Management of patients on oral anticoagulants in dental practice

Medical history and thromboembolic risk

As clinicians we treat patients with a number of comorbidities. In understanding the need for anticoagulation, the causes for coagulopathy must be considered.

Atrial fibrillation

Atrial fibrillation (AF) is the absence of organized atrial contractions, promoting blood stasis in the atria, which in turn increases the risk of thrombus formation.²

It is the most common sustained cardiac arrhythmia in the UK, affecting 1.2 million people, and affects seven in 100 people over the age of 65.^3,4 It affects men more than women and increases the risk five-fold of arterial thromboembolism, which clinically presents as ischaemic stroke.⁴ Risk factors for AF include family history of AF, heart failure, hypertension or other form of cardiovascular disease, diabetes, thyroid disorders and excessive alcohol intake. Symptoms include dizziness, light-headedness, fatigue, palpitations, syncope, chest pain and shortness of breath, whereas some patients may have no symptoms at all. Diagnosis is made by pulse checks, electrocardiogram (ECG) and echocardiograph.⁵

The CHA₂DS₂-VASc score (Table 1) is used to determine risk of stroke among patients and has been developed to guide clinicians in prescription of anticoagulant therapy.⁶ Those with a CHA₂DS₂-VASc score of 2 and above are considered to have a moderate to high risk of thromboembolism. Anticoagulation in this cohort of patients is recommended, and has been shown to significantly reduce thromboembolic events and subsequent clinical stroke.⁷

Venous thromboembolism

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are two manifestations of venous thromboembolism (VTE); others include myocardial infarction, stroke, heart failure, kidney failure and peripheral artery disease. DVT mainly affects the large veins of the thigh or legs, resulting in a unilateral swelling, tenderness, pain, warmth and red discolouration of the overlying skin. PE is a result of cleavage of the original clot from the vein wall, which travels to the lungs, blocking the blood supply, resulting in shortness of breath, rapid breathing, chest pain and tachycardia. Diagnosis for DVT is made via ultrasound and for PE is via a computer tomography scan and increased D-dimers in the blood.⁸

Risk factors that predispose a person to VTE include a body mass index over 25, advancing age, smoking, oral contraception and history of myocardial infarction within 1 month. Also to consider are persisting risk factors such as malignancy, family history, heart failure, varicose veins, and provoked risk factors such as immobility (eg a leg in a plastercast). However, risk of VTE is greatest in individuals who have already suffered one episode of VTE (such as DVT/PE) within the last 3 months and those with a history of VTE associated with a high-risk inherited thrombophilia (factor V Leiden, prothrombin 20210, protein C or S and antithrombin deficiency). Individuals with cancer have a moderate risk, and those with an event more than 1 year ago have a low risk of VTE complications, remaining on anticoagulation for secondary prevention⁹ (Figure 1).

Anticoagulation is the mainstay of therapy for patients with VTE (where initial treatment may be with injectable heparin). Most patients with VTE are anticoagulated for a finite period (3–12 months) following a first episode of VTE.¹⁰

Selected patients at increased risk of recurrent thrombosis beyond this period often benefit from indefinite anticoagulation (eg cancer-related VTE). Anticoagulation is administered in this setting to reduce the lifetime risk of recurrent thrombosis and VTE-associated death.^11,12,13,14 Therefore, for those with a recent DVT or PE, the risk is estimated based on the interval since diagnosis.

Patients who require dental surgery within the first 3 months following an episode of VTE are likely to benefit from delaying elective surgery, even if the delay is only for a few weeks, to allow stabilization of the International Normalised Ratio (INR). Without anticoagulation, the early risk of recurrent VTE was approximately 50%; treatment with warfarin for 1 month reduced this risk to 8–10%, and after 3 months of warfarin therapy the risk declined to 4–5%.¹⁵

Prosthetic heart valves

Surgical replacement of a diseased heart valve (due to valve stenosis or incompetence caused by congenital heart disease, rheumatic fever or endocarditis, cardiomyopathy and myocardial infarction) with a prosthetic valve aims to improve symptoms (such as shortness of breath, unusual tiredness and swelling or oedema),¹⁶ and prolong life, but also exposes the patient to potential prosthesis-related complications. The frequency of serious complications depends on the valve type and position, and other clinical risk factors (eg, cardiac arrhythmia).¹⁰ Complications include embolic events, bleeding, valve obstruction (due to thrombosis), infective endocarditis, structural deterioration (particularly for bioprosthetic valves) and patient–prosthesis mismatch. Thromboembolic and anticoagulation-related problems are by far the most frequent complications of mechanical valves.¹⁷

Warfarin is the drug of choice for long-term therapy in patients with prosthetic heart valves, to prevent valve thrombosis and thromboembolic events.¹⁰ The intensity of therapy varies with the type of valve, the site of valve replacement and the presence or absence of underlying risk factors for thrombus formation.

