DENTAL CONSIDERATIONS IN PATIENTS TAKING NEW ANTIPLATELET AND ANTICOAGULANT DRUGS

Atherosclerosis and the resulting cardiovascular and cerebrovascular diseases (myocardial infarction, coronary artery disease and stroke) are the leading cause of mortality and morbidity in the developed countries. Worldwide, over 10 million deaths per annum are caused by arterial thrombosis (ischaemic stroke, heart disease, peripheral gangrene). Leading in the treatment and prevention of thrombotic complications are the anticoagulant and antiplatelet drugs which are taken by millions of patients worldwide. A review of the literature shows that clinical trials involving dental extractions in patients taking antithrombotic drugs have been conducted for more than 50 years and are still ongoing. Recently, new antiplatelet and anticoagulant drugs: direct thrombin inhibitors, factor Xa inhibitors and a new class of oral thienopyridines (inhibitors of Glycoprotein IIb/ IIIa and P2Y12 receptors) have been introduced on the market and are becoming increasingly common. The implications of these drugs during dental treatment are not yet known, and there is not enough information available within the literature on safe use during dental surgery. The purpose of the present review is to discuss the pharmacological properties of the new antiplatelet and anticoagulant drugs, their usage in the perioperative setting, and some guidance for dental practitioners performing invasive dental procedures.


INTRODUCTION
With prolonged life expectancy, the number of elderly patients requiring dental treatment increases. These patients often are with chronic diseases, treated with multiple medications. The leading cause of mortality and disability in the world are cardiovascular and cerebrovascular diseases. The cardiovascular diseases annually cause nearly one-third of the planet's mortality, 47 percent of mortality in Europe and over 60 percent in Bulgaria. Lead-ing in the treatment of these diseases and the prevention of their complications are the antithrombotic medications, which application grows at an annual rate above 10% [1].
Arterial and venous thrombosis has an important impact on worldwide morbidity and mortality. Worldwide over 10 million deaths per annum are caused by arterial thrombi, resulting in ischaemic stroke, heart disease or peripheral gangrene.
Platelets are the key pro-thrombotic element in the arterial thrombosis, forming aggregates interconnected by fibrin, thus antiplatelet drugs are leading in the treatment of arterial thrombosis. Half a million deaths related to venous thromboembolism occur in the European Union per year [2]. Venous thrombi consist mainly of fibrin with few cells in between. Anticoagulants are the drugs of choice to prevent or treat these conditions [2].
Three main classes of antiplatelet agents are licensed for the treatment of atherothrombosis: acetylsalicylic acid (aspirin), P2Y12 inhibitors (ticlopidine, clopidogrel, prasugrel, cangrelor, ticagrelor), and GpIIb/IIIa receptor antagonists (abciximab, eptifibatide, and tirofiban). While the latter have intravenous administration in ACS in combination with other antithrombotic agents (their effect being unpredictable when administered orally), the former two classes are widely used chronically [3].

NEW ÀNTIPLATELET ÀGENTS
The clinical efficacy of aspirin, ticlopidine, and clopidogrel is only partial because they inhibit TXA2-mediated or ADP-mediated platelet aggregation, leaving the activity of other platelet agonists such as thrombin largely unaffected. Another drawback is the high inter-individual variability in platelet inhibition by clopidogrel, which is attributed to differences in the extent of clopidogrel prodrug metabolism. Clinical, cellular and genetic factors have been associated with clopidogrel resistance. This variability is clinically important since many studies have demonstrated that patients exhibiting high on-treatment platelet reactivity (clopidogrel resistance or hyporesponsiveness) are not adequately protected from major adverse cardiac events. It is estimated that approximately one-third https://doi.org/10.5272/jimab.2020262.3144 of clopidogrel-treated patients exhibit a diminished ex vivo platelet response to clopidogrel [4].
Ticlopidine, clopidogrel, prasugrel, and ticagrelor are approved P2Y12 antagonists, whereas cangrelor is still in clinical development. Ticlopidine is not frequently prescribed, owing to its unfavourable safety profile; whereas clopidogrel is the most widely used P2Y12 inhibitor. Prasugrel and ticagrelor are novel P2Y12 receptor inhibitors. Prasugrel acts as an irreversible oral inhibitor of the P2Y12 receptor. Ticagrelor, a cyclopentyl-triazolo-pyrimidine, is the first orally available reversible antagonist of the P2Y12 receptor (Table 1) [5].

