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https://doi.org/10.5272/jimab.2020262.3144 Journal of IMAB Journal of IMAB - Annual Proceeding (Scientific Papers). 2020 Apr-Jun;26(2) ISSN: 1312-773X https://www.journal-imab-bg.org Review article

DENTAL CONSIDERATIONS IN PATIENTS TAKING NEW ANTIPLATELET AND DRUGS

Atanaska S. Dinkova1, Hristo I. Daskalov1, Delian Delev2 1) Department of Oral Surgery, Faculty of Dental Medicine, Medical University of Plovdiv, Bulgaria 2) Department of and Clinical Pharmacology, Medical University of Plovdiv, Bulgaria.

ABSTRACT ing in the treatment of these diseases and the prevention Atherosclerosis and the resulting cardiovascular and of their complications are the , cerebrovascular diseases (, coronary which application grows at an annual rate above 10% [1]. artery disease and ) are the leading cause of mortal- ity and morbidity in the developed countries. Worldwide, Arterial and venous has an important im- over 10 million deaths per annum are caused by arterial pact on worldwide morbidity and mortality. Worldwide over thrombosis (ischaemic stroke, heart disease, peripheral gan- 10 million deaths per annum are caused by arterial thrombi, grene). resulting in ischaemic stroke, heart disease or peripheral Leading in the treatment and prevention of throm- gangrene. botic complications are the anticoagulant and antiplatelet are the key pro-thrombotic element in the drugs which are taken by millions of patients worldwide. arterial thrombosis, forming aggregates interconnected by A review of the literature shows that clinical trials fibrin, thus antiplatelet drugs are leading in the treatment involving dental extractions in patients taking anti- of arterial thrombosis. Half a million deaths related to ve- thrombotic drugs have been conducted for more than 50 nous thromboembolism occur in the European Union per years and are still ongoing. year [2]. Venous thrombi consist mainly of fibrin with few Recently, new antiplatelet and anticoagulant drugs: cells in between. are the drugs of choice to direct inhibitors, factor Xa inhibitors and a new prevent or treat these conditions [2]. class of oral (inhibitors of Glycoprotein IIb/ Three main classes of antiplatelet agents are licensed IIIa and receptors) have been introduced on the mar- for the treatment of atherothrombosis: acetylsalicylic acid ket and are becoming increasingly common. The implica- (), P2Y12 inhibitors (, , tions of these drugs during dental treatment are not yet , , ), and GpIIb/IIIa known, and there is not enough information available antagonists (, , and ). While within the literature on safe use during dental surgery. The the latter have intravenous administration in ACS in com- purpose of the present review is to discuss the pharmaco- bination with other antithrombotic agents (their effect be- logical properties of the new antiplatelet and anticoagu- ing unpredictable when administered orally), the former two lant drugs, their usage in the perioperative setting, and some classes are widely used chronically [3]. guidance for dental practitioners performing invasive den- tal procedures. NEW ÀNTIPLATELET ÀGENTS The clinical efficacy of aspirin, ticlopidine, and Keywords: haemostasis alteration, blood coagula- clopidogrel is only partial because they inhibit TXA2-me- tion disorders, new antiplatelet drugs, dental management diated or ADP-mediated aggregation, leaving the antiplatelet, oral surgery, NOA, thrombosis. activity of other platelet agonists such as thrombin largely unaffected. Another drawback is the high inter-individual INTRODUCTION variability in platelet inhibition by clopidogrel, which is With prolonged life expectancy, the number of eld- attributed to differences in the extent of clopidogrel erly patients requiring dental treatment increases. These pa- metabolism. Clinical, cellular and genetic factors tients often are with chronic diseases, treated with multi- have been associated with clopidogrel resistance. This vari- ple medications. The leading cause of mortality and dis- ability is clinically important since many studies have dem- ability in the world are cardiovascular and cerebrovascu- onstrated that patients exhibiting high on-treatment plate- lar diseases. The cardiovascular diseases annually cause let reactivity (clopidogrel resistance or hyporespo- nearly one-third of the planet’s mortality, 47 percent of nsiveness) are not adequately protected from major adverse mortality in Europe and over 60 percent in Bulgaria. Lead- cardiac events. It is estimated that approximately one-third

3144 https://www.journal-imab-bg.org J of IMAB. 2020 Apr-Jun;26(2) of clopidogrel-treated patients exhibit a diminished ex vivo clopidogrel is the most widely used P2Y12 inhibitor. platelet response to clopidogrel [4]. Prasugrel and ticagrelor are novel P2Y12 receptor inhibi- Ticlopidine, clopidogrel, prasugrel, and ticagrelor tors. Prasugrel acts as an irreversible oral inhibitor of the are approved P2Y12 antagonists, whereas cangrelor is still P2Y12 receptor. Ticagrelor, a cyclopentyl-triazolo-pyrimi- in clinical development. Ticlopidine is not frequently pre- dine, is the first orally available reversible antagonist of scribed, owing to its unfavourable safety profile; whereas the P2Y12 receptor (Table 1) [5].

