New oral anticoagulants and their implications for dental

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Authors O’Connell, John Edward

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 Peer-reviewed
JOURNAL OF THE IRISH DENTAL ASSOCIATION

New oral anticoagulants and their

implications for dental patients
Anticoagulation therapy is used in several conditions to prevent or
treat thromboembolism. Over the last 40 years, warfarin has been
the oral anticoagulant of choice and has been considered the
mainstay of treatment. However, its use is limited by a narrow
therapeutic index and complex pharmacodynamics, necessitating
regular monitoring and dose adjustments.
Recently, two new oral anticoagulants - dabigatran etexilate (a
direct thrombin inhibitor) and rivaroxiban (a factor Xa inhibitor) -
have been approved for use in North America and Europe. Unlike
warfarin, dabigatran and rivaroxiban are relatively small molecules
that work as anticoagulants by targeting specific single steps of the
coagulation cascade. Their advantages, relative to warfarin, include:
predictable pharmacokinetics; limited food and drug interactions;
rapid onset of action; and, short half-life. They require no
monitoring. However, they lack a specific reversal agent.
The number of patients taking dabigatran and rivaroxaban is
increasing. Therefore, it is inevitable that dentists will be required
to perform invasive procedures on this cohort of patients. This
paper outlines the various properties of the new oral anticoagulants
and the most recent guidelines regarding the management of these
dental patients taking these medications.
Journal of the Irish Dental Association 2014; 60 (3): 137-143

John Edward O’Connell

Introduction without its disadvantages. Its use is limited
MB, BDS, MRCS, FFD RCSI Anticoagulation therapy is indicated in by a narrow therapeutic index and complex
Department of Surgery, several conditions to prevent, treat, or pharmacodynamics, necessitating regular
Cork University Hospital reduce the recurrence risk of monitoring and dose adjustments. In
thromboembolism. Included in these addition, it has multiple drug and dietary
Leo FA Stassen conditions are: deep vein thrombosis (DVT); interactions. These disadvantages created an
FRCS (Ed) FDS RCS MA FTCD pulmonary embolism (PE); atrial fibrillation; impetus for the development of novel oral
FFSEM(UK) FFD RCSI prosthetic and rheumatic heart valves; anticoagulants with a wider therapeutic
Consultant Oral and myocardial infarction; transient ischaemic index, less interactions, and a predictable
Maxillofacial Surgery attacks; and, stroke. Over the last 40 years, level of anticoagulation at a specific dose.
the coumarin-derivative, vitamin K Recently, two new oral anticoagulants,
Address for correspondence: antagonist, warfarin has been the oral dabigatran etexilate (a direct thrombin
John Edward O’Connell anticoagulant of choice and has been inhibitor) and rivaroxiban (a factor Xa
Department of Surgery considered the mainstay of treatment. inhibitor) have been approved for use in
Cork University Hospital Indeed, it has, along with other vitamin K North America and Europe. In Europe, both
Wilton, Cork antagonists, been the most widely-available, dabigatran and rivaroxiban are licensed for
[email protected] orally-administered anticoagulant. 1,2 short-term primary prevention of venous
However, like all medicines, warfarin is not thromboembolic events in adult patients

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TABLE 1: Indications for and pharmacology of oral anticoagulants.

Warfarin Dabigatran Rivaroxaban

Indications DVT, PE Prevention of CVA in AF VTE prophylaxis in elective THR, TKR

Prevention of thrombosis in AF VTE prophylaxis in elective THR, TKR
Prevention of recurrent MI
MHV

Dose and regimen Titrated according to INR Range: 110-150mg BD for AF; 220mg daily 10mg once daily
Once daily for THR/TKR

Site(s) of action Factors II, VII, IX, and X Thrombin Factor Xa

Proteins C and S

Oral bioavailability ~100% 3-7% 80-100%

Time to peak plasma 2-8 hours 2-4 hours 2.5-4 hours

concentration (Tmax)
Half-life (T½) 20-60 hours 12-17 hours 5-13 hours
Up to 28 hours in severe renal impairment

Metabolism Primarily CYP2C9 (liver) Esterase catalyzed hydrolysis in plasma/liver Liver: CYP3A4, CYP3A5, CYP2J2