Prasugrel (Efient®)
Prasugrel is a third generation thienopyridine, which acts as a selective and irreversible inhibitor of the P2Y12 receptor. Prasugrelexhibits a more rapid antiplatelet effect ex vivo compared with clopidogrel owing to its faster metabolic activation.
Pharmacokinetics/pharmacodynamics.Prasugrel is an oral prodrug that requires conversion into an active metabolite (R-138727) by the hepatic cytochrome P450 (CYP) system. Prasugrel is transformed through hydrolyzation of esterases into the thiolactone, R-95913 and then further metabolized via oxidation of intestinal and hepatic CYP450 into active metabolite R-138727 [6]. The active metabolite of prasugrel appears rapidly in the blood after ingestion, showing a significant effect after 15 min with a median time to reach a 20% inhibition of platelet aggregation 30 min after administration [7]. Inhibition of platelet aggregation reaches a steady-state after 2-4 days [6]. Prasugrel's metabolites are eliminated with a median halflife ranging from 3 to 9 h. Two-thirds of metabolites are excreted in the urine, one-third in feces [7].

Ticagrelor(Brilique™, AZD6140)
Ticagrelor is an adenosine triphosphate analogue, which belongs to new chemical class cyclopentyltriazolo-pyrimidines. It is the first reversibly binding oral ADP receptor P2Y12 antagonist, which is highly selective for the receptor.
Pharmacokinetics/pharmacodynamics. Ticagrelor' sactive form does not need the metabolic activation required with thienopyridines. Ticagrelor targets the P2Y12 receptor via a mechanism that is non-competitive with ADP, suggesting the existence of a binding site on P2Y12 independent to that of ADP. Thus, ticagrelor may act through an allosteric mechanism preventing G-protein-mediated signal transduction following ADP binding to P2Y12 [8].
Ticagrelor is administered twice a dayorally. It is rapidly absorbed in the small intestine, and its plasma half-life occurs between 1.5 and 3 hours after administration with a steady-state concentration after 2 to 3 days. Ticagrelor is eliminated through the gastrointestinal tract, with less than 1% through the urine, suggesting that renal dose adjustment is not necessary.
Ticagrelor is metabolized in the liver primarily through CYP3A4/5 isoenzymes. Some of the ticagrelor metabolites exhibit antiplatelet activity. One of them, AR-C 124910XX, is present at approximately one-third of the plasma concentration of ticagrelor and has a half-life of 8-12 hours. Following cessation, the antiplatelet effects of ticagrelor decline rapidly over 72 h and normal platelet reactivity is achieved after approximately 5 days [4]. Concomitant use of CYP3A4 inhibitors such as ketoconazole, diltiazem, ritonavir, and clarithromycin or inducers (rifampicin, phenytoin, carbamazepine, and dexamethasone) can prolong the plasma half-life of ticagrelor, so it should be avoided [9].

Cangrelor
Cangrelor is a reversible, short-acting, potent, competitive P2Y12 inhibitor that has the advantage of being an active drug not requiring metabolic conversion, although it is not orally available.
Pharmacokinetics/pharmacodynamics.With a plasma half-life of 3-9 min, cangrelor after intravenous administration achieves a high level of platelet inhibition within 5 min and reaches steady state concentration within 15-30 min. of administration. Cangrelor is not a prodrug, it is administered in an active form, and it is metabolized in the plasma by dephosphorylation to its nucleoside, which is inactive. In contrast to clopidogrel and prasugrel, cangrelor is rapidly reversible [10]. The combination of the very short half-life and reversible binding underlie the rapid recovery of platelet function in 1-2 hours following the termination of intravenous infusion of cangrelor. The onset of action of clopidogrel and prasugrel is delayed when co-administrated with cangrelor, demonstrating that cangrelor favourably binds to the P2Y12 receptor and prevents the inhibition of prasugrel's or clopidogrel's metabolite [4].

