Antiplatelets & Anticoagulation Drugs: Dental Implications
Dr Parmanand Dhanrajani (firstname.lastname@example.org) – BDS, MDS, MSc, MSC, FRACDS, FDSRCS, FFDRCSI Oral Surgeon
Dr Patrick Chung – Consultant anaesthetist MB BS (1st Class Hons), FANZCA
Dr Mark Smith – BDS Manager, Clinical Quality and Safety
Dr Christopher Ho – BDS, Dentist
Many patients with cardiovascular disorder, including coronary heart disease, cerebrovascular disease, atrial fibrillation and venous throm-boembolic disease, take antiplatelet and/or anticoagulant drugs. Over the last five decades warfarin has been the oral anticoagulant of choice and has been considered as mainstay of treatment. However, the frequent requirement for monitoring and multiple drug and food interactions have fuelled the need for development of newer oral anticoagulants. As a direct result of this, a new generation of oral anticoagulants has been developed to treat and prevent thromboembolic disorders, the direct thrombin inhibitors and the factor Xa inhibitors. They require no monitoring; exhibit predictable pharmacokinetics, have limited food and drug interactions, and a rapid onset of action and a short half-life. However, they lack a specific reversal agent. Complementary medicines, including fish oil, garlic, ginger, green tea and glucosamine, have a weak antiplatelet effect, but this is usually not clinically significant. This paper describes the importance and implications of these drugs in the dental management.
Many dental patients are taking “blood thinners” medications to prevent the formation of potentially harmful blood clots for various medical conditions involving the arterial system e.g.: stroke, heart attack and the venous system e.g. deep vein thrombosis (DVT) or pulmonary embolism (PE). However, these medications interfere with the body’s normal clotting mechanism to stop blood flow at a site of tissue injury, which is of concern to dentists for procedures that cause bleeding 1,2,3,4. There are two main processes by which the body normally forms a blood clot. The first involves platelets, which clump, together at wound site to form a platelet plug, which slows the flow of blood through the vessel and forms a matrix. The antiplatelet drugs inhibit clumping. The next phase is coagulation when proteins in the blood interact with each other to fill in the spaces between the platelets, stabilize the clot, and make it more solid until bleeding stops. The anticoagulants drugs inhibit the activation of these proteins 3,4,5,6.
Aspirin inhibits the metabolism of arachadonic acid by irreversibly inhibiting cycloxygenase enzymes, preventing the production of prostaglandins. By inhibiting cycloxygenase 2 (COX2), aspirin prevents the production of prostaglandins responsible for mediating pain and inflammation, therefore, acting as an anti-inflammatory, antipyretic, and an analgesic. However, due to its non-specific mechanism, aspirin also inhibits cyclooxygenase 1 (COX1) which produces physiologically important prostaglandins responsible for platelet aggregation, the protective function of the stomach lining and maintains kidney function (Fig 1).
By inhibiting COX1, aspirin irreversibly blocks the formation of Thromboxane A2 in platelets producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (7-10 days). Low dose aspirin (75mg daily) is indicated in patients at risk of myocardial infarction and ischaemic stroke, especially in those who have undergone cardiac procedures 4,7,8.
Aspirin does not usually cause significant bleeding from extraction wounds. For dentoalveolar surgery (including extractions), there is no indication to temporarily cease prescribed regular aspirin. Patients are warned of having higher chance of bruising if aspirin is not ceased, but the risk is minor compared with the risk of embolism if aspirin is not ceased. Local measures are sufficient to achieve haemostasis, including infiltration of adrenaline containing local anaesthetic, insertion of oxidised cellulose and suturing. Clopidogrel (Plavix) and Prasugrel is antiplatelet medication used in patients following myocardial infarction, ischaemic stroke and ischaemic vascular disease. They are commonly used with aspirin to prevent stent thrombosis for up to one year after coronary stent placement. They are also used in patients who had ischaemic events despite treatment with aspirin or who cannot tolerate aspirin (Chart 1). Acute coronary syndromes are usually treated with dual antiplatelet therapy (aspirin and clopidogrel). Clopidogrel and Prasugrel irreversibly inhibits platelets aggregation and cross linking of platelets by fibrin by activating cytochrome P450 in liver. The half-life is approximately eight hours at an optimal daily dose of 75mg 9,10,11.