Mechanism of Time to reach a Metabolism Route of Elimination Time required Class Drug peak plasma to active to restore pla- action elimination half-life concentration metabolite telet function ------Salicylates (COX Inhibition of Acetylsalicylic acid, 30-40 minutes No by Irreplaceable 30% on the 48 h inhibitors) Aloxipyrine, Carba- deacetylation to inhibition of salate , platelets Indufene, Abciximab ------(ReoPro)monoclonal 10-30 min No Degradation by 10-30 min 48 h antibody 7E3 (c7E3 proteolysis in the Fab) i.v. kidney ------Glycoprotein IIb / Reversibly binding Eptifibatide No renal 2,5 h 4 h IIIa antagonists to the platelet (Integrilini.v. (98%). receptor glycopro- tein (GP) IIb/IIIa ------Tirofiban (Aggrastat) No Urine (65%); 2 h 4-8 h i.v. feces (25%) ------Platelets glycopro- Roxifiban p.o. Yes tein (GP) IIb/IIIa antagonist ------Platelets glycopro- Orbofiban p.o. 18h tein (GP) IIb/IIIa antagonist ------Thienopyridines P2Y12 reversible Clopidogrel p.o. 2-4 hours Yes Liver through a 2- 6–8 hours 5-7 days (40% receptor inhibition (300 mg.) step process on 3 days) involving CYP3A5 / 2CD19 to an active metabolite ------P2Y12 reversible Ticlopidine p.o. 2 hours Yes Liver 12 hours 12 hours (single receptor inhibition CYP2CD19 to an dose) 4-5 days active metabolite (multiple intake) ------P2Y12 reversible Prasugrel p.o. 1-2 hours Metabolite (R- Liver 2-15 h 2 weeks receptor inhibition (60 mg.) 138727) CYP2CD19 to an active metabolite ------Sulphonylurea P2Y12 reversible p.o. i.v. 20 min No Liver and kidney No 8 hours after receptor inhibition single dose of 10 mg: longer at high dose (-1 day) ------ADP-analogue P2Y12 irreversible Cangrelor i.v. 3-9 min No Liver (58%) and minutes 1-2 h receptor inhibition kidney(35%) ------Cyclopentyl- P2Y12 irreversible Ticagrelor p.o. 1,5-3 hours No Liver to an active 6–12 hours 5 days triazolopyrimidine receptor inhibition metabolite ------Phosphodieste- Inhibition of phos- p.o. 75 min No Liver glucoro- 10 hours 2 days (?) rase inhibitor phodiesterase nidation to an active metabolite ------Phosphodieste- selective inhibitor of p.o. - No Liver CYP3A4/ 11–13 hours 2 days (?) rase III inhibitor twice-daily 2CD19 . To type III active metabolite ------

J of IMAB. 2020 Apr-Jun;26(2) https://www.journal-imab-bg.org 3145 TP-receptor PAR-1 Inhibition (S18886) 30 min-2 hours No ? 6-10 hours ? antagonist selective thrombo- p.o. xane (TP) antagonist ------PAR-1 receptor PAR-1 Inhibition SCH 205831 p.o. Orally No ? No ? inhibitor derived from the natural product ------PAR-1 Inhibition (CSH- Hours after the No Liver, biliary No 126–269 hours - 530348) p.o. loading dose excretion PAR-1 selective ------receptor inhibitors PAR-1 Inhibition SCH 602539 p.o. No ------PAR-1 Inhibition Atopaxar (E5555) No p.o. ------

------Inhibition of high- 24 hours 12 hours shearstress-induced AJW200 IgG4 platelet aggregation humanized in a concentration monoclonal antibody dependent manner to human vWF derived from Sp2/0 vWF antagonists mouse myeloma (humanized cells. - - - - - monoclonal antibody Binds with high ARC1779 1-2 hours 2 hours 8–12 hours to Vwf) afûnity to the second-generation, activated vWF A1- nuclease resistant domain and inhibits aptamer, which has vWF dependent been conjugated to a platelet aggregation 20-kDA through preventing polyethylene glyco Gp-Ib receptor to interact with Willebrand factor

