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1 VOLUME 64. N.1. FEBBRAIO 2015

2 REVIEWS MINERVA STOMATOL 2015;64:21-46 Anticoagulant therapy in patients undergoing dental interventions: a critical review of the literature and current perspectives G. ISOLA 1, 2, G. MATARESE 1, G. CORDASCO 1, F. ROTONDO 3, A. CRUPI 1, L. RAMAGLIA 2 Patients treated with oral anticoagulant therapy (OAT) represent an issue to the dentist, as an increasing number of people are using anticoagulant drugs for cardiovascular disease. The choice of an eventual suspension or continuation of anticoagulant therapy is important when considering an efficient management of the patient. Patients in anticoagulant therapy and requiring dental procedures sometimes represent therapeutic concerns especially concerning the suspension of the anticoagulant treatment. At the moment there is no consensus among international experts of a possible discontinuation of therapy before invasive dental procedures. In this paper, the authors try to focus on this topic through a critical review of the literature. Most of the studies suggest the continuation of the anticoagulant treatment with heparin before invasive oral surgical interventions. Based on the data of the literature, two rules must be adopted in clinical practice: 1) maintenance of anticoagulation related to the international normalized ratio (INR); 2) local application of antifibrinolytic agents to ensure a proper hemostatic process. Given the widespread use of anticoagulant drugs in cardiovascular disease, dentists must often face the problem of the therapy and, since there is no consensus on the management of these patients, the authors propose, after a thorough critical review of the literature, the implementation of a multiphase protocol of surgical approach to be implemented with safety in daily clinical practice. Key words: Anticoagulants - Heparin - Warfarin - Surgery, oral. Corresponding author: G. Isola, Department of Specialist Medical-Surgical Experimental Sciences and Odontostomatology, University of Messina, AOU Policlinico G. Martino, Via Consolare Valeria 1, Messina, Italy. 1Department of Specialist Medical Surgical Experimental Sciences and Odontostomatology University of Messina, Messina, Italy 2Department of Neurosciences, Reproductive and Odontostomatological Sciences School of Medicine University Federico II, Naples, Italy 3Division of Hematology Department of General Surgery and Oncology University of Messina, Messina, Italy The World Health Organization has published alarming data regarding the death rate due to coronary and cerebrovascular diseases. In fact, every year 17 million people in the world die because of cardio-vascular diseases, especially heart attack and stroke. 1 Smoking, physical inactivity and an unhealthy diet are some well-known incorrect habits and important well defined risk factors for these diseases. In industrialized countries, due to an improvement of life quality and the introduction of specific drugs, the mortality rate has declined in recent years. 2, 3 Dental infections, osteomyelitis, periodontal diseases 4 and complications deriving from dental surgical operations, such as oral surgery, 5, 6 could all give rise to extended bacterial infections in the organism, with a consequent production of bacterial lipopolysaccharide 7 and hence a consequent reaction of the immune system. 8, 9 The pathological involvement of the Vol No. 1 MINERVA STOMATOLOGICA 21

3 ISOLA Dental management in patients with anticoagulant therapy inflammatory response of the other organs and/or systems in vasculopathic patients is undoubtedly a critical aggravating factor of the clinical condition. 10 Oral health, therefore, should also be regarded as a relevant condition, which indirectly contributes to non-deterioration of risk in patients with cardio-cerebrovascular diseases. Operation stress or drugs can affect the cardiovascular system activating the sympathetic nervous system with a consequent release of endogenous catecholamine, chromotrope and dromotrope positive cardiac effects, rise in arterial pressure and in O 2 consumption; all these effects can cause metabolic dysfunction or ischemic events, which may potentially induce some damage in the myocardium and/or the brain. 11 A strict collaboration between the dentist and the general practitioner may result in an optimized approach in both evaluating the entire clinical situation correctly and conducting therapeutic strategies with the greatest advantages and the slightest risks for patients with cardio-cerebrovascular diseases. Anticoagulant drugs Anticoagulants are a group of drugs used against thrombotic disorders in patients at risk. In particular, they are used to prevent deep vein thrombosis, peripheral artery embolism, stroke, myocardial infarction and others. These drugs are: oral anticoagulants, heparin, low molecular weight heparin. Oral anticoagulants These drugs act by antagonizing the effects of vitamin K. Vitamin K is essential in the carboxylation process of coagulative factors and to bind Ca 2+, which is very important for their formation. 12 In the absence of vitamin K, a coagulative cascade is not efficient (vitamin K is, in fact, used as a hemostatic agent). Oral anticoagulants antagonize the regeneration of vitamin K thus inducing a condition of functional deficiency 13 (Figure 1). Consequently, a failure of the biological activity of these coagulative vitamin K dependent factors occurs with a Figure 1. Diagram of a coagulative cascade. 22 MINERVA STOMATOLOGICA February 2015