Premature discontinuation of dual antiplatelet therapy after placement of coronary stent markedly increases the risk of stent thrombosis, by 15%, which frequently leads to myocardial infarction 14. Do not stop Clopidogrel or prasugrel without expert advice. Current available information suggests that the risk of bleeding in patients undergoing invasive dental procedures (for example extraction) is low, provided that local hemostatic measures (suturing, gelatine sponge, gauze soaked 5% tranexamic acid, tranexamic mouth rinse) are used (Table 1).
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 (VIII, IX, X and prothrombin II) affecting the formation of fibrin clot. These factors are synthesised in the liver in precursor form and activated by carboxylation of specific glutamic residues, which require vitamin K in its reduced form as a cofactor 6,8,12,13.
In the UK it is estimated that at least 1% of the population and 8% of those over 80 are tak-ing it regularly. It was first used in 1955 to treat American President Dwight D Eisenhower for a coronary event.
It is currently used in:
1. Prevention of venous thrombosis and embolism in rheumatic heart disease and atrial fibrillation (AF)
2. Treatment and prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE)
3. Stroke prophylaxis
4. AF and valvular heart disease (International Normalised Ratio) (INR target 2.5-3)
5. Mechanical heart valves (INR target 4)
The maximum anticoagulant effect of warfarin takes 48 to 72 hours to develop, with an estimated duration of action of two to five days and a reported half-life of two and half days. It is important that both the patient and their medical practitioner understand how the patient’s warfarin treatment should be managed in relation to tooth extraction. It is not uncommon for patients to reduce their warfarin dose without consultation or, alternatively, to consult with their medical practitioner who may unnecessarily suggest the traditional course of ceasing anticoagulants for minor surgical procedures. Owing to the risk of potentially fatal thromboembolism, cessation of warfarin therapy prior to dental treatment is not recommended. Instead, an INR should be taken 24 to 48 hours pre-operatively to establish the degree of anticoagulation. In general, it is safe to proceed with an invasive dental procedure (including administration of local anaesthesia, periodontal or endodontic surgery and routine/surgical extractions) if the INR is less than 2.2. If the INR is greater than 2.2 to 4, the dentist should liaise with the treating physician in order to safely reduce warfarin dosage. Local measures are necessary to achieve haemostasis including tranexamic acid mouthwash 15. Due to warfarin’s long half-life, a period of three to five days is required for reduction in the level of anticoagulation, as reflected in a reduce INR 14,15,16. Finally, all dentists should be cognisant of the potential interaction between warfarin and other drugs commonly used in dentistry, including azole antifungals, macrolide antibiotics, and NSAIDs (Table 1).
The rationale for change:
Warfarin has been the established oral anticoagulant for the last 50 years, being effec-tive in the prevention and treatment of venous and arterial thromboembolic disorders. However, the frequent requirement for INR monitoring, multiple drug and food interactions, unpredictable pharmacokinetics, slow onset of action and long half-life has fuelled the need for development of newer oral anticoagulants. As a direct result of this, a new generation of oral anticoagulants has been developed to treat and prevent thromboembolic disorders, direct thrombin inhibitors and the factor Xa inhibitors (Chart 2).
Newer oral anticoagulants (NOACs): Recently, new oral anticoagulants have been approved for use by various drugs approval authorities around the world. One of them is dabigatran etexilate, a thrombin inhibitor and ravaroxiban (Xeralto), a factor Xa inhibitor. Dabigatran etixilate (Pradaxa) is the first of a new generation of oral anticoagulants, which are now available on the anticoagulant market. Dental surgeons in the primary care setting and those in the secondary hospital care setting will very soon be faced with decisions on the safety of surgical procedures on patients in whom these new anticoagulants are present. These are licensed for short-term primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip or knee replacement surgery, while dabigatran is also licensed for prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation, plus one or more additional factors. Dabigatran is contra-indicated in patients with a prosthetic valve requiring anticoagulant treatment. As they are pharmacologically distinct from warfarin, they have different side-effect profile and have raised concern in regards to bleeding complications. Unlike warfarin, dabigatran and rivaroxiban are relatively small molecules that work as anticoagulants by targeting specific single steps of coagulation cascade 3,5,7,16,17. In addition, they are reported to have fewer drug interactions, no significant food interactions, and provide predictable anticoagula-tion at a specific dose, without the need of regular monitoring and alteration in dose. It is therefore in-cumbent on all of us to become familiar with these drugs, their indications and method of action, and in particular the management of those patients re-quiring invasive dental procedures, so that these patients are managed in safe manner (Table 1).