Prasugrel (Efient®) Ticagrelor(Brilique™, AZD6140) Prasugrel is a third generation , Ticagrelor is an triphosphate analogue, which acts as a selective and irreversible inhibitor of the which belongs to new chemical class cyclopentyl- P2Y12 receptor. Prasugrelexhibits a more rapid triazolo-. It is the first reversibly binding oral antiplatelet effect ex vivo compared with clopidogrel ow- ADP receptor P2Y12 antagonist, which is highly selec- ing to its faster metabolic activation. tive for the receptor. /pharmacodynamics.Prasugrel is Pharmacokinetics/pharmacodynamics. Ticagrelor’ an oral prodrug that requires conversion into an active sactive form does not need the metabolic activation re- metabolite (R-138727) by the hepatic cytochrome P450 quired with thienopyridines. Ticagrelor targets the P2Y12 (CYP) system. Prasugrel is transformed through receptor via a mechanism that is non-competitive with hydrolyzation of esterases into the thiolactone, ADP, suggesting the existence of a binding site on P2Y12 R-95913 and then further metabolized via oxida- independent to that of ADP. Thus, ticagrelor may act tion of intestinal and hepatic CYP450 into active through an allosteric mechanism preventing G-protein-me- metabolite R-138727 [6]. The active metabolite of diated signal transduction following ADP binding to prasugrel appears rapidly in the blood after ingestion, P2Y12 [8]. showing a significant effect after 15 min with a median Ticagrelor is administered twice a dayorally. It is time to reach a 20% inhibition of platelet aggregation 30 rapidly absorbed in the small intestine, and its plasma min after administration [7]. Inhibition of platelet aggre- half-life occurs between 1.5 and 3 hours after administra- gation reaches a steady-state after 2–4 days [6]. tion with a steady-state concentration after 2 to 3 days. Prasugrel’s metabolites are eliminated with a median half- Ticagrelor is eliminated through the gastrointestinal tract, life ranging from 3 to 9 h. Two-thirds of metabolites are with less than 1% through the urine, suggesting that re- excreted in the urine, one-third in feces [7]. nal 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

3146 https://www.journal-imab-bg.org J of IMAB. 2020 Apr-Jun;26(2) plasma concentration of ticagrelor and has a half-life of herited deficiency of GPIIb/IIIa receptors in Glanzmann 8–12 hours. Following cessation, the antiplatelet effects thrombasthenia only rarely produces spontaneous brain of ticagrelor decline rapidly over 72 h and normal plate- haemorrhage, the most feared complication of anticoagu- let reactivity is achieved after approximately 5 days [4]. lant and antiplatelet therapy. Concomitant use of CYP3A4 inhibitors such as The success of blockade of GPII / IIIa platelet ketoconazole, diltiazem, ritonavir, and clarithromycin or receptors with intravenous agents (abciximab, inducers (rifampicin, phenytoin, carbamazepine, and dex- eptifibatide, tirofiban) leads to the development of sev- amethasone) can prolong the plasma half-life of ticagrelor, eral oral GPIIb/IIIaantagonists [10]. Unfortunately, the oral so it should be avoided [9]. inhibitors are not clinically effective due to their low that leads to a large peak-trough difference Cangrelor and to drug-induced conformational changes in GPIIb / Cangrelor is a reversible, short-acting, potent, com- IIIa and possible pharmacogenomics effects in response petitive P2Y12 inhibitor that has the advantage of being to the drugs, in particular, the PlA polymorphism in GPIIb an active drug not requiring metabolic conversion, al- / IIIa. The other novel platelet inhibitors are currently in though it is not orally available. advanced clinical testing [12]. Pharmacokinetics/pharmacodynamics.With a plasma half-life of 3–9 min, cangrelor after intravenous Routine monitoring administration achieves a high level of platelet inhibition Platelet function testing was initially designed for within 5 min and reaches steady state