4 Dental management in patients with anticoagulant therapy ISOLA Dabigatran Dabigatran was approved by the US FDA in October 2010 for the treatment of nonreduction of the carboxylation process up to 40% and a concomitant reduction of the single coagulative factors by approximately 50%. 8, 14 Two drugs are main available on the market as Coumadin (warfarin sodium, Bristol-Myers Squibb Srl, Rome, Italy) and Sintrom (acenocumarolo, Novartis Farma, Origgio, Varese, Italy). A 5-mg tablet of Coumadin has the same anticoagulant effect of a 2.5 mg tablet of Sintrom. Both drugs are very effective and are largely used when thrombotic risk is particularly high. Heparin Heparin is a biological substance, usually derived from animals, composed of a mixture of linear and complex polysaccharides. Heparin is found in the cells of tissues containing mast cells and is not found in plasma under normal conditions. Dermatan- and heparan-sulphate, both heparin-derived compounds, are constituents of most cells and MEC matrix; the molecules of heparan sulphate in the internal surface of the vassal endothelium work by interacting with antithrombin (heparin is a cofactor), ensuring a natural antithrombotic mechanism. 15 Thus, heparin works by activating antithrombin III, which blocks the IIa, Xa and thrombin factors from clotting blood. To ensure an adequate effect and hence to block thrombin and Xa factor, concentrations of at least U/mL should be achieved. Heparin can be used in vivo by injection (or in vitro, to prevent blood or plasma clotting) with a concentration at least 5000 U/L to obtain to 25,000 U/L. Low molecular weight heparins Low molecular weight heparins are derived from the same heparin, but they are different for both pharmacokinetic and pharmacodynamic properties. Given their low molecular weight, they do not exert their anticoagulant effect through an inhibition of thrombin but through an inhibition of the by factor Xa antithrombin. 16 These compounds are available on the market as Clexane (enoxaparin, Sanofi-Aventis, Origgio, Varese, Italy), Fluxum, (Parnaparin, Alfa Wassermann, Alanno, Pescara, Italy), Fraxiparin (Nadroparin, GlaxoSmithKline, Verona, Italy) and others. New oral anticoagulants Some interest in the development of new anticoagulation medications is growing because of the limitations of injectable-administered heparin and the interaction and monitoring concerns associated with vitamin K antagonists such as warfarin. Because of the related risk of hemorrhage and the subsequent problems in the effective use of warfarin therapy, antithrombotic anticoagulant therapy with warfarin is not used enough in medical and dental fields despite clear documented guideline indications. Direct thrombin inhibitors constitute one class of drugs that has been increasing in popularity for the prevention and treatment of different diseases such as venous thrombo-embolism and for the prevention of strokes in atrial fibrillation. These classes of medications represent a new field for research, with multiple studies investigating both their efficacy and their safety for the treatment of these conditions. Great attention has been paid to the development of new drugs in the last few years: in particular, oral antithrombin (anti- IIa factor) and anti-xa factor drugs as potential replacements for oral vitamin K antagonist anticoagulants. Currently, oral anti-xa and anti-iia agents have been approved by the Food and Drug Administration (FDA) and others are advancing quickly in medical clinical development. 17 Among these drugs are the dabigatran etexilate, an orallyadministered direct thrombin inhibitor and the Xa factor inhibitors: rivaroxaban and apixaban. Vol No. 1 MINERVA STOMATOLOGICA 23

5 ISOLA Dental management in patients with anticoagulant therapy valvular atrial fibrillation, and by August 2011, approximately one million prescription have been made in the USA. 18 Dabigatran has also been demonstrated to be as effective as warfarin in the prevention and treatment of recurrent venous thrombo-embolism and pulmonary embolism. 19 According to its action mechanism dabigatran etexilate binds to the active site on the thrombin molecule (IIa factor) so that it cannot catalyse the reaction of fibrinogen into fibrin. Unlike warfarin, dabigatran etexilate directly inhibits both clot-bound and free thrombin 20 (Figure 2). This drug prolongs the activated partial thromboplastin time (aptt), ecarin clotting time (ECT), and thrombin time (TT) at the usual recommended therapeutic doses, but it has little effect on prothrombin time (PT)/INR at clinically relevant plasma concentrations. 21 This medication has minimal drug/drug interactions and results in effective antithrombotic action within a few hours after ingestion. Dabigatran etexilate is usually administered twice daily with a bioavailability following an oral bioavailability administration of 3-7%, and it has a fairly rapid onset of action, with maximum plasma concentration occurring 2-4 hours after intake 22 and its terminal half-life is hours (14-17 hours in the elderly). Otherwise, with a twicedaily administration of dabigatran etexilate, the plasma concentrations reached a steady state within 2 to 3 days. As shown by report, the main frequently adverse effects associated with dabigatran (>15% of patients) were gastritis-like symptoms, including dyspepsia, abdominal discomfort/ pain. Few hemorrhage events were reported in 8-33% of patients and major bleeding events (i.e., gastrointestinal hemorrhage) in <6% of the patients. 23 As shown by different reports, routine coagulation monitoring is not required for patients being maintained on dabigatran. 19, 24 TT and ECT tests are the most sensitive for quantifying the anticoagulant effects of dabigatran drugs. Van Ryn et al. 21 suggest that during an emergency, aptt and/or TT would usually be the most accessible tests for monitoring the anticoagulant effects of dabigatran, because the ECT test, performed on snake venom, is not commonly available. However, on the other hand, another study 25 demonstrated that for monitoring the anticoagulant effect of direct thrombine inhibitor (including dabigatran), TT is also too sensitive, and the laboratory test result was prolonged to >200 seconds; therefore, the authors recommend the use Figure 2. Mechanism of dabigatran action. 24 MINERVA STOMATOLOGICA February 2015