The Food and Drug Administration (FDA), USA, first approved Dabigatran etexilate in 2010, to reduce the stroke and systemic embolization risk in patients with non-valvular atrial fibrillation, it is now also used, in EU, and Canada, for thromboembolic prophylaxis in patients who have recently undergone a total hip or knee replacement. Recent studies have shown that dabigatran, given at a fixed dose does not require monitoring and is as effective as warfarin in preventing embolic events in patients with atrial fibrillation. However, significant concerns regarding the lack of a reversal agent, and difficulty in precisely monitoring its anticoagulant effect remain 6,9,11,18,20.
It is a specific, reversible, direct thrombin inhibitor that, unlike warfarin, inhibits both free and fibrin bound thrombin, so that fibrinogen cannot be converted to fibrin. Dabigatran etexilate is a pro-drug which, following oral administration is converted to its active form, dabigatran. When administered orally, the bioavailability is approximately 3-7%. It is rapidly absorbed and is metabolised by the liver. It has a rapid onset of action with the peak plasma concentration of 0.5-4 hours. When administered twice daily, a steady state plasma concentration is reached within two or three days. The half-life elimination is 12-14 hours in healthy patients, 14-17 hours in elderly, and up to 27 hours in patients with severe renal impairment. Unlike warfarin, routine monitoring of the anticoagulants effect of dabi-gatran is not required. The thrombin clotting time (TT), and eca-rin clotting time (ECT) are reported to be the most sensitive tests for quantifying the anticoagulant effects of dibagatran. Currently, there is no reversal agent for dibagatran. However, ow-ing to its short half-life, discontinuation of the drug may be suffi-cient to resolve minor haemorrhage, with the exception of patients with renal impairment. It appears that dabigatran has few clinically significant drug and food interactions. Ketocanazole, verapam-ril and amiodarone may increase its anticoagulant effect, whilst rifampicin may decrease its effect. There are no clinical trials supporting specific measures in the event of haemorrhage in dental patients taking dabigatran. The most current information suggests that patients taking dabigatran can undergo invasive dental procedures without alteration of dose. As is the case with all other patients, irrespective of coagulation status, local haemostatic measures (absorbable gelatine or oxidized cellulose pellets, sutures, gauze soaked in 5% tranexamic acid and/or mouth wash) should be employed in events of bleeding. Owing to the risk of thromboembolism, dabigatran should never be discontinued without prior consultation with the treating physician. Dabigatran should only be recommended post-operatively once a stable clot has formed, thereby minimising the risk of bleeding. If discontinuation of anticoagulation is not safe, and extensive oral surgery procedure is required, peri-operative bridging anticoagulation with an appropriate dose of subcutaneous LMWH or unfractionated heparin is recommended (Table 2).
Rivaroxaban is an orally administered, selective, reversible, direct inhibitor of activated factor X (factor Xa), and is currently indicated for prophylaxis of venous thromboembolism (VTE) in adults after hip or knee replacement surgery.
Rivaroxaban is an oxazolidinone derivative that inhibits factor Xa and interrupts both the extrinsic and intrinsic coagulation pathways, thereby inhibiting thrombin formation. It is rapidly absorbed and has a rapid onset of action of two and a half to four hours. The half-life is five to nine hours in healthy adults, and 11-13 in the elderly (due to decreased total and renal clearance). Oral bioavailability is 80- 100% and the duration of effect is 10-18 hours. It is excreted in the urine (66%) and faeces (28%). Like dabigatran, routine monitoring of rivaroxaban is not required. However, in an emergency situation, measurement of the level of anticoagu-lation may be indicated. Anti-factor Xa assay is repotedly the most accurate measurement of the anti-coagulant effect of rivaroxaban. Approximately 1-10% of patients taking rivaroxa-ban experience an adverse reaction in the form of bleeding, nausea etc.
Unlike warfarin, there is no specific agent to reverse the anti-coagulant effect of rivaroxaban. However, owing to its short duration of action, discontinuation of the drug should be sufficient to arrest persistent minor haemorrhage. Severe or life-threatening haemorrhage may require the use of blood product transfusion, recombinant factor VIIa, or prothrombin complex concentrate (PCC). Two-thirds of rivaroxaban is metabolised by cytochrome P450 (CYP) system, especially CYP3A4. Therefore, the concomitant use of rivaroxaban with inhibitors or inducers of CYP3A4 should be avoided which can be a risk for bleeding, including erythromycin, ketoconazole, and amiodarone. Non-steroidal and opioid analgesics should be used with caution in patients taking rivaroxaban 19,21,22.