concentration within identification of platelets function disorders. Later, in de- 15–30 min. of administration. Cangrelor is not a prodrug, tecting the role of platelets in the development of athero- it is administered in an active form, and it is metabolized thrombosis, these tests become useful for monitoring of in the plasma by dephosphorylation to its , the therapy [13]. which is inactive. In contrast to clopidogrel and prasugrel, Numerous platelet function tests are available (e.g. cangrelor is rapidly reversible [10]. The combination of turbidometric light transmittance, Verify Now, Thrombe- the very short half-life and reversible binding underlie the lastogram, Multiplate, Platelet Function Analyser-100). rapid recovery of platelet function in 1–2 hours follow- Currently laboratory control of the antiplatelet therapy is ing the termination of intravenous infusion of cangrelor. not widely applied in the clinical practice due to the lack The onset of action of clopidogrel and prasugrel is de- of a standardized drug resistance definition found in some layed when co-administrated with cangrelor, demonstrat- patients and to the lack of a generally accepted test for ing that cangrelor favourably binds to the P2Y12 receptor platelet function testing. In addition, there is controversy and prevents the inhibition of prasugrel’s or clopidogrel’s in the interpretation of the laboratory results of resistance, metabolite [4]. as is not clear whether they directly turn into an inad- equate biological response with a direct clinical applica- Integrin áIIbâ3 (GPIIb / IIIa) receptor antagonists tion [14]. Expression of the functionally active integrin áIIbâ3 (GPIIb/IIIa)on the platelet surface is the final stage of Drug-drug interactions platelet aggregation, making it the subject of develop- Membrane transporter proteins such as P gpcan ment for new antiplatelet drugs [10]. In the mid-70s, have important effects on the pharmacokinetics of the Nurden and Caen in France, and Phillips in the U.S.A. drugs. Verapamil, diltiazem, , dronedarone, found deficiencies of two different platelet membrane carvedilol, captopril and amiodarone are inhibitors of P- glycoproteins in several tribes with Glanzmann throm- gp, which also plays an important role in the intestinal basthenia. They have been defined as glycoproteins GPIIb efflux of clopidogrel and ticagrelor. Moreover, in vitro and GPIIIa, existing as a Ca-dependent complex (GPIIb/ studies have indicated that ticagrelor and its active IIIa) on the surface of the platelets. metabolite, AR C124910XX, are inhibitors of the P gp Following recognition that the expression of func- transporter. The activity of carboxylesterases, which play tionally active integrin aIIbb3 (GPIIb/IIIa)on the platelet an important role in the biotransformation of many drugs, surface is the final common pathway of platelet aggrega- can be inhibited or induced by drugs such as dexametha- tion, this glycoprotein became the target of novel sone, phenobarbital, and polycyclic aromatic hydrocar- antiplatelet drugs [11]. bons [4]. Correlation of all these findings suggested that blockade of GPIIb/IIIa receptors could be a particularly Dental considerations desirable therapeutic strategy because, firstly, the Most practical recommendations consider dental monoclonal antibodies to GPIIb/IIIa are more potent in- procedures as minor interventions associated with a low hibitors of platelet function than aspirin; secondly, GPIIb/ risk of bleeding and self-limited blood loss that can be IIIa is platelet-specific; thirdly, inhibition of GPIIb/IIIa managed with local haemostatic agents. According to the still leaves platelet adhesion largely intact, contributing Scottish Dental Clinical Effectiveness Programme guid- to haemostasis without causing thrombotic damage; and ance, dental interventions based on the associated bleed- fourthly, the haemorrhagic diathesis produced by the in- ing risks can be divided as: (Table 2.) [15].

