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RESEARCH

Novel oral anticoagulants and exodontia: the evidence


S. Nathwani*1 and C. Wanis2

In brief
Presents an overview on the use and pharmacology Explores the current evidence-based management Outlines recommendations for practice for the
of anticoagulant medications. of patients on novel oral anticoagulants during oral management of patients on novel oral anticoagulants
surgical treatments. in primary and secondary care settings.

Background Haemostasis is crucial for the success of oral surgical treatment as bleeding problems can cause complications
both pre- and post-operatively. Patients on anticoagulant drugs present a challenge due to their increased risk of bleeding.
Aims To review the evidence for the management of oral surgery patients on novel oral anticoagulant therapy. Methods A
literature review was conducted in May 2016 of free-text and MESH searches (keywords: apixaban, dabigatran, rivaroxaban
and dental extractions) in the Cochrane Library, PubMed and CINAHL. Trial registers, professional bodies for guidelines
and OpenGrey for unpublished literature were also searched. Studies were selected for appraisal after limits were applied
(adult, human and English only studies) and inclusion/exclusion criteria imposed. Results Five studies were identified for
critical appraisal using the CASP tools. These were a combination of systematic reviews and case series. Two case series
were excluded due to low quality evidence. Curtin et al., Davis et al. and Constantinides et al. together with guidelines from
the Scottish Dental Clinical Effectiveness Programme, have highlighted a protocol in managing these patients in a dental
surgical setting. Conclusion Patients on novel anticoagulant therapy requiring dental surgery can be managed appropriately
either without discontinuation of therapy or a delay in dose. For those patients at higher risks of postoperative bleeding
complications, it is advised to liaise with the specialist physician.

Background In the UK it is estimated that at least 1% of NOACs were first developed in order to
the population and 8% of the over-80s are taking improve the characteristics of an ideal oral
Warfarin (a coumarin derivative) is the most it regularly.2 It was first used in 1955 to treat anticoagulant (Table 1).
widely used anticoagulant in the world. It is a American president Dwight D. Eisenhower for
vitamin K antagonist and inhibits vitamin K a coronary event. It is currently used in: Rivaroxaban
dependent synthesis of clotting factors (VII, 1. Prevention of venous thrombosis and
IX, X and prothrombin II) affecting formation embolism in rheumatic heart disease and Rivaroxaban is an oxazolidinone derivative
of fibrin clot. These factors are synthesised in atrial fibrillation (AF) and a highly selective direct Factor Xa inhibitor
the liver in precursor form and activated by 2. Treatment and prophylaxis of deep vein with good oral bioavailability. Inhibition of
carboxylation of specific glutamic acid residues thrombosis (DVT) and pulmonary Factor Xa interrupts the intrinsic and extrinsic
which require vitamin K in its reduced form embolism (PE) pathway of the haematological coagulation
as a cofactor. Warfarin more specifically acts 3. Stroke prophylaxis cascade (Fig.  1), inhibiting both thrombin
by inhibiting the reduction that converts the 4. AF and valvular heart disease (International formation and development of thrombi.
epoxide form of vitamin K to its reduced form Normalised Ratio [INR] target 23) Rivaroxaban does not inhibit thrombin and
by competitive antagonism due to molecular 5. Mechanical heart valves (INR target 34) therefore has no effects on platelets.3 It is a drug
similarity between warfarin and vitamin K.1 which is taken once daily in 10 mg, 15 mg or
However, in recent years the advent of novel 20 mg doses. It has a rapid onset of action of
1
Luton and Dunstable NHS Foundation Trust Hospital, Oral
oral anticoagulants (NOACs), comprising: approximately 2.5–4 hours, and a half-life of
and Maxillofacial Surgery, Lewsey Road, Luton, LU4 0DZ; • Factor Xa inhibitors: rivaroxaban (Xarelto), 5–9 hours (increased in older patients). It is
2
Oral and Maxillofacial Surgery, Barnet and Chase Farm
NHS Hospitals, 127 The Ridgeway, Enfield , EN2 8JL
apixaban (Eliquis), edoxaban (Lixiana) contra-indicated in patients with creatinine
*Correspondence to: S. Nathwani and direct thrombin (factor IIa) inhibitor: clearance of <15 ml/min, whereby creatinine
Email: shrina.nathwani@ldh.nhs.uk
dabigatran (Pradaxa), have been used as an clearance is an assessment of the rate and effi-
Refereed Paper. Accepted 19 January 2017 alternative to warfarin to treat patients with ciency of kidney filtration. It can be measured
DOI: 10.1038/sj.bdj.2017.364 non-valvular AF, and in the prevention of by serum or urine creatinine, but most
©
British Dental Journal 2017; 222: 623-628
stroke and systemic embolism. commonly by the amount of creatinine present