Renal elimination 90-100% 80-85% 66%

Need for monitoring Regular INR None None

Abbreviations CYP cytochrome P MI myocardial infarction

DVT deep venous thrombosis PE pulmonary embolus
AF atrial fibrillation INR international normalised ratio THR total hip replacement
CVA cerebrovascular accident MHV mechanical heart valve TKR total knee replacement

who have undergone elective total hip or knee replacement surgery, the management of those patients requiring invasive dental
while dabigatran is also licensed for prevention of stroke and systemic procedures, so that these patients are managed in a safe manner. This
embolism in adult patients with non-valvular atrial fibrillation, plus present paper outlines the various properties of the new oral
one or more additional risk factors. Dabigatran is contra-indicated in anticoagulants and the most recent guidelines regarding the
patients with a prosthetic heart valve requiring anticoagulant management of these patients in dental practice.
treatment.3 Unlike warfarin, dabigatran and rivaroxiban are relatively
small molecules that work as anticoagulants by targeting specific Materials and methods
single steps of the coagulation cascade.4 In addition, they are reported
to have fewer drug-drug interactions, no significant food interactions, Dabigatran (Pradaxa®; Boehringer Ingelheim)
and provide predictable anticoagulation at a specific dose, without In October 2010, the Food and Drug Administration (FDA), USA, first
the need for regular laboratory monitoring and alterations of dose.5,6,7 approved the use of dabigatran etexilate to reduce the stroke and
The pharmacologic properties of dabigatran, rivaroxaban, and systemic embolisation risk in patients with non-valvular atrial
warfarin are outlined in Table 1. fibrillation. It is now also used, in the EU and Canada, for
As the number of patients taking dabigatran and rivaroxaban thromboembolic prophylaxis in patients who have recently
increases, it is inevitable that dentists will encounter them in the near undergone a total hip or knee replacement.8,9 Recent studies have
future. It is therefore incumbent on all of us to become familiar with shown that dabigatran, given at a fixed dose (owing to predictable
these drugs, their indications and method of action, and in particular pharmacokinetics) does not require monitoring and is as effective as

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warfarin in preventing embolic events in patients with atrial Reversal agent