Integrin áIIbâ3 (GPIIb / IIIa) receptor antagonists
Expression of the functionally active integrin áIIbâ3 (GPIIb/IIIa)on the platelet surface is the final stage of platelet aggregation, making it the subject of development for new antiplatelet drugs [10]. In the mid-70s, Nurden and Caen in France, and Phillips in the U.S.A. found deficiencies of two different platelet membrane glycoproteins in several tribes with Glanzmann thrombasthenia. They have been defined as glycoproteins GPIIb and GPIIIa, existing as a Ca-dependent complex (GPIIb/ IIIa) on the surface of the platelets.
Following recognition that the expression of functionally active integrin aIIbb3 (GPIIb/IIIa)on the platelet surface is the final common pathway of platelet aggregation, this glycoprotein became the target of novel antiplatelet drugs [11].
Correlation of all these findings suggested that blockade of GPIIb/IIIa receptors could be a particularly desirable therapeutic strategy because, firstly, the monoclonal antibodies to GPIIb/IIIa are more potent inhibitors of platelet function than aspirin; secondly, GPIIb/ IIIa is platelet-specific; thirdly, inhibition of GPIIb/IIIa still leaves platelet adhesion largely intact, contributing to haemostasis without causing thrombotic damage; and fourthly, the haemorrhagic diathesis produced by the in-herited deficiency of GPIIb/IIIa receptors in Glanzmann thrombasthenia only rarely produces spontaneous brain haemorrhage, the most feared complication of anticoagulant and antiplatelet therapy.
The success of blockade of GPII / IIIa platelet receptors with intravenous agents (abciximab, eptifibatide, tirofiban) leads to the development of several oral GPIIb/IIIaantagonists [10]. Unfortunately, the oral inhibitors are not clinically effective due to their low bioavailability that leads to a large peak-trough difference and to drug-induced conformational changes in GPIIb / IIIa and possible pharmacogenomics effects in response to the drugs, in particular, the PlA polymorphism in GPIIb / IIIa. The other novel platelet inhibitors are currently in advanced clinical testing [12].

Routine monitoring
Platelet function testing was initially designed for identification of platelets function disorders. Later, in detecting the role of platelets in the development of atherothrombosis, these tests become useful for monitoring of the antiplatelet drug therapy [13].
Numerous platelet function tests are available (e.g. turbidometric light transmittance, Verify Now, Thrombelastogram, Multiplate, Platelet Function Analyser-100). Currently laboratory control of the antiplatelet therapy is not widely applied in the clinical practice due to the lack of a standardized drug resistance definition found in some patients and to the lack of a generally accepted test for platelet function testing. In addition, there is controversy in the interpretation of the laboratory results of resistance, as is not clear whether they directly turn into an inadequate biological response with a direct clinical application [14].

Drug-drug interactions
Membrane transporter proteins such as P gpcan have important effects on the pharmacokinetics of the drugs. Verapamil, diltiazem, quinidine, dronedarone, carvedilol, captopril and amiodarone are inhibitors of Pgp, which also plays an important role in the intestinal efflux of clopidogrel and ticagrelor. Moreover, in vitro studies have indicated that ticagrelor and its active metabolite, AR C124910XX, are inhibitors of the P gp transporter. The activity of carboxylesterases, which play an important role in the biotransformation of many drugs, can be inhibited or induced by drugs such as dexamethasone, phenobarbital, and polycyclic aromatic hydrocarbons [4].

Dental considerations
Most practical recommendations consider dental procedures as minor interventions associated with a low risk of bleeding and self-limited blood loss that can be managed with local haemostatic agents. According to the Scottish Dental Clinical Effectiveness Programme guidance, dental interventions based on the associated bleeding risks can be divided as: (Table 2.) [15].
Few studies showed that risk of haemorrhage in patients taking direct thrombin inhibitors is similar to those taking warfarin with . For patients requiring simple dental extraction or minor oral surgery as localized periodontal surgery, apical osteotomy, incisional biopsies or excision of a localized mucosal lesion, it can be assumed that the risk is similar to that of patients taking vitamin k antagonists and with an INR < 3.
Surgical procedures should be performed as late as possible after the last intake of dabigatran and local haemostatic measures as suturing, gelatine sponge or cellulose mesh, tranexamic acid mouth rinse mast be considered for control of postoperative bleeding [15,17].
Patients who are treated with antiplatelet medications may have additional medical conditions: liver impairment or alcoholism; kidney failure; thrombocytopenia, haemophilia, or other hematologic disorders; treatment with cytotoxic medication that can increase the risk of prolonged bleeding after dental treatment. In these situations, dental practitioners are advised to consult the patient's physician to determine whether care can safely be delivered in a primary care office [17]. Any suggested modification to the medication regimen prior to dental surgery should be done in consultation with and on the advice of the patient's physician [18,19].

Pain control in the postoperative period
In the postoperative period for pain control Paracetamol is the most suitable choice for patients taking dabigatran. Concomitant treatment of new antiplatelets with NSAIDs may increase the risk of bleeding [19].