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Table 1 Comparison between warfarin and NOACs

Warfarin NOACs

Dose changes Can be unstable and require dose changes Stable anticoagulation at a fixed dose, requiring minimal dose changes

None required (for emergency setting:thrombin time, Ecarin clotting


Routine monitoring Yes, INR time and activated partial thrombin time for dabigatran. For
rivaroxaban, antifactor Xa more sensitive)

Onset Slow Rapid

Half life Long Short

Therapeutic margin Narrow Wide

Side effects Many, as involves P450 metabolism pathway Few, as does not fully involve P450 pathway

Many, as cytochrome P450 involved in metabolism (for example, azole Dabigatran > rivaroxaban/apixaban
Drug interactions
antifungals, metronidazole, carbamazepine) (for example, carbamazepine)

Food interactions Some food interactions (for example, alcohol, grapefruit/cranberry juice) None significant

Praxbind for dabigatran


Antidote/reversal agent Vitamin K, fresh frozen plasma Recombinant factor Xa for rivaroxaban/apixaban (currently under
development)

in a urine sample collected over 24hours. drug at present therefore it will not form part Dabigatran has little effect on INR. In October
Normal values for men is 97–137 ml/min and of the literature search within this article. 2015 the US FDA approved idarucizumab, a
88–128 ml/min for females (although this can monoclonal antibody fragment (Praxbind,
be reduced in patients older than 50 years). Dabigatran Boehringer Ingelheim Pharmaceuticals, Inc.,
Reduced creatinine clearance values can be Germany) as a reversal agent for patients on
indicative of kidney disease or damage (for Dabigatran is administered orally as the Dabigatran in emergency surgery, or in life-
example due to heart failure or cancer). prodrug dabigatran etexilate, which is rapidly threatening or uncontrolled bleeding.8
Thereafter in 2011, the United States Food and completely converted to dabigatran after Careful patient selection is important before
and Drug Administration (US FDA) approved ingestion, through esterase-catalysed hydroly- considering prescribing NOACs. Patients are
rivaroxaban for prophylaxis and treatment of sis in plasma.7 It is a selective and reversible prescribed NOACs for prevention of stroke
DVT, which may lead to PE, in adults undergo- direct thrombin (factor IIa) inhibitor, which and systemic embolism with non-valvular AF,
ing hip and knee replacement surgery4 and for binds to the active site of the free and clot- and at least one or more of the following:
stroke prevention in people with non-valvular bound thrombin molecule, so it cannot • Have had a stroke or transient ischaemic
AF.5 In 2012, the National Institute for Health transform fibrinogen into fibrin. Dabigatran attack (TIA) in the past
and Clinical Excellence (NICE) recommended has an indirect effect on platelet formation by • Are aged 75 or older
rivaroxaban for the prevention and treatment reducing the thrombin mediated activation of • Have high blood pressure
of venous thromboembolism (VTE).6 platelets.8 It is a drug which is taken twice daily • Have diabetes
in 110 mg or 150 mg doses, depending on the • Have heart failure with symptoms.
Apixaban patient’s renal function. It has a quick onset
of approximately 0.5–4 hours, and its half-life NOACs should be avoided in patients with
Apixaban, like rivaroxaban is a direct Factor is 12–15  hours (increased in patients with severe renal impairment, clinically significant
Xa inhibitor and similarly modulates the reduced renal functions). It is contra-indicated active bleeding, pregnancy and breast feeding,
formation of the prothrombinase complex. in patients with creatinine clearance of <30 ml/ hepatic impairment or liver disease expected
Apixaban does not inhibit thrombin and min due to a risk of overdose. Dabigatran to have any impact on survival, concomitant
has no effects on platelets. It is a drug was approved by NICE in March 2012  as a treatment with systemic ketoconazole, cyclo-
which is taken twice daily in 2.5 mg or 5 mg treatment to prevent stroke and systemic sporin, itraconazole, tacrolimus, voriconazole
doses. It has a rapid onset of approximately embolism in people with non-valvular AF. and dronedarone.
1–3 hours, and its half-life is 12 hours. It is Anticoagulation is determined with the use of: The current management of these patients, as
contra-indicated in patients with creatinine • aPTT (activated partial thrombin time) with patients on other anticoagulant and anti-
clearance of <15 ml/min. It was approved by provides a qualitative indication of antico- platelet therapy, is clinician dependent. Different
NICE in February 2013 for the prevention of agulation but is not suitable for quantifica- surgeons provide different pre-operative advice
stroke and systemic embolism in people with tion of effect regarding cessation or delaying of these drugs.
non-valvular AF. • TT (thrombin time) has a linear dose This can provide a number of difficulties:
Other NOACs have become available to response relationship with dabigatran • Confusion among patients regarding pre-
use, such as Edoxaban (Lixiana®) which was • Ecarin clotting time allows direct measure- operative preparation
approved by NICE in September 2015 for the ment of dabigatran activity but is not widely • Inconsistencies among operating staff
same indications. There is limited data on this used. • Attendance at hospital accident and

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RESEARCH

Fig. 1 Mechanism of action of warfarin and NOACs. Reproduced with permission from I. Sabir et al. Oral anticoagulants for Asian
patients with atrial fibrillation, Nat Rev Cardiol 2014; 11: 290–303, Springer Nature

Contact activation Tissue factor


(intrinsic) pathway (extrinsic) pathway

XII XIIa

XI XIa Tissue factor

Warfarin
IX IXa VIIa VII (indirect) via VKORC1)
Apixaban
Betrixaban
VIIIa Edoxaban
Rivaroxaban
Warfarin
(indirect) via VKORC1) X Xa X

Va
Warfarin
(indirect) via VKORC1) Prothrombin
(II) Thrombin Dabigatran
(II)
V

Fibrinogen Fibrin
(I) (Ia)