Conditions that increase risk of bleeding

Patient factors can also contribute to bleeding risk. These patient-related risks can be quantified using bleeding risk scores (HAS-BLED). A high HAS-BLED (Table 2) score (≥3) allows the clinician to identify patients at potential risk of serious bleeding.^18,19,20

The scoring system highlights to clinicians the effects of chronic renal failure and liver diseases, and the associated platelet dysfunction or reduction in coagulation factors. In addition, the Scottish Dental Clinical Effectiveness Programme Guidance²¹ (SDCEP) also highlights other conditions of which clinicians should be aware, such as haematological malignancy, treatments for malignancy, inherited bleeding disorders (eg haemophilia and Von Willebrand disease), as well as idiopathic thrombocytopenic purpura (ITP).

The HAS-BLED score draws attention to the potentially reversible risk factors for bleeding, for example uncontrolled blood pressure, labile INRs if on warfarin and concomitant use of NSAIDs, as well as other antiplatelet or anticoagulant drugs.²² It does not suggest that anticoagulants should be stopped. Other drugs that increase the risk of bleeding include cytotoxic medications, prescribed for autoimmune conditions and rheumatological or inflammatory bowel disease (eg infliximab, etanercept, sulfasalazine, methotrexate, azathioprine, mycophenolate, leflunamide, hydrochloroquine), which can reduce platelet numbers and impair liver function, with subsequent effect on the production of coagulation factors. Also, drugs affecting the nervous system, such as selective serotonin reuptake inhibitors (eg citalopram, sertraline, fluoxetine) can impair platelet aggregation.²¹

Warfarin

Warfarin, a coumarin derivative, is the most widely used anticoagulant in the world. It is a vitamin K antagonist and inhibits vitamin K-dependent synthesis of clotting factors (VII, IX, X and prothrombin II; Table 3) affecting formation of fibrin clots (Figure 2). Precursors of these factors are synthesized in the liver and then activated by carboxylation of specific glutamic acid residues, which require vitamin K in its reduced form as a co-factor. Warfarin more specifically acts by inhibiting the reduction that converts the epoxide form of vitamin K to its reduced form by competitive antagonism due to molecular similarity between warfarin and vitamin K.²³ It is currently used in:

Current guidance^9,21,25 for the management of patients on warfarin is highlighted in Figure 3.

Direct oral anticoagulants

Direct oral anticoagulants (DOACs), previously novel oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban and edoxaban, have been National Institute of Health and Care Excellence (NICE)-recommended (2012–2015) for the prevention of stroke and systemic embolism in non-valvular AF caused by hypertension or hyperthyroidism, and as options for the treatment and prevention of PE and DVT. Warfarin remains the mainstay of therapy, albeit not exclusively, for valvular AF caused by valve disease or an artificial valve.²⁶ In addition, apixaban, dabigatran and rivaroxaban have been approved by NICE as options for the prophylaxis of VTE in adults after elective hip- or knee-replacement surgery. Rivaroxaban has also been approved as an option for prophylaxis of atherothrombotic events (with or without antiplatelet drug) for people with coronary heart disease and after acute coronary syndrome. Rivaroxaban is also indicated for people with symptomatic peripheral artery disease at high risk of ischaemic events.²⁴ The benefits of DOACs over warfarin include:

However, DOACs have a shorter half-life and, therefore, a missed dose can increase the risk of a thromboembolic event, suggesting the importance of patient counselling to ensure the value of adherence is understood. Adherence is difficult to verify in these patients as there is no routine monitoring. There also remains concern about the availability of specific testing assays and a drug-specific antidote, highlighting issues about the treatment of life-threatening bleeding and management of patients requiring urgent or invasive procedures.

Contraindications of DOACs include:

Dabigatran etexilate (Pradaxa)

Dabigatran etexilate is a pro-drug that is hydrolysed through esterase catalysis in plasma to the biologically active dabigatran. It has an indirect effect on platelet formation by reducing thrombin-mediated activation of platelets acting as a direct thrombin inhibitor (IIA), preventing transformation of fibrinogen into fibrin²⁷ (Figure 2).

Dabigatran etexilate has, so far, several known drug–drug interactions and no known drug–food interactions, providing predictable anticoagulation with no requirement for regular coagulation monitoring (Table 4).