Similar to dabigatran, there are no clini-cal trials in the literature offering specific recommendations for the management of dental patients taking rivaroxaban. It is not necessary to discontinue rivaroxaban for uncomplicated extractions and other similar invasive procedures in the patients with normal renal function. Local haemostatic measures, as described previously, should be employed when necessary. For patients undergoing elective oral/maxillofacial surgery, where the bleeding risk is significant, rivaroxaben should be discontinued only after consultation with the treating physician, for at least 24 hours before surgery (Table 3).
Oral vitamin K antagonists have, for many years been the main-stay on management for venous thromboembolism and pre-vention. Despite their widespread use, they are not without problem. They require regular monitoring and dose titration. In addition, they have multiple food and drug interactions. De-spite this, the availability of an antidote, especially vitamin K, is somewhat reassuring. Recently, the search for a better alterna-tive to vitamin K antagonists has resulted in the production of newer oral anticoagulants (NAOCs), direct thrombin (factor IIa) inhibitors: dabigatran (Pradaxa), and factor Xa inhibitors, namely rivaroxaban (Xeralto), aixaban (Equilis), edoxaban (Lixiana) have been used as an alternative to warfarin to treat the patients with non-valvular atrial fibrillation, and the prevention of stroke and systemic embolism 23,24.
There advantages, relative to warfarin, include predictable phar-macokinetics, limited food and drug interactions, rapid onset of action and short half-life. They also require no regular monitoring or dose titration. Most current guidelines are largely based on expert opinion and pharmacologic properties of the new oral anticoagulants. Cur-rent available information suggests that the risk of bleeding in patients undergoing invasive dental procedures (for example extraction) is low, provided that local haemostatic measures (suturing, gelatine sponge, gauze soaked 5% tranexamic acid, tranexamic mouth rinse) are used and the patient has normal renal function. Indeed, the risk seems to be analogous to patients taking warfarin and with an INR of between two and three. For patients requiring multiple extractions, or oral/maxillofacial procedures, consideration must be given to discontinuation of dibagatran/rivaroxaban, with the duration determined by renal function and bleeding risk. However, dentists should not discon-tinue oral anti coagulants without prior consultation with the pa-tient’s physician. If discontinuation is not feasible, due to risk of venous thromboembolism, bridging with LMWH or intravenous fractionated heparin is required. (Table 2)
The most common question asked in past few years on antiplate-let and anticoagulant drugs is their influence on perioperative and postoperative bleeding. These drugs are used in modern era in increasing numbers for managing thrombotic risk in our ageing populations. Frequently patients are just not taking one-blood thinner but on multiple ones so called dual or triple therapy and gets more complicated when they are on additional complimentary medications. These additional drugs may be as harmless looking as turmeric, garlic, or may be as significant as antidepressants, corticosteroids and non-steroidal anti-inflammatory drugs 23,24.
The guidelines 16,17,18,19,20 so far published in literature suggests how to manage patient taking individual antiplatelet /anticoagulant drug but not elaborates how to manage patients on multiple drugs regimen with bleeding risk.
Current guidelines suggest assessing each patient’s individual bleeding risk by looking at following sources:
• Patient related factors such as age, underlying medical conditions, oral health, smoking etc.
• Drug related factors such as antiplatelet/anticoagulant drugs, single or dual or multiple
therapy, herbal medications, complementary drugs or antidepressants or anti-inflammatory drugs
and their interactions.
• Surgical procedures to be carried out such as simple forceps extraction, surgical removal of multiple teeth including pathology and degree of tissue trauma etc.
The patients with multiple drug therapy and other medical conditions such as impaired renal functions etc. are best to be managed by consulting patients treating physicians or cardiologist. One should never interfere with patient’s drug schedule without informing or getting permission from the treating doctor (Table 3). This is the flow chart of the protocol used to manage patients taking blood thinner/anticoagulants visiting our department for the treatment (Flow chart).
As the number of patients taking newer oral anticoagulants such as dibagatran/rivaroxaban increases, it is inevitable that dental community will encounter them in near future. It is therefore incumbent on all of us to become familiar with these drugs, their indications and mechanism of action, and in particular, the man-agement of those patients requiring invasive dental procedures.
As our experience with these medicines increases, so will our understanding of appropriate management measures. Currently, no specific protocols are available and further observational studies and randomised controlled trials are required to properly define management guidelines.