XIIIa

Cross-linked
fibrin clot

emergency departments with postoperative selected for appraisal after limits applied (adult, to indicate preoperative drug cessation,12 with
haemorrhage human and English only studies and inclusion/ the drug restarted soon after haemostasis. The
• Delays in treatment as clinicians attempt exclusion criteria imposed). paper highlights the adoption of this protocol
to contact physicians regards drug by the Thrombosis Guidelines Group, which
management. Results recommends dental surgical procedures
should be performed 12 hours after the last
The aim of this paper is to clarify, with the A review of the literature has identified five dose of dabigatran, extractions performed with
aid of evidence-based literature, protocols for studies and one guideline for general dental minimal trauma and with the use of postopera-
the management of patients on NOACs. practitioners in the Scottish Dental Clinical tive local haemostatic measures.
Effectiveness Programme (SDCEP). Of the NICE Clinical Knowledge Summaries
Method five studies, two were excluded (case studies). advise that extraction of up to three teeth,
Curtin et al.11 highlight the lack of guidance periodontal or implant surgery is considered
A literature review was conducted in May for patients on these medications requiring to have ‘no clinically important bleeding risk’
2016  of free-text and MESH searches with dental extractions from manufacturers. and recommend any procedures be carried
the keywords: apixaban, dabigatran, rivaroxa- General recommendations for rivaroxaban out before the next dose of NOAC is due or
ban and dental extractions, in the Cochrane and apixaban include drug cessation for 18–24  hours after the last dose (which may
Library, PubMed and CINAHL. Trial registers, 24–48 hours before surgery dependent on the require missing a dose of the twice daily
professional bodies for guidelines and bleeding risk of the procedure. This should be NOACs; dabigatran and apixaban). The drugs
OpenGrey for unpublished literature were also followed by recommencing the drug as soon can be restarted six hours after haemostasis has
searched. Singular and plural forms of words, as haemostasis has been achieved. The recom- been achieved with the use of local haemostatic
synonyms, acronyms, different spellings, mendations stipulate the need to make an measures.
brand and generic names, truncation, and individual assessment with an account for the Constantinides et al.7 is a systematic review
lay and medical terminology were all used risk of bleeding versus systemic embolism. For of the literature. The RELY (Randomised
in the PICO analysis. Boolean operators ‘OR’, dabigatran, manufacturer recommendations Evaluation of Long-Term Anticoagulation
‘AND’ and ‘NOT’ were all applied. Studies were stipulate the need to measure renal function Therapy) trial in 2009 highlighted the efficacy

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comparing NOACs with low molecular weight


Table 2 Factors affecting bleeding risk
heparin and warfarin, which showed no sta-
Patient factors Surgical factors tistically significant increased risk of bleeding
(although studies were flawed in the classifica-
Age Invasiveness
tion of bleeding). As per Constantinides et al.,7
Renal functionality Difficulty of surgery the anticoagulation effects of dabigatran are
Acquired or congenital coagulation defects comparable to warfarin with an INR of
Antiplatelet/anticoagulant therapies (including drug interaction)
between 2–3.  The authors recommend for
simple extractions that the risk of postop-
Haematological malignancy erative bleeding is low with local haemostatic
Ongoing cancer treatment (chemotherapy) measures. For multiple/surgical extractions or
significant oral and maxillofacial procedures,
of dabigatran against warfarin. The study be commenced after formation of a stable clinicians should consider discontinuation of
included 18,113 patients who were taking clot or as soon as reasonably possible due dabigatran before the procedure with timing to
dabigatran for AF, 4,591 whom underwent to the increased risk of stroke should it be be determined by the patients renal function.