J of IMAB. 2020 Apr-Jun;26(2) https://www.journal-imab-bg.org 3147 Table 2. Bleeding risks and dental procedures recommended by the Scottish Dental Clinical Effectiveness Pro- gramme [15].

Dental procedures that are unlikely to Dental procedures that are likely to cause bleeding cause bleeding Low bleeding risk procedures High bleeding risk procedures Local anaesthesia by infiltration, Simple extractions (1–3, with re- Complex extractions, adjacent intraligamentary or mental nerve block; stricted wound size); extractions that will cause a large Local anaesthesia by inferior dental block wound, or more than three extrac- or other regional nerve blocks; tions at once; Basic periodontal examination (BPE); Incision and drainage of intraoral Flap raising procedures; swellings; Elective surgical extractions; Supragingival removal of plaque, calculus, Detailed six-point full periodontal Periodontal surgery; and stain; examination; Periradicular surgery; Direct or indirect restorations with Root surface instrumentation (RSI); Crown lengthening; supragingival margins; Dental implant surgery; Endodontics (orthograde); Direct or indirect restorations with subgingival margins. Impressions and other prosthetic proce- Gingival recontouring; dures; Fitting and adjustment oforthodontic Biopsies. appliances.

Few studies showed that risk of haemorrhage in pa- NEW ORAL ANTICOAGULANTS tients taking direct thrombin inhibitors is similar to those For more than 80 yr, vitamin K antagonists have taking with INR 2 - 3 [16]. For patients requiring been the most frequently prescribed oral anticoagulants. simple dental extraction or minor oral surgery as localized Although highly effective agents they do have numerous periodontal surgery, apical osteotomy, incisional biopsies or limitations: an unpredictable pharmacological profile in excision of a localized mucosal lesion, it can be assumed different patients, based on genetic factors; multiple foods that the risk is similar to that of patients taking vitamin k and drug interactions, and therefore require frequent labo- antagonists and with an INR < 3. ratory monitoring and dose adjustment. They have a slow Surgical procedures should be performed as late as onset and offset of action and a hypercoagulable state as possible after the last intake of and local haemo- a result of warfarin-mediated and S deficiency static measures as suturing, gelatine sponge or cellulose that develops in some patients [20]. Therefore, they have mesh, tranexamic acid mouth rinse mast be considered for a narrow therapeutic window, the risk of stroke and sys- control of postoperative bleeding [15, 17]. temic embolism increases with lower levels of anticoagu- Patients who are treated with antiplatelet medications lation (INR <2.0) and bleeding risk is higher when the INR may have additional medical conditions: liver impairment is above 3.0. VKAs have a long half-life and a slow onset or alcoholism; kidney failure; , haemo- of action requiring binding therapy, and after cessation, philia, or other hematologic disorders; treatment with cyto- the drug is eliminated from the plasma slowly for 3-5 days toxic that can increase the risk of prolonged [21]. All this leads to the search for new molecules and bleeding after dental treatment. In these situations, dental the discovery of the direct anticoagulants (Table 3): fac- practitioners are advised to consult the patient’s physician tor Xa inhibitors and direct thrombin inhibitors. Unlike to determine whether care can safely be delivered in a pri- vitamin K antagonists, they do not require frequent moni- mary care office [17]. Any suggested modification to the toring, are administered orally and act on specific and sin- medication regimen prior to dental surgery should be done gle purposes of the coagulation cascade. They have a wide in consultation with and on the advice of the patient’s phy- therapeutic margin, low drug- to- drug interactions and sician [18, 19]. no significant food interactions [22, 23]. Their limitations are the lack of effective antidote, high cost and limita- Pain control in the postoperative period tions in patients with kidney disease. Prior to surgery, dis- In the postoperative period for pain control Paraceta- continuation of their intake depends on creatinine clear- mol is the most suitable choice for patients taking dabigatran. ance for 12-120 hours [24]. Concomitant treatment of new antiplatelets with NSAIDs may increase the risk of bleeding [19].

3148 https://www.journal-imab-bg.org J of IMAB. 2020 Apr-Jun;26(2) Table 3. Anticoagulant drugs

Class Mechanism Drug Time to reach Route of Route of Elimination Drug of action peak plasma administration elimination half-life detection concentration tests Indirect action 60-120 min Per os Liver 8-11 hours INR derivatives Indirect action Warfarin sodium 1-1,30 hours Per os Liver 36-42 hours INR 1,3-Indanediones Chlorindione 1,3-Indanediones Diphenindione 1,3-Indanediones 5 – 10 hours Others Thioclomarol Factor Xa second-generation inhibitors low molecular Bemiparin s.c. 5.3 hours weight heparin Anti-Xa Heparin group/ Certoparin s.c. glycosamino- glycans/ Dalteparin s.c., i.v. Renal 3-5 hours s.c 2,1-2,3 h i.v. Enoxaparin s.c., i.v. Liver into low 4.5 hours molecular weight species by either or both desulfation and depolymerization Nadroparin 3-5 hours SC (except for Renal 3,5 hours (Fraxiparine) haemodialysis) (SC dose) Parnaparin 2-4 hours s.c. Renal Reviparin Renal 90% for Anti-Xa Tinzaparin Minor metabolisation 200 min. for activity, 67% for in liver by desulfation Anti-Xa activity, Anti-IIa activit and/or depolymerization; 257. min for excretion via kidneys in Anti-IIa activity almost unchanged form Renally excreted 17-21 hours unchanged Renal sodium Renal Renal Renal Factor Xa Direct Reversible 3-4 hours Per os 25 % renal, 9-12 hours PT, anti Xa inhibitors Xa Inhibitor (Elequis®) twise daily 55 % intestinal, testing remnant hepatic Factor Xa Direct Xa 3-4 hours Per os Liver 20 hours inhibitors Inhibitors onse daily Factor Xa Direct Xa 1-2 hours Renal elimi- Metabolized in the 6-11 hours PT, anti Xa inhibitors Inhibitors nation 50%, biliary-fecal system testing not recommen- in about 65% and ded if e GFR is mainly excreted <30 mL/min by the kidneys Factor Xa Direct Xa Otamyxaban inhibitors Inhibitors Factor Xa Direct Xa 2,5-4 hours Per os onse 66 % renal, 5–10 h; PT, anti Xa inhibitors Inhibitors (Xarelto®) or twise daily 28 % in feces 12–13 h in testing patients > 75 years Factor Xa Bivalent Hirudine i.v. i.v. Kidneys i.v. 40 min inhibitors s.c. 150–240 min