This paper is dedicated in the memory of Professor Mark Jolly, Department of Oral Surgery and Oral Medicine, University of Sydney, Australia.
1. Firriolo FJ, Hupp WS Beyond warfarin: the new generation of oral anticoagulants and their implications for the management of dental patients. Oral Surg Oral Med Oral Pathol Oral Radiol 2012; 113(4): 431-441.
2. Rybak I, Ehle M, Buckley L, Fanikos J. Efficacy and safety of novel anticoagulants compared with established agents. Ther Adv Haematol. 2011; 2(3): 175-195.
3. Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New Oral Anticoagulants: their advantages and disadvantages compated with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Therapeutic and Clinical Risk Management 2015; 11: 967-977.
4. Wang C-Z, Moss J, Yuan C-S. Commonly used dietary supplements on coagulation function during surgery. Medicines (Basel) 2015; 2(3): 157–185.
5. Brieger D. Anticoagulation: A GP primer on new anticoagulants. Australian Family Physician 2015; 43(5): 253-259.
6. Patel JP, Woolcombe SA, Patel RK, Obisesan O, Roberts LN, Bryant C, and Arya R. Managing direct oral anticoagulants in patients undergoing dentoalveolar surgery. British Dental Journal 2017; 222: 245-249.
7. Nathwani S, Wanis C. Novel oral anticoagulants and exodontia: the evidence. British Dental Journal 2017; 222: 623-628.
8. Nathwani S, Martin K. Exodontia in dual platelet therapy: the evidence. British Dental Journal 2016; 220: 235-238.
9. Milner J, Hoffhines A. The discovery of aspirins antithrombotic effects. Tex Heart Inst J 2007; 34: 179-186.
10. Undas A, Brummel-Ziedines K, Mann K. Anti-thrombotic properties of aspirin and resistance to aspirin: beyond strictly platelet actions. Blood 2007; 109: 2285-2292.
11. Vane J, Botting R. The mechanism of action of aspirin. Thromb Res 2003; 110: 255-258.
12. Payne D,Hayes P,Jones C, Belham P, Naylor A, Goodall. A Combined therapy with clopidogrel and aspirin significantly increases the bleeding time through a synergistic antiplatelet action. J Vasc Surg 2002; 35: 1204-1209.
13. Robless P, Mikhailidis D, Stansby G. Systematic review of antiplatelet therapy for the prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease. Br J Surg 2001; 88: 787-800.
14. Scottish Dental Clinical Effectiveness Programme. Management of dental Patients Taking Anticoagulants or Antiplatelet Drugs. 2015. Available online on http://www.Sdcep.org.uk/wp-content/uploads/2015/09/SDCEP-Anticoagulants-Quick-Reference-Guide.pdf (accessed September 2017).
15. Grines CL, Bonow RO, Casey DE, Gardner TJ, Lockhart PB, Moliterno DJ et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from American College of Physicians. Circulation 2007; 115(6): 813-818.
16. Carter G, Goss AN, Lloyd J, Tocchetti R. Current concepts of the management of dental extractions for patients taking warfarin. Aust Dent J 2003;48(2): 89-96; quiz 138.
17. Expert writing group. Therapeutic Guidelines – Oral and Dental. 2nded. Therapeutic Guidelines Ltd. Melbourne. 2012
18. Dubois V, Dincq S, Douxfils J et al. Perioperative management of patients on direct oral anticoagulants. Thromb J 2017:15; 14. https://thrombosisjournal. biomedcentral.com/articles/10.1186/s12959-017-0137-1
19. Keeling D, Campbell Tait R, Watson H. Peri-operative management of anticoagulation and antiplatelet therapy. Br J Haematology 2016; 175: 602-613.
20. Spyropoulos AC, Al-Badri A, Sherwood MW, Douketis JD. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery. J Thromb Haemost 2016; 14: 875-85.
21. National Blood Authority. Preoperative bleeding risk assessment and intervention resource: quick reference guide. https://www.blood.gov.au/system/files /documents/preop-bleed-risk-assessment-resource.pdf. Accessed 08/09/17
22. Heidbuchel H, Verhamme P, Alings M et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015 Oct;17(10):1467-507
23. Australian Medicines Handbook. Accessed via https://amhonline.amh.net.au/ Australian Medicines Handbook Pty Ltd. Last updated July 2017.
24. The Perioperative Use of Natural Medicines. Natural Medicines database. TRC 2017 Therapeutic Research Center. Last updated Sep 2017.