invasive procedures (10% of which included discontinued. In patients where discontinuation is not appro-
dental procedures). The anticoagulant was In 2010, the ROCKET-AF study discovered priate and extensive oral surgery procedures
stopped in these patients according to renal a significant reduction in the number of TIAs are planned, bridging to low molecular weight
function. The incidence of major bleeding and systemic embolic events with rivaroxaban heparin is advised.
risk peri-operatively for invasive surgical pro- compared with warfarin in patients with AF. Finally, the Scottish Dental Clinical
cedures was similar for patients on dabigatran The rate of major bleeding associated with an Effectiveness Programme14 have described
and warfarin (3.8% for 110 mg–5.1% for 150 invasive procedure was 2.3% and was similar a protocol for the dental management of
mg dabigatran; 4.6% warfarin). However, in with the two anticoagulants. patients on NOACs. Dental procedures are
patients on 110 mg dabigatran twice daily As with dabigatran, the authors conclude the categorised according to ‘low risk of postop-
there was a statistically reduced rate of major same protocol be followed for rivaroxaban, with erative bleeding complications’ and ‘high risk
bleeding. discontinuation to be discussed with the patient’s of postoperative bleeding complications’. For
There was an increased risk of bleeding in physician. Therefore, for uncomplicated dental the low risk procedures, the NOACs need not
those requiring emergency surgery or bridging extractions rivaroxaban can be continued in be discontinued or delayed. For high risk pro-
anticoagulation. Similarly, there was 1.2% risk patients with normal renal function (where local cedures, it is suggested that patients delay or
of thromboembolic event in both anticoagu- haemostatic measures are used). Where there is miss a dose (dependent on NOAC taken). For
lant therapies. an increased risk of bleeding or impaired hae- example, if a patient on rivaroxaban requires
The paper suggests the level of antico- mostasis, like dabigatran, rivaroxaban should a high risk procedure, it may not be necessary
agulation achieved by dabigatran is similar be discontinued 24 hours before surgery (with to stop the medication at all, as it is taken once
to warfarin at an INR of 2–3.  To minimise need for increased discontinuation if there is daily, as long as the procedure is performed as
bleeding risk (where dabigatran is continued) reduced renal function). Due to its rapid onset late as possible after the last dose. If a patient
the recommendation is to perform surgery of action, continuation should be 24–48hours on apixaban requires a high risk procedure, it
as late as possible after the last dose and use after surgery. may be necessary to miss the morning/evening
local haemostatic measures postoperatively. In The ARISTOTLE trial (apixaban versus dose of the medication (Table 3). It is thereaf-
the case of elective surgery (multiple surgical warfarin) showed similar results of bleeding ter advised that NOACs may be continued no
extraction), there should be consideration of (1.6% versus 1.9%) for dental extractions, sooner than four hours after haemostasis has
drug cessation which is reliant on: colonoscopy, and ophthalmologic surgery. been achieved.
• Patient’s renal function Constantinides et al.7 conclude there is limited
• The risk of bleeding (Table 2). data to make reliable suggestions with regards Discussion
to management of these patients, but to follow
Constantinides et al.7 also highlight that TT the protocol outlined above until further Despite the limited evidence and lack of
or aPTT performed before surgical treatment studies can be performed. robust long-term clinical data on the effects of
can indicate, if normal, that the anticoagu- Davis et al.13 reviews the literature in relation NOACs on postoperative bleeding following
lant effect of dabigatran has resolved. Due to dabigatran in patients requiring oral surgery. dental extractions, the literature review has
to rapid onset of the drug, dabigatran can The paper considers a Cochrane review highlighted that patients on NOACs can be