fibrillation. The Randomised Evaluation of Long-Term Anticoagulation Currently, there is no reversal agent for the dabigatran. However,
Therapy (RE-LY) trial demonstrated that, compared with warfarin, owing to its short half-life, discontinuation of the drug may be
dabigatran 150mg twice daily is more effective at preventing stroke sufficient to resolve minor haemorrhage, with the exception of
and systemic embolisation with a similar risk of major bleeding, patients with renal impairment. For more persistent or major
whereas dabigatran 110mg twice daily is associated with a lower risk bleeding, supportive measures such as pressure, vessel ligation, fluid
of major bleeding and a similar rate of stroke and systemic replacement, and transfusion of blood products can be employed.
embolisation.10 It has also been shown to be equivalent to warfarin in Recombinant factor VII (rFVIIa), prothrombin complex concentrates,
the prevention and management of recurrent venous thrombo- and/or haemodialysis may also be considered.15
embolism (VTE) and PE.11 However, significant concerns regarding the
lack of a reversal agent, and difficulty in precisely monitoring its anti- Drug interactions
coagulant effect remain. Unlike Warfarin, it appears that dabigatran has few clinically significant
drug and food interactions. Ketoconazole, verapamil, and amiodarone
Mechanism of action and pharmacology may increase its anticoagulant effect, whilst rifampicin may decrease its
It is a specific, reversible, direct thrombin inhibitor that, unlike effect. The risk of bleeding whilst on dabigatran may be increased by
warfarin, inhibits both free and fibrin-bound thrombin.12 It binds to concomitant use of other anticoagulants, antiplatelets, and
the active site on the thrombin molecule (Factor II a) so that salicylates.12 Stangier reported that the concomitant use of the non-
fibrinogen cannot be converted into fibrin.5 steroidal anti-inflammatory drug (NSAID), diclofenac sodium, and
Dabigatran etexilate is a pro-drug which, following oral administration dabigatran did not produce a significant interaction.17 Nevertheless,
is converted to its active form, dabigatran. When administered orally, given that non-cox-selective NSAIDs inhibit platelet aggregation and
the bioavailability is approximately 3-7%. It is rapidly absorbed and is are associated with gastro-intestinal bleeding and peptic ulcer disease,
metabolised by the liver. It has a rapid onset of action with a peak it may be prudent to avoid their use in patients taking dabigatran.
plasma concentration at 0.5-4 hours.13,14 When administered twice Paracetamol and opioid analgesics are suitable alternatives.18
daily, a steady state plasma concentration is reached within two to
three days.13 The half-life elimination is 12-14 hours in healthy Specific dental considerations
patients, 14-17 hours in the elderly, and up to 27 hours in patients Unfortunately, to date, there are no clinical trials supporting specific
with severe renal impairment (i.e., creatinine clearance <15-30 measures in the event of haemorrhage in dental patients taking
ml/min). There is no evidence for an alteration in pharmacodynamics dabigatran. The most current information suggests that patients
in patients with moderate hepatic impairment (Child-Pugh B).14 taking dabigatran can undergo invasive dental procedures without
alteration of dose. As is the case with all patients, irrespective of
Laboratory testing/monitoring coagulation status, local haemostatic measures (absorbable gelatin or
Unlike warfarin, routine monitoring of the anticoagulant effect of oxidized cellulose pellets, sutures, gauze soaked in 5% tranexamic
dabigatran is not required. However, certain situations such as acid, pressure) should be employed in the event of bleeding. Owing
emergency surgery, intra-cranial/cerebral bleeding, and overdose may to the risk of thromboembolism, dabigatran should never be
require assessment of anticoagulation. The thrombin clotting time discontinued without prior consultation with the treating physician.
(TT), and ecarin clotting time (ECT) are reported to be the most Firriolo and Hupp, studied data from reports on post-extraction
sensitive tests for quantifying the anticoagulant effects of dabigatran. bleeding in patients receiving low molecular weight heparin
However, the ECT test is not widely available. The activated partial (LMWH).5,19,20 In addition, they looked at the recommendations of
thromboplastin time (aPTT), whilst widely available, is less sensitive van Ryn et al regarding the discontinuation of dabigatran before
particularly at higher dabigatran doses.15,16 Most dentists are familiar elective general surgery, and concluded that there should not be a
with the prothrombin time (PT), often expressed as the international significant risk for serious bleeding after dental treatment, including
normalised ratio (INR). However, this test is less sensitive than others most uncomplicated dental extractions, in patients with normal renal
and cannot be relied upon to determine the anticoagulant effect of function and without other risk factors for bleeding.15 However, they
dabigatran. continue to say that a temporary cessation of dabigatran may be
required in patients requiring major oral/maxillofacial surgery. If this
Adverse reactions is the case, dabigatran should be discontinued (following
The RE-LY trial reported that more than 15% of patients experienced consultation with the patients physician) at least 24 hours (or longer
gastritis type symptoms.10 Minor bleeding events were reported in 8- in renal impairment) before elective surgery. In addition,
33%, and major bleeding in less than 6%. In addition, it reported consideration should be given to performing a TT or aPTT six to 12
drug hypersensitivity (including urticaria, rash, and pruritus), allergic hours prior to surgery, which, if normal, indicates that the
edema, anaphylactic reaction, and anaphylactic shock in less than coagulation is normal and that the anticoagulant effect of dabigatran
0.1% of patients. has resolved.5,15,21