J of IMAB. 2020 Apr-Jun;26(2) https://www.journal-imab-bg.org 3149 Factor Xa Bivalent i.v. Combination of ~25 minutes in inhibitors i.v. renal mechanisms patients with and proteolytic normal renal cleavage function Direct thrombin Monovalent 1 hour Renal 45 min (F II) inhibitors Direct thrombin Monovalent Dabigatran 2-4 hours 80 % renal, 12–14 h; aPTT, TT, (F II) inhibitors (Pradaxa®) 20 % hepatic 14–17 h in ecarincloting Not recommended elderly; 15–18 h time if eGFR <60 mL/min; in moderate renal contraindicated if impairment; up to eGFR<30 mL/min; 28 h in advanced renal elimination 80% renal impairment Direct thrombin Monovalent Melagatran i.v. No Renal (80%) 1.5–2 hours in aPTT, PT, TT, (F II) inhibitors young, healthy OCT assay people, up to 4–5 hours in 70-year- old patients Direct thrombin Monovalent 1,5-2,5 h Melagatran Renal (80%) 3-5 hours aPTT, PT, TT, (F II) inhibitors p.o. OCT assay

New oral anticoagulants Apixaban(Elequis®) In 2004, Ximelagatran was licensed by the European Apixaban is the most recently introduced direct an- Medical Agency, thus becoming the first oral thrombin in- ticoagulant. Apixaban (Eliquis) is taken twice a day. It is hibitor on the market. As a result of potential hepatotoxic- a reversible orally administered FXainhibitor with the same ity, it was withdrawn soon after [25]. Since 2008, further therapeutic indications of dabigatran and rivaroxaban. new oral anticoagulants have been introduced. These in- Pharmacokinetics/pharmacodynamics. After oral clude the direct thrombin inhibitor, dabigatran, and the di- administration, the peak plasma concentration is reached rect inhibitors, such as rivaroxaban, apixaban, and in 1–3 h with a bioavailability of approximately 60 %. edoxaban. Other new oral anticoagulants (NOACs) are cur- The half-life of the drug is about 12 h, and it is excreted rently being tested in clinical trials. almost totally in bile. As rivaroxaban, no specific reversal Dabigatran (Pradaxa®) agent exists for apixaban. In case of emergency situations, Dabigatran etexilate (Pradaxa®, Boehringer recombinant factor VIIa, recombinant factor Xa or acti- Ingelheim, Spain) is the first orally administered direct vated thrombin complexes can be used. However, few data thrombin inhibitor. It was the first approved NOA in 2008 are available for a correct management of apixaban in case by the EU and in 2010 by the Food and Drug Administra- of haemorrhage, and further studies are needed in this re- tion (FDA). spect [27]. Pharmacokinetics/pharmacodynamics. Dabigatran is taken twice daily. It is a specific, reversible direct Rivaroxaban(Xarelto®) thrombin inhibitor that, after oral administration, is rap- Rivaroxaban is an oral selective, reversible direct idly absorbed and converted to its active form, through FXa inhibitor that binds with the part of factor XaIthat ca- esterase catalysed hydrolysis in the plasma. Mechanism talyses the activation of prothrombin (factor II). of action of dabigatran is to bind with the active site on Pharmacokinetics/pharmacodynamics. Rivaroxaban free and clot-bound thrombin (factor IIa), so it cannot is most commonly taken once a day, either in the morning transform fibrinogen into fibrin. It has a rapid onset of ac- or at night. It can inhibit free factor Xa but also clot bound tion with a peak plasma concentration at 0.5–4 h. Twenty factor Xa, and factor Xa bound to the prothrombinase com- percent of the absorbed drug undergoes hepatic metabo- plex. The drug reaches the peak plasma concentration in lism, while 80% is excreted unchanged via the renal sys- 2.5–4 h after oral administration. The half-life is 5.7– 9.2 tem, and the dosage must be reduced in patients with re- h (up to 12–13 h in patients older than 75 years) Elimina- nal impairment (Creatinine Clearance (CrCl) < 50 ml/ tion is 66 % renal and 28 % in feces [28]. min). The half-life elimination is determined by renal function and in healthy patients is 12-14 h, 14-17 h in Edoxaban elderly, up to 18 hours in patients with CrCL between 30 Edoxaban is a direct, highly selective and competi- and 50 ml/min and up to 28 h in advanced renal impair- tive inhibitor of factor Xa. It is indicated for the preven- ment (creatinine clearance <15–30 ml/min). Creatinine tion of stroke/systemic embolism in (AF) levels should also be considered even the medication is and for the treatment of venous thromboembolism (VTE). discontinued before a surgical procedure [26]. Pharmacokinetics/pharmacodynamics. It has a bioavailability of 62%. Co-administration of strong P- glycoprotein inhibitors (e.g. ketoconazole, amiodarone,