Table 3 Suggested NOAC regimen for day of treatment

NOAC Usual drug schedule Morning dose (pre-treatment) Post-treatment dose

Apixaban or Dabigatran Twice a day Miss morning dose Usual time in evening

Once a day, morning Delay morning dose 4 hours after haemostasis


Rivaroxaban
Once a day, evening Not applicable Usual time in evening/4 hours after haemostasis

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Table 4 Evidence-based protocol identified according to anticipated risk of postoperative bleeding

Minor surgical procedures Intermediate surgical procedures Major surgical procedures


(low risk of bleeding) (moderate risk of bleeding) (high risk of bleeding)

multiple extractions >3 teeth, surgical extractions


SImple extraction <3 teeth, incision and drainage of oral and maxillofacial surgery (orthognathic, salivary,
(flap raising procedures), skin cancer excision/
dental abscess trauma, cancer)
reconstruction, jaw cysts, implant placement, biopsies

Discontinue before
DO NOT discontinue daily dose
Delay or miss the morning dose surgery depending on renal function and physician
If possible, perform surgery as long as possible after
Restart 4 hours after haemostasis has been achieved consult (>24 hours preoperatively)
last dose
Local haemostatic measures Restart postoperatively as per specialist advice
Local haemostatic measures
(>24 hours postoperatively)