Dabigatran was approved for use by the European Medicines Agency (EMA) in 2010, based upon the findings of the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial in which warfarin, was compared with dabigatran.²⁸ The RE-LY trial showed that a 150-mg twice-daily dose of dabigatran had a lower rate of stroke and systemic embolism than warfarin, but a similar rate of bleeding (3.8%, 110 mg twice-daily dabigatran; 5.1%, 150 mg twice-daily dabigatran; and 4.6% warfarin). The RE-COVER trial showed similar rates of recurrent VTE (1.2%) for both dabigatran and warfarin, but the risk of clinically relevant bleeding for dabigatran was significantly lower.²⁹

However, the approval of dabigatran for use in AF is not without some controversy. It has also been linked with an increase in the incidence of myocardial infarction and a risk of overdose in people with impaired renal excretion.³⁰

Rivaroxaban (Xarelto)

Rivaroxaban is a selective and direct inhibitor of factor Xa (Table 5). Factor Xa is found in both the intrinsic and extrinsic pathways of the coagulation cascade (Figure 2), and is responsible for conversion of prothrombin (factor II) to thrombin (factor IIa). Rivaroxaban inhibits both free and clot-bound factor Xa, without having a direct effect on platelet aggregation,²⁷ therefore, prolonging the clotting time.

It was approved by the EMA in 2008, based on the findings of the ROCKET-AF trial.³¹ It found that factor Xa inhibitors reduced the incidence of stroke and systemic embolism events compared with warfarin in patients with AF. Of the 4692 anticoagulant interruptions in this trial, 40% were for invasive surgical procedures. The thromboembolic risk during anticoagulant interruption was similar for rivaroxaban and warfarin (0.3% and 0.4%), and the bleeding risk was similar between both anticoagulants (2.3% major bleeding associated with invasive procedures). Furthermore, the EINSTEIN trial showed that there was a significant reduction in major bleeding in patients on rivaroxaban, when compared to the control group of enoxaparin and warfarin for the treatment of DVT or PE.³²

Apixaban (Eliquis)

Apixaban, like rivaroxaban, is a direct factor Xa inhibitor and similarly modulates the formation of the prothrombinase complex (Table 6). Apixaban does not inhibit thrombin and has no effects on platelets (Figure 2).

It was approved by the EMA in 2011 following the results from the ARISTOTLE trial (Apixaban for Reduction in Stroke and other Thromboembolic Events in AF.³³

The ARISTOTLE trial revealed that apixaban was superior to warfarin for the prevention of stroke and systemic embolism. A total of 9260 procedures was performed on patients where anticoagulation was interrupted (60% of patients). The peri-operative thromboembolic risk was 0.57% for warfarin and 0.35% for apixaban. The rate of major bleeding associated with surgery was 1.8% (apixaban 1.6% and warfarin 1.9%, and continued apixaban 1.6% vs interrupted 1.7%): procedures were considered low risk (dental procedures were included) and highlighted similar outcomes for patients taking warfarin and apixaban, irrespective of whether anticoagulation was discontinued.

Edoxaban (Lixiana)

Edoxaban is a direct and specific inhibitor of factor X preventing catalysis of prothrombin to thrombin (Table 7). Developed in Tokyo, Japan, it was EMA approved in 2015. The Hokusai-VTE trial identified a reduction in VTE episodes when edoxaban was compared to warfarin.³⁴

Assessment of bleeding risk

The estimated risk to the patient of a thromboembolic event resulting from brief DOAC interruption is judged to be extremely small, while the risk of a bleeding complication if the DOAC is continued is also likely to be small, but depends on the procedure involved and the individual patient. The potential risks from either continuing or interrupting a patient's DOAC medication are so finely balanced that the anticoagulant management options and risks should be discussed with the patient. The SDCEP²¹ has categorized dental procedures, as shown in Table 8. The approach to the peri-operative management of patients on DOACs is based on an approximate calculation of the half-life of the drug and thus its persistence in the circulation, taking into account renal function. This is combined with consideration of the bleeding risk of the proposed procedure and a clinical evaluation of the patient's individual risk factors for thrombosis and bleeding (eg concomitant medications, age, history of bleeding complications). Current strategies for elective surgery do not routinely include measurement, either non-specific or specific, of coagulation parameters to assist in quantification of DOAC levels.⁹ Therefore, each patient should be considered individually, and any dental procedure should be postponed until sufficient information about a patient's medical history has been obtained. Three essential factors should be considered before starting any procedure for these specific patients:

NICE recommendations highlight that dental interventions, such as extraction of one to three teeth, periodontal surgery, incision of abscess, and implant positioning have no clinically important bleeding risk. Therefore, a dental procedure can be performed just before the next dose of DOAC is due, or approximately 18–24 hours after the last dose of DOAC was taken (DOAC should be restarted 6 hours later). This means that one dose of DOAC may be missed. For procedures with low or high bleeding risk, the DOAC should be stopped at relevant intervals (24 hours and 48 hours, respectively), and the patient's renal function will determine the interval of DOAC cessation.²⁴

The British Society of Haematology advises that patients with normal renal function undergoing planned low-risk procedures should not take a DOAC dose for 24 hours before the procedure. For higher-risk procedures, the last DOAC dose should be 48 hours before the procedure. This again may vary in accordance with renal function. Following minor or low-risk procedures in patients with a low bleeding risk, anticoagulation can be recommenced 6–12 hours after the procedure, if haemostasis has been achieved.⁹

The European Society of Cardiology³⁰ concurs with this advice and that dental surgery is considered a procedure with minor bleeding risk. These procedures can be performed safely in primary care with use of local haemostatic measures, without suspending DOAC treatment or 12–24 hours after the last DOAC intake, and then restarted 6 hours later. The patient may only leave the practice, if bleeding has completely stopped, and is provided with post-operative written instructions about (a) measures to be taken in case of bleeding; (b) contact details in case of emergency; (c) date and time of last DOAC and other medications; and (d) anticipated time of next DOAC and other medications after haemostasis.

Recommendations for practice

The current guidance regarding patients on a single anticoagulant therapy is that they can be managed appropriately with local haemostatic measures post-operative to dental surgery in primary care. The SDCEP highlights that the arrest of bleeding is a core skill for primary dental care and the dental practitioner should have the necessary equipment and skills to perform appropriate local haemostatic measures competently for dental procedures likely to cause bleeding.²¹

The culmination of advice from the relevant bodies is highlighted below and is applicable to the aforementioned anticoagulant therapy that can present to the clinician:

Conclusion

In the case of the death related to patient A, the PCC¹ highlighted a number of breaches in patient care. The GDC found a failure to document in the clinical records and confirm whether:

The GDC concluded that the extractions could have been undertaken in primary care had the appropriate investigations been carried out and advice given, as well as the relevant guidelines followed, to reduce the risk of post-operative bleeding. The outcome was a 12-month suspension.

This highlights the importance of evidence-based continual professional development, audit, self-reflection and attaining opportunities to work under supervision to ensure a process of lifelong learning. As clinicians, our aim is to help those in need and put patients' interests first. When trust in the ability to provide quality clinical care is breached, patients can be placed at serious risk of harm.

Future considerations

There continues to be limited evidence and lack of robust long-term clinical data on the effects of anticoagulants and, more specifically, DOACs, on post-operative bleeding following dental treatment. There are conflicting recommendations that address the peri-procedural management of DOACs for dental procedures.

Several studies^35,36,37,38 have highlighted that there is no need to discontinue DOACs because bleeding can be easily controlled by local haemostatic measures. In the Dental Extractions on NOAC Without Stopping Therapy (DENTST) study,⁸ the aim was to determine the safety of DOAC continuation compared with warfarin for dental extractions with regard to bleeding outcomes. Patients were shown to have no clinically major bleeding, and furthermore bleeding rates were comparable between warfarin (INR of 2–4) and DOACs (despite different dosing schedules). Therefore, timing dental treatment to avoid DOAC peak concentration is unlikely to provide clinical benefit, omitting DOAC doses increases the risk of VTE, and on DOAC recommencement there is a risk of bleeding. There is increasing evidence in support of DOAC continuation for dental procedures in primary care, albeit with methodological limitations in many of the published studies.^{39,40,41,42,43} Findings in the RE-LY,²⁸ RE-COVER,²⁹ ROCKET AF,³¹ EINSTEIN³² and ARISTOTLE³³ studies also confirm that bleeding is similar for those taking DOACs or warfarin. This suggests the possibility of DOAC continuation, but with control of other patient and procedural factors, where cessation (or timing of last dose) is not required, and confusion among patients and clinicians in the management of anticoagulants is avoided.

Patients at increased risk of bleeding (frail elderly, those with relevant medical complications, or on concurrent antiplatelet therapy, and those requiring extensive surgical treatment) should be considered for referral to secondary care for specialist input. In these cases, any decision to alter the DOAC regimen should be made on a case-by-case basis, balancing those factors likely to increase the risk of bleeding (including risk of re-attendance with bleeding) with the risk of thrombosis.

Further studies are encouraged to determine the true risks of bleeding after oral surgical procedures, and to provide an evidence-based approach in their management.