NEW ORAL ANTICOAGULANTS
For more than 80 yr, vitamin K antagonists have been the most frequently prescribed oral anticoagulants. Although highly effective agents they do have numerous limitations: an unpredictable pharmacological profile in different patients, based on genetic factors; multiple foods and drug interactions, and therefore require frequent laboratory monitoring and dose adjustment. They have a slow onset and offset of action and a hypercoagulable state as a result of warfarin-mediated protein C and S deficiency that develops in some patients [20]. Therefore, they have a narrow therapeutic window, the risk of stroke and systemic embolism increases with lower levels of anticoagulation (INR <2.0) and bleeding risk is higher when the INR is above 3.0. VKAs have a long half-life and a slow onset of action requiring binding therapy, and after cessation, the drug is eliminated from the plasma slowly for 3-5 days [21]. All this leads to the search for new molecules and the discovery of the direct anticoagulants (Table 3): factor Xa inhibitors and direct thrombin inhibitors. Unlike vitamin K antagonists, they do not require frequent monitoring, are administered orally and act on specific and single purposes of the coagulation cascade. They have a wide therapeutic margin, low drug-to-drug interactions and no significant food interactions [22,23]. Their limitations are the lack of effective antidote, high cost and limitations in patients with kidney disease. Prior to surgery, discontinuation of their intake depends on creatinine clearance for 12-120 hours [24].

New oral anticoagulants
In 2004, Ximelagatran was licensed by the European Medical Agency, thus becoming the first oral thrombin inhibitor on the market. As a result of potential hepatotoxicity, it was withdrawn soon after [25]. Since 2008, further new oral anticoagulants have been introduced. These include the direct thrombin inhibitor, dabigatran, and the direct factor X inhibitors, such as rivaroxaban, apixaban, and edoxaban. Other new oral anticoagulants (NOACs) are currently being tested in clinical trials.

Dabigatran (Pradaxa®)
Dabigatran etexilate (Pradaxa®, Boehringer Ingelheim, Spain) is the first orally administered direct thrombin inhibitor. It was the first approved NOA in 2008 by the EU and in 2010 by the Food and Drug Administration (FDA).
Pharmacokinetics/pharmacodynamics. Dabigatran is taken twice daily. It is a specific, reversible direct thrombin inhibitor that, after oral administration, is rapidly absorbed and converted to its active form, through esterase catalysed hydrolysis in the plasma. Mechanism of action of dabigatran is to bind with the active site on free and clot-bound thrombin (factor IIa), so it cannot transform fibrinogen into fibrin. It has a rapid onset of action with a peak plasma concentration at 0.5-4 h. Twenty percent of the absorbed drug undergoes hepatic metabolism, while 80% is excreted unchanged via the renal system, and the dosage must be reduced in patients with renal impairment (Creatinine Clearance (CrCl) < 50 ml/ min). The half-life elimination is determined by renal function and in healthy patients is 12-14 h, 14-17 h in elderly, up to 18 hours in patients with CrCL between 30 and 50 ml/min and up to 28 h in advanced renal impairment (creatinine clearance <15-30 ml/min). Creatinine levels should also be considered even the medication is discontinued before a surgical procedure [26].

Apixaban(Elequis®)
Apixaban is the most recently introduced direct anticoagulant. Apixaban (Eliquis) is taken twice a day. It is a reversible orally administered FXainhibitor with the same therapeutic indications of dabigatran and rivaroxaban.
Pharmacokinetics/pharmacodynamics. After oral administration, the peak plasma concentration is reached in 1-3 h with a bioavailability of approximately 60 %. The half-life of the drug is about 12 h, and it is excreted almost totally in bile. As rivaroxaban, no specific reversal agent exists for apixaban. In case of emergency situations, recombinant factor VIIa, recombinant factor Xa or activated thrombin complexes can be used. However, few data are available for a correct management of apixaban in case of haemorrhage, and further studies are needed in this respect [27].

Rivaroxaban(Xarelto®)
Rivaroxaban is an oral selective, reversible direct FXa inhibitor that binds with the part of factor XaIthat catalyses the activation of prothrombin (factor II).
Pharmacokinetics/pharmacodynamics. Rivaroxaban is most commonly taken once a day, either in the morning or at night. It can inhibit free factor Xa but also clot bound factor Xa, and factor Xa bound to the prothrombinase complex. The drug reaches the peak plasma concentration in 2.5-4 h after oral administration. The half-life is 5.7-9.2 h (up to 12-13 h in patients older than 75 years) Elimination is 66 % renal and 28 % in feces [28].

Edoxaban
Edoxaban is a direct, highly selective and competitive inhibitor of factor Xa. It is indicated for the prevention of stroke/systemic embolism in atrial fibrillation (AF) and for the treatment of venous thromboembolism (VTE).
Pharmacokinetics/pharmacodynamics. It has a bioavailability of 62%. Co-administration of strong Pglycoprotein inhibitors (e.g. ketoconazole, amiodarone, verapamil, or quinidine) causes an increased effect of edoxaban, necessitating a dose reduction of 50%. Dose adjustment should be made in patients with moderate renal impairment [29].