managed appropriately with local haemostatic patient’s physician/cardiologist (who may postoperative bleeding complications can
measures postoperative to dental extractions. consider bridging anticoagulation). It may be arrested before the weekend
Discontinuation of these drugs should only be be necessary to ensure the effect of the • Bleeding should be managed with local hae-
considered in conjunction with the prescribing drug is reduced by pre-operative aPTT mostatic measures in this group of patients,
physician, due to the individual pharmacoki- or TT, which if still raised may require an such as gelatin sponge/oxidised cellulose
netic variability which is dependent on liver/ increased period of drug cessation mesh, sutures and gauze pressure packs
renal function, sex, weight, age, drug interfer- • Assessment of the risk of thromboembolic • Consider staged extractions for the control
ence and genetics. These factors will influence event, with high risk patients including of intra-operative bleeding
whether a drug should be interrupted or any mitral valve prosthesis, stroke, cardio- • Avoid the concomitant use of drugs that
continued, as well as the potential risks of embolic event, venous thromboembolism may interfere with peak plasma concentra-
thromboembolic event which are considered <3 months, severe thrombophilia or active tions of NOACs (for example non-steroidal
on a case by case basis. cancer (diagnosed <6 months or undergo- anti-inflammatories for pain control)
All papers conclude that the management ing treatment). Lower risk patients include • Discontinuation of NOACs is not necessary
of these patients should include the following aortic-valve prosthesis in patients without for uncomplicated/simple dental extrac-
(Table 4): AF/prior to stroke, and venous thrombo- tions and procedures (where the patient has
• Assess the surgical and patient factors embolism >12 months (with no other risk normal renal function and there is only a
(Table 2) factors). standard bleeding risk)
• Categorise the procedure into low, moderate • In patients where there is a concern of
or high risk of postoperative bleeding Recommendations for practice increased intra-operative or postoperative
• For minor surgical procedures there is bleeding, NOACs can be discontinued/dose
no need to discontinue the anticoagulant Limited data is available regarding the man- delayed
medication as the risk of thrombotic event agement of dental patients on NOACs, and • Consider delay of any invasive dental proce-
outweighs the risk of post-operative haem- remains a concern among clinicians. Further dures for patients on a time limited course of
orrhagic complications studies are encouraged to determine the true therapy, or in patients at the start of therapy
• If possible, perform the surgery as long as risks of bleeding after oral surgical procedures (where initial doses may be higher)
possible after the last dose and to provide an evidence-based approach in • For high risk surgical interventions,
• Consider local factors (such as inflamma- their management. treatment should be delayed until discon-
tion of soft tissues) Based on the findings of the articles tinuation of the NOAC has been prepared
• Application of local haemostatic measures, appraised and pharmacological profiling of the and arranged accordingly with the patient’s
including pressure application with gauze, drugs discussed, the following recommenda- cardiologist, and based on their renal
use of gelatin sponge/oxidised-cellulose tions can be made (Table 4): function (especially for general anaesthe-
mesh (for example, Surgicel), suturing and • Ensure a detailed and current medical sia cases where staged extractions are not
the use of 5% tranexamic mouthwash four history is noted feasible)
times daily for five  days postoperatively • Explain the risks and benefits of performing • Patients must be instructed on when to
(where available) any dental treatment in patients on NOACs commence their NOAC therapy as part of
• For intermediate surgical procedures whether therapy is/is not continued the postoperative instruction
(multiple extractions, surgical extractions) • Assessment of surgical complexity (clinical • Severe postoperative bleeding can be
it is necessary to stop, miss a dose or delay and radiographic) that would suggest managed with application of mechani-
the NOAC dose simple extraction (for example periodon- cal pressure, haemostatic measures, and
• For major surgical procedures (head and tally compromised teeth) versus surgical maintenance of intravascular volume with
neck surgery, extensive oral and maxil- extraction (for example bulbous root fluid replacement (and consideration of
lofacial procedures), NOAC cessation is morphology) haemodialysis in emergency situations).
dependent on the patient’s renal function • Appointments for extractions to be made in Where available reversal agents identified
and followed by discussion with the the morning and early in the week so that previously should be considered.

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