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Dabigatran should only be recommenced post-operatively once a yet to approve its use in the setting of atrial fibrillation, based on a
stable clot has formed, thereby minimising the risk of bleeding. This perceived lack of evidence.29
is particularly important with dabigatran, and indeed rivaroxaban, as
unlike warfarin, their onset of effect is predictable and rapid. Mechanism of action and pharmacology
If discontinuation of anticoagulation is not considered safe, and Rivaroxaban is an oxazolidinone derivative that inhibits factor Xa and
extensive oral surgery is required, peri-operative bridging interrupts both the extrinsic and intrinsic coagulation pathways,
anticoagulation with an appropriate dose of subcutaneous LMWH or thereby inhibiting thrombin formation.12
unfractionated heparin is recommended. It is rapidly absorbed and has a rapid onset of action of two and a half
The RE-LY trial involving over 18,000 patients, looked at (amongst to four hours. The half-life is five to nine hours in healthy adults, and
other things) the levels of bleeding in dabigatran versus warfarin.10 11-13 in the elderly (due to decreased total and renal clearance).30
Whilst the level of both major and minor bleeding was lower amongst Oral bioavailability is 80-100% and the duration of effect is 10-18
the cohort taking dabigatran, no significant statistical significance was hours.4 It is excreted in the urine (66%) and faeces (28%).31
found.
A secondary analysis of the RE-LY trial showed that 4,591 patients had Laboratory testing/monitoring
undergone at least one invasive procedure, with cessation of Like dabigatran, routine monitoring of rivaroxaban is not required.
anticoagulation pre-operatively.22 Interestingly, 10% (460) of these However, in an emergency situation, measurement of the level of
procedures were dental, which was the second most common type of anticoagulation may be indicated. Anti-factor Xa assay is reportedly
surgery. Dabigatran was discontinued 24-72 hours (average 49 hours) the most accurate measurement of the anti-coagulant effect of
or more pre-operatively, based on renal function and bleeding risk, rivaroxaban (as well as LMWHs).21 In addition, some authors suggest
and warfarin was discontinued an average of 114 hours pre- that aPTT and PT (with rivaroxaban specific calibration) may also be
operatively. The analysis demonstrated similar rates of perioperative used.32,33 The activated aPTT and HepTest® are prolonged dose-
bleeding for both dabigatran and warfarin. More specifically, the dependently; however, they are not recommended to assess the
incidences of major perioperative bleeding were 3.1% with pharmacodynamic effect of rivaroxaban.30
dabigatran 110mg, 5.1% with dabigatran 150mg, and 4.6% with
warfarin.44 However, despite the fact that approximately 460 dental Adverse reactions
procedures were included in this study, it is difficult to find specific Approximately 1-10% of patients taking rivaroxaban experience an
perioperative measures or guidelines as information regarding the adverse reaction.34 Major bleeding occurs in 1-2%, and minor
duration and type of procedure are limited. Therefore, it is important bleeding in 4-7%. Nausea occurs in 1% of patients.
to highlight that it is difficult to recommend this study as a guide for
the management of patients requiring dental procedures. Reversal agent
Romond et al., in a recent paper, describe the successful management Unlike warfarin, there is no specific agent to reverse the anti-coagulant
of a patient taking dabigatran who required multiple extractions.23 As effect of rivaroxaban. However, owing to its short duration of action,
per the recommendations of van Ryn et al., they held the patients’ discontinuation of the drug should be sufficient to arrest persistent
dabigatran 24 hours prior to the procedure, which involved eight minor haemorrhage. Severe or life-threatening haemorrhage may
extractions, alveoloplasty, and tuberosity reduction.15 They reported require the use of blood product transfusion, recombinant Factor VIIa,
no prolonged post-operative bleeding. Interestingly, they also stated or prothrombin complex concentrate (PCC).35,36
that had the patient required only one to three extractions,
consideration would have been given to not stopping the patients’ Drug interactions
dabigatran. Weitz et al., also suggest that dabigatran does not need Two thirds of rivaroxaban is metabolised by the Cytochrome P450
to be stopped in cases where the bleeding risk is low and cites dental (CYP) system, especially CYP3A4. In addition, rivaroxaban is also a
extractions as an example.24 substrate of P-gp transporters.5 Therefore, the concomitant use of
rivaroxaban with inhibitors or inducers of CYP3A4 should be
Rivaroxaban (Xarelto®; Bayer) avoided.35,37 CYP3A4 inhibitors, which can increase the serum
Rivaroxaban is an orally-administered, selective, reversible, direct concentration of rivaroxaban and therefore the risk of bleeding,
inhibitor of activated factor X (factor Xa), and is currently indicated for include erythromycin, ketoconazole, and amiodarone. Clarithromycin
prophylaxis of venous thromboembolism (VTE) in adults after hip or is considered a strong CYP 3A4 inhibitor, and a moderate P-gp
knee replacement surgery. A number of studies have demonstrated inhibitor. However, the increase in peak serum concentration of
that rivaroxaban can reduce VTE and all cause mortality in these rivaroxaban when administered with a twice-daily dose of
patients.25,26,27 Clarithromycin 500mg was found to be of no clinical relevance in one
The ROCKET-AF trial investigated the effectiveness of rivaroxaban, study.38 Conversely, CYP3A4 inducers such as phenytoin, rifampicin
relative to warfarin, in the reduction of ischaemic stroke or systemic and St Johns wort may increase the metabolism of rivaroxaban,
embolism in patients with atrial fibrillation.28 However, the FDA has thereby decreasing the level of anticoagulation. Non-steroidal and