Routine monitoring
Routine monitoring of the anticoagulant effect of NOA is not required. In the emergency situation, the thrombin clotting time (TT) and the ecarin clotting time (ECT) are the most sensitive tests for measuring the anticoagulation rate. Activated partial thromboplastin time (aPTT) is less sensitive, but also can be used in case of emergency. [24,26,30,31].FXaIs, including rivaroxaban, slightly prolong prothrombin time (PT) and aPTT. No routine monitoring of rivaroxaban is generally required; however, in case of an emergency,anti-factor Xa is reported as the most accurate measurement of anticoagulation [28].
In October 2015, the U.S. Food and Drug Administration approved antidote of dabigatran Idarucizumab, a monoclonal antibody (Praxbind®, BoehringerIngelheim Pharmaceuticals, Inc., Germany) for the treatment of patients on dabigatran etexilate when reversal of the anticoagulant effect is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. For minutes Idarucizumab completely reverses the anticoagulant activity of dabigatran in 88 to 98 % of patients [32].

Drug-drug interactions
Dabigatran has few clinically significant drug and food interactions. Concomitant intake of Ketoconazole, amiodarone and verapamil may increase the anticoagulant effect of dabigatran, whilst rifampicin may decrease its effect. The risk of bleeding may alsobe increased by concomitant use of other anticoagulants, antiplatelets, non-cox-selective NSAIDs and salicylates. Paracetamol and opioid analgesics are appropriate alternatives for pain management [33].
Drug-drug interactions affecting the pharmacokinetics of rivaroxaban Co-administration of apixabanand rivaroxaban with the strong CYP3A4 (e.g. phenytoin, carbamazepine, phenobarbital, rifampicin) leads to over 50% decrease of plasma concentration of the drugs. P-gp inhibitors, such as Ketoconazole and ritonavir, may increase dramatically plasma concentrations of apixaban [33,34].

Dental considerations
The major concern in the treatment of patients taking DOACs is the risk of haemorrhage in dental surgical procedures. Depending on the type of dental procedure and the medical condition of the patient, the risk of bleeding should be considered with the risk of thrombo-embolic complications.
Several treatment approaches can be considered: continue DOACs, time dental treatment as late as possible after the last DOACs dose, discontinue DOACs for 24hrs, or discontinue DOACs for 48hrs [35].
Patients taking NOAC who requires a dental procedure with low bleeding risk, treatment should be made without interrupting of the anticoagulant medication.
Patients, who are taking NOAC and requires a dental procedure with higher bleeding risk, should omit (apixaban, dabigatran) or delay (rivaroxaban) their morning dose on the day of their dental treatment. If the patient takes rivaroxaban once daily in the evening, there is no need for modification of the intake, as long as at least 4 hours are past after the dental treatment [15].
In addition: Treatment preferably should be planned early in the day to allow monitoring and management of bleeding complications. Surgical trauma should be minimized over separate visits, and more complex cases should be referred to a more experienced dentist or an oral surgeon. Local haemostatic measures as gelatine sponge and wound suturing should be used to achieve haemostasis.
Advise the patient on the next drug intake: For rivaroxaban (taken once a day), the delayed morning dose may be taken 4 hours after haemostasis has been achieved. The next dose should be taken as usual the following morning. If the patient normally takes their rivaroxaban in the evening, they can take this at the usual time as no earlier than 4 hours after haemostasis has been achieved.
For apixaban or dabigatran (taken twice a day), having missed the morning dose, the patient should take their evening dose at the usual time as long as no earlier than 4 hours after haemostasis has been achieved.
Advise the patient to contact the practice for advice if bleeding occurs prior to, or after, restarting their NOAC.
The patient should avoid missing subsequent doses of their NOAC unless absolutely required in an emergency situation to control bleeding [15].
Unlike warfarin, where the dose can be adjusted according to the INR, the new drugs are prescribed at fixed doses. Depending on the pharmacokinetics of the drug, patients with impaired liver (alcohol dependence, chronic viral or autoimmune hepatitis, primary biliary cirrhosis) or renal function (Table 4), with a myelodysplastic disorder, haematological malignancy or other bleeding disorders (Willebrand's disease, haemophilia, idiopathic thrombocytopenic purpura) and patients on chemotherapy may have a higher risk of bleeding following an invasive dental procedure. These patients should be referred to an oral and maxillofacial surgeon, especially when the required extractions are complex, extensive or have a high risk of postoperative bleeding [36]. The French Working Group on Perioperative Hemostasis and the French Study Group on Thrombosis and Hemostasis suggests extended interruption of treatment prior to interventions with a high risk of bleeding. [30] (Table 4).