoroethylene (PTFE) strips as an adjunct to epinephrine impregnated gauze versus
aluminum chloride. Med Oral Patol Oral Cir Bucal 2020;25:e634–43.

62. von Arx T, Jensen SS, H€anni S, Schenk RK. Haemostatic agents used in periradicular surgery: an
experimental study of their efficacy and tissue reactions. Int Endod J 2006;39:800–8.
63. Pen~arrocha-Oltra D, Mene ndez-Nieto I, Cervera-Ballester J, et al. Aluminum chloride versus
electrocauterization in periapical surgery: a randomized controlled trial. J Endod 2019;45:89–93.

64. Witherspoon DE, Gutmann JL. Haemostasis in periradicular surgery. Int Endod J 1996;29:135–
49.

65. Ng W, Jerath A, Wasowicz M. Tranexamic acid: a clinical review. Anaesthesiol Intensive Ther
2015;47:339–50. Î
66. Puia SA, Hilber EM, Garcia-Blanco M. Randomized clinical trial comparing three local hemostatic
agents for dental extractions in patients under chronic anticoagulant therapy - a comparative
study. Ann Maxillofac Surg 2020;10:292–6.
67.  Valle Castan
Zubizarreta-Macho A, 
~o S, Montiel-Company JM, Mena-Alvarez J. Effect of
computer-aided navigation techniques on the accuracy of endodontic access cavities: a
systematic review and meta-analysis. Biology (Basel) 2021;10:212.
68. Djulbegovic B, Hozo I, Li SA, et al. Certainty of evidence and intervention’s benefits and harms are
key determinants of guidelines’ recommendations. J Clin Epidemiol 2021;136:1–9.

69. Scottish Dental Clinical Effectiveness Programme. Clinical effectiveness programme. Available at:
https://www.sdcep.org.uk/wp-content/uploads/2015/09/SDCEP-Anticoagulants-Guidance.
pdf; 2018. Accessed June 8, 2021.

70. Oprea AD, Popescu WM. Perioperative management of antiplatelet therapy. Br J Anaesth
2013;111(Suppl 1):i3–17.

JOE  Volume -, Number -, - 2021 Perioperative Antiplatelet and Anticoagulant Management 9