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opioid analgesics should be used with caution in patients taking have multiple food and drug interactions. Despite this, the
rivaroxaban.5 availability of an antidote, specifically Vitamin K, is somewhat
reassuring. In the event of a significant or life-threatening bleed,
Specific dental considerations prothrombin complex concentrate may also be used. Recently, the
Similar to dabigatran, there are currently no clinical trials in the search for a better alternative to Vitamin K antagonists has resulted
literature offering specific recommendations for the management of in the production of two new drugs, namely dabigatran etexilate
dental patients taking rivaroxaban. and rivaroxaban. Their advantages, relative to warfarin, include
Turpie et al., suggest that interruption of rivaroxaban is not required predictable pharmacokinetics, limited food and drug interactions,
for simple dental extractions.39 The guidelines given above in relation rapid onset of action, and short half-life. They also require no
to dabigatran are also applicable to rivaroxaban. Therefore, it is not regular monitoring or dose titration. A Cochrane review of 14
necessary to discontinue rivaroxaban for uncomplicated extractions studies, incorporating 27,746 patients, comparing direct thrombin
and other similar invasive dental procedures in patients with normal inhibitors to vitamin K antagonists and LMWH showed no
renal function. Local haemostatic measures, as described previously, statistically significant difference in the risk of bleeding.45 However,
should be employed when necessary. For patients undergoing elective the lack of a specific reversal agent remains a concern.
oral/maxillofacial surgery, where the bleeding risk is significant, The RE-LY trial, which was referred to in the above section on
rivaroxaban should be discontinued (only after consultation with the dabigatran, looked at (amongst other things) the levels of bleeding
patients physician) for at least 24 hours before surgery. A longer time in dabigatran versus warfarin.10 Whilst the level of both major and
period will be required in patients with renal dysfunction.4,40 minor bleeding was lower amongst the cohort taking dabigatran,
no noteable statistical significance was found. However, significant
Warfarin concerns have since been raised regarding severe bleeding events
The guidelines for management of dental patients taking warfarin, (in patients whose anticoagulation was not stopped) and their
have previously been well described in the literature.41-44 However, for management (or lack thereof) in patients taking dabigatran.46-47
completeness, a summary of the management of dental patients To our knowledge, there are no randomised controlled trials
taking warfarin is included here. Warfarin inhibits the enzyme vitamin looking at the peri-operative management of bleeding in dental
K epoxide reductase, therefore inhibiting the formation of vitamin K- patients taking dabigatran or rivaroxaban. Romond et al. describe
dependent coagulation factors II, VII, IX, and X, and proteins C and S. the successful management of a patient taking dabigatran who
The maximum anticoagulant effect of warfarin takes 48 to 72 hours to underwent multiple extractions.22
develop, with an estimated duration of action of two to five days and Van Diermen et al. in an extensive literature review and summary
a reported half-life of two and a half days. It is important to stress that, of papers dealing with the management of dental patients
owing to the risk of a potentially fatal thromboembolism, cessation of receiving oral anti-thrombotic medication (including the novel oral
warfarin therapy prior to dental treatment is not recommended. anticoagulants) proposed an updated clinical practice guideline for
Instead, an INR should be taken 24 to 48 hours pre-operatively to dentists.48 They concluded that the evidence does not support
establish the degree of anticoagulation. In general, it is safe to proceed cessation of oral antithrombotic medication for simple dental
with an invasive dental procedure (including administration of local procedures. More specifically, they recommend that novel oral
anaesthesia, periodontal or endodontic surgery, and routine/surgical anticoagulant treatment (including dabigatran and rivaroxaban)
extractions) if the INR is less than or equal to 3.5. Local haemostatic should not be interrupted to facilitate simple dental procedures
measures should be employed routinely. If the INR is greater than 3.5, (e.g., up to three dental extractions, up to three dental implants,
the dentist should liaise with the treating physician in order to safely and periodontal surgery).
reduce the warfarin dosage. Due to warfarin’s long half-life, a period Most current guidelines are largely based on expert opinion and
of three to five days is required for a reduction in the level of the pharmacologic properties of the new oral
anticoagulation, as reflected in a reduced INR. An INR again needs to anticoagulants.5,12,15,18,22
be taken 24 to 48 hours prior to the procedure to ensure that it is less Current available information suggests that the risk of bleeding in
than or equal to 3.5. Finally, all dentists should be cognisant of the patients undergoing invasive dental procedures (for example,
potential interaction between warfarin and other drugs commonly extractions) is low, provided that local haemostatic measures
used in dentistry, including azole antifungals, macrolide antibiotics, (suturing, gelatin sponge, gauze soaked 5% tranexamic acid,
and NSAIDs. tranexamic acid mouth rinse) are used and the patient has normal
renal function. Indeed, the risk seems to be analogous to patients
Discussion taking warfarin and with an INR of between two and three. For
Oral vitamin K antagonists have, for many years, been the patients requiring multiple extractions, or oral/maxillofacial
mainstay of management for VTE treatment and prevention. procedures, consideration must be given to discontinuation of
Despite their widespread use, they are not without problem. They dabigatran/rivaroxaban, with the duration determined by renal
require regular monitoring and dose titration. In addition, they function and bleeding risk.15 However, as stated previously,

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