3150 https://www.journal-imab-bg.org J of IMAB. 2020 Apr-Jun;26(2) verapamil, or quinidine) causes an increased effect of Several treatment approaches can be considered: edoxaban, necessitating a dose reduction of 50%. Dose ad- continue DOACs, time dental treatment as late as possible justment should be made in patients with moderate renal after the last DOACs dose, discontinue DOACs for 24hrs, impairment [29]. or discontinue DOACs for 48hrs [35]. Patients taking NOAC who requires a dental proce- Routine monitoring dure with low bleeding risk, treatment should be made with- Routine monitoring of the anticoagulant effect of out interrupting of the anticoagulant medication. NOA is not required. In the emergency situation, the Patients, who are taking NOAC and requires a den- thrombin clotting time (TT) and the ecarin clotting time tal procedure with higher bleeding risk, should omit (ECT) are the most sensitive tests for measuring the anti- (apixaban, dabigatran) or delay (rivaroxaban) their morn- coagulation rate. Activated partial thromboplastin time ing dose on the day of their dental treatment. If the patient (aPTT) is less sensitive, but also can be used in case of takes rivaroxaban once daily in the evening, there is no emergency. [24, 26, 30, 31].FXaIs, including rivaroxaban, need for modification of the intake, as long as at least 4 slightly prolong (PT) and aPTT. No rou- hours are past after the dental treatment [15]. tine monitoring of rivaroxaban is generally required; how- ever, in case of an emergency,anti-factor Xa is reported as In addition: the most accurate measurement of anticoagulation[28]. Treatment preferably should be planned early in the In October 2015, the U.S. Food and Drug Adminis- day to allow monitoring and management of bleeding com- tration approved antidote of dabigatran Idarucizumab, a plications. Surgical trauma should be minimized over sepa- monoclonal antibody (Praxbind®, BoehringerIngelheim rate visits, and more complex cases should be referred to a Pharmaceuticals, Inc., Germany) for the treatment of pa- more experienced dentist or an oral surgeon. Local haemo- tients on dabigatran etexilate when reversal of the antico- static measures as gelatine sponge and wound suturing agulant effect is needed for emergency surgery/urgent pro- should be used to achieve haemostasis. cedures, or in life-threatening or uncontrolled bleeding. For Advise the patient on the next drug intake: For minutes Idarucizumab completely reverses the anticoagu- rivaroxaban (taken once a day), the delayed morning dose lant activity of dabigatran in 88 to 98 % of patients [32]. may be taken 4 hours after haemostasis has been achieved. The next dose should be taken as usual the following morn- Drug-drug interactions ing. If the patient normally takes their rivaroxaban in the Dabigatran has few clinically significant drug and evening, they can take this at the usual time as no earlier food interactions. Concomitant intake of Ketoconazole, than 4 hours after haemostasis has been achieved. amiodarone and verapamil may increase the anticoagu- For apixaban or dabigatran (taken twice a day), hav- lant effect of dabigatran, whilst rifampicin may decrease ing missed the morning dose, the patient should take their its effect. The risk of bleeding may alsobe increased by evening dose at the usual time as long as no earlier than 4 concomitant use of other anticoagulants, antiplatelets, hours after haemostasis has been achieved. non-cox-selective NSAIDs and salicylates. Advise the patient to contact the practice for advice and opioid analgesics are appropriate alternatives for pain if bleeding occurs prior to, or after, restarting their NOAC. management [33]. The patient should avoid missing subsequent doses Drug-drug interactions affecting the pharmacoki- of their NOAC unless absolutely required in an emergency netics of rivaroxaban Co-administration of apixabanand situation to control bleeding [15]. rivaroxaban with the strong CYP3A4 (e.g. phenytoin, Unlike warfarin, where the dose can be adjusted ac- carbamazepine, phenobarbital, rifampicin) leads to over cording to the INR, the new drugs are prescribed at fixed 50% decrease of plasma concentration of the drugs. P-gp doses. Depending on the pharmacokinetics of the drug, pa- inhibitors, such as Ketoconazole and ritonavir, may in- tients with impaired liver ( dependence, chronic vi- crease dramatically plasma concentrations of apixaban ral or autoimmune hepatitis, primary biliary cirrhosis) or [33, 34]. renal function (Table 4), with a myelodysplastic disorder, Concomitant treatment with edoxabanis contraindi- haematological malignancy or other bleeding disorders cated in subjects receiving ritonavir, cyclosporine, eryth- (Willebrand’s disease, haemophilia, idiopathic thrombocy- romycin, azithromycin, clarithromycin, ketoconazole, topenic purpura) and patients on chemotherapy may have itraconazole because these drugs increase its steady-state a higher risk of bleeding following an invasive dental pro- plasma concentrations [29]. cedure. These patients should be referred to an oral and maxillofacial surgeon, especially when the required extrac- Dental considerations tions are complex, extensive or have a high risk of postop- The major concern in the treatment of patients tak- erative bleeding [36]. The French Working Group on ing DOACs is the risk of haemorrhage in dental surgical Perioperative Hemostasis and the French Study Group on procedures. Depending on the type of dental procedure and Thrombosis and Hemostasis suggests extended interruption the medical condition of the patient, the risk of bleeding of treatment prior to interventions with a high risk of bleed- should be considered with the risk of thrombo-embolic ing. [30] (Table 4). complications.

J of IMAB. 2020 Apr-Jun;26(2) https://www.journal-imab-bg.org 3151 Table 4. Recommendations on the interval between last dose of direct or non-vitamin-K-dependent oral anticoagulant and intervention/procedure depending on bleeding risk and renal function* [30]

Apixaban/edoxaban/rivaroxaban Dabigatran Renal function Low High Low High (CrCl mL/min) Bleeding bleeding bleeding Bleeding risk risk risk risk ≥ 80 ≥ 24 h ≥ 48 h ≥ 24 h ≥ 48 (–72*) h 50 - 79 ≥ 24 h ≥ 48 (–72*) h ≥ 36 h ≥ 72 (–96*) h 30 - 49 ≥ 24 h ≥ 48 (≥ 72–96*) h ≥ 48 h ≥ 96 h 15 - 29 ≥ 36 h ≥ 48 (≥ 96*) h No indication for DOACs! <15 No indication for DOACs!

Pain control in the postoperative period procedures. In the existing literature, there are not yet a Concomitant treatment of NOA with NSAIDs may sufficient number of studies defining a clear protocol for increase the risk of bleeding. dental management in concomitant use of these drugs. Paracetamol or opioid medications are safer alter- In a review by Muñoz-Corcuera et al. the authors natives for pain control. [18] Dabigatran acts as a sub- suggest that each case should be treated individually, tak- strate of P- glycoprotein 1 (P-gp 1), a significant protein ing into consideration the risk of embolism, bleeding and of the cell membrane that pumps many foreign substances renal function [26]. Depending on the risk of bleeding, out of cells. The concomitant assumption of strong P-gp Curto et al. classified dental treatments in two groups: 1 inducers like dexamethasone, rifampicin or carba- procedures with low and procedures with medium/high mazepine, has been reported to significantly decrease the risks of bleeding [37]. Low-risk procedures include sim- plasma concentration and peak serum concentration of ple tooth extractions, oral surgery lasting less than 45 dabigatran. Hence, these drugs are not recommended in minutes and muco-gingival surgical procedures. The ex- patients taking DTIs. The administration of Pgp 1 inhibi- traction of more than three teeth at once and oral surgery tors like ketoconazole (and possibly itraconazole, eryth- lasting more than 45 minutes were considered medium/ romycin, clarithromycin) should be avoided [34]. high risk procedures. In this group, the instructions to stop DOACs should be consulted with the specialist phy- DISCUSSION sician. The authors suggest that for low risk procedures Millions of people worldwide are taking haemos- discontinuation of dabigatran is not necessary, and tasis altering medications, and the need of teeth extrac- apixaban can be administered at a usual dose on the day, tion requires a special approach. Routine practice in the after the procedure [37]. past was the discontinuation of the therapy prior to den- tal extraction. Nowadays, discontinuation of oral anti- CONCLUSION platelet and anticoagulant drugs is not recommended be- Currently, available evidence suggests that most cause the risk of severe thromboembolic complications dental interventions can be safely performed without the outweighs the risk of bleeding. With the introduction of interruption of the antithrombotic therapy. However, fur- the new P2Y12 inhibitors (prasugrel, ticagrelor, cangrelor) ther studies are needed to establish evidence-based guide- and the direct oral anticoagulants (dabigatran, lines for the periprocedural antithrombotic management rivaroxaban, and apixaban) the dental practitioners are of patients receiving direct oral anticoagulants or novel facing an obscure risk of bleeding during oral surgical antiplatelet agents.

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Please cite this article as: Dinkova AS, Daskalov HI, Delev D. Dental considerations in patients taking new antiplatelet and anticoagulant drugs. J of IMAB. 2020 Apr-Jun;26(2):3144-3154. DOI: https://doi.org/10.5272/jimab.2020262.3144

Received: 08/07/2019; Published online: 20/05/2020

Address for correspondence: Atanaska Spasova Dinkova DMD, PhD Oral surgery department, Faculty of dental medicine, Medical University of Plovdiv, 3, HristoBotevblvd., Plovdiv, Bulgaria E-mail: [email protected] 3154 https://www.journal-imab-bg.org J of IMAB. 2020 Apr-Jun;26(2)