6 Dental management in patients with anticoagulant therapy ISOLA Dabigatran and rivaroxaban Dabigatran acts as a substrate of the transporter P-gp (glycoprotein P); thereof aptt, as well prothrombinase-induced clotting time assay when accessible. Rivaroxaban and apixaban Rivaroxaban has been tested in a large, double-blind, multicenter clinical randomized clinical trials (RCT) on patients with atrial fibrillation for the management of stroke prophylaxis. The rivaroxaban oncedaily oral-direct Xa factor inhibition was compared to vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. 26 This report has shown that the incidence of cerebral hemorrhage was statistically reduced in patients that were given rivaroxaban compared to the control group (warfarin). Rivaroxaban has been approved by the FDA for the prevention of deep venous thrombosis in patients undergoing knee or hip replacement. Rivaroxaban is usually administered once daily and shows a rapid onset time (3-4 hours). Once at a steady state, the terminal half-life is 6-9 hours (up to 13 hours in elderly patients). 27 Oral bioavailability is %, and plasma protein binding is 92-95%. 19 Approximately 51% of rivaroxaban usually undergoes metabolic degradation process. 28 The most frequent adverse effects associated with the use of rivaroxaban are minor bleeding events in 5% of patients (including postsurgical site bleeding events requiring sometimes transfusion) and nausea in 1% of patients. 29 Moreover, it was demonstrated that the use of blood derived, component transfusion, or administration of prothrombin complex concentrate or recombinant activated factor VII (rfviia) may be valued in cases of serious life-threatening bleeding due to rivaroxaban 30 because it was reported that this drug slightly prolongs PT and aptt values. 25 In any case, literature suggests that no routine laboratory coagulation test should be required for patients receiving rivaroxaban, except in particular circumstances, such as renal failure, obesity, or severely underweight patients. 20, 31 The apixaban drug is another Xa factor inhibitor that has been evaluated in exten- sive clinical studies for the prevention and management of deep venous thrombosis and was developed for stroke prevention in patients with atrial fibrillation. Some studies, which compared apixaban to aspirin therapy in subjects with atrial fibrillation, showed that this Xa antagonist factor was more effective than aspirin in preventing stroke. 32 Moreover, in a trial on patients with atrial fibrillation that presented thrombo-embolic events, this agent was found to be more effective and safer than warfarin for the prevention of strokes. 33 Apixaban is being studied by the FDA for the prevention of deep venous thrombosis following surgery. Other Xa factor inhibitors, such as edoxaban, are also in development for similar use. Warfarin Pharmacological interaction The association of other drugs with oral anticoagulants may interest OTA action. In case of association of anti-inflammatory drugs in patients undergoing therapy with warfarin, in the absence of clearly inflammatory pathology, the use of pain medications such as acetaminophen and noramidopyrine that do not interfere with oral anticoagulants is preferable. Given the gastrolesive effect of anti-inflammatory drugs, it is appropriate to use low gastrolesive drugs that do not interfere with oral anticoagulants, and the ibuprofen could be avoid, if necessary. The interaction (enhancement or inhibition) between oral anticoagulants and certain drugs in current use has been shown with antibiotics drugs (ciprofloxacin, isoniazid, metronidazole), anti-inflammatory drugs (asprine and piroxicam) and cardiovascular drugs (amiodarone, propanole, propafenone) 34, 35 (Table I). Vol No. 1 MINERVA STOMATOLOGICA 25

7 ISOLA Dental management in patients with anticoagulant therapy Table I. The main pharmacological interaction of oral anticoagulants. Drugs decreasing OAT activity a) Stimulus of synthesis of dependent vitamin K factors Vitamin K Estrogens b) Enzymatic induction Barbiturates Hidrous cloral Rifampicina Fenitoina and other barbiturates c) Reduced absorption Griseofulvina Colestiramina, adsorbents, antiacids Generally, the usual parameters for the evaluation of physiological time of bleeding are: APTT, PT, INR (Table II). Activated partial prothombin time (APTT) is a perfore, it appears that the assumption of dabigatran concomitantly with P-gp inducers is usually not recommended, while its use concomitantly with P-gp inhibitors should be avoided if possible. 36 Strong P-gp inducers (rifampin, but also dexamethasone and carbamazepine) have been reported by some studies to significantly decrease the plasma concentrationversus-time curve and peak serum concentration of dabigatran, and its concomitant use is not recommended. 37 Concomitant therapy with clarithromycin (a moderate P-gp inhibitor) resulted in an insignificant effect on dabigatran concentrations; 38 therefore, it seems to be to suggest that concomitant use of dabigatran and P-gp inhibitors, such as ketoconazole (and possibly itraconazole, erythromycin, and precisely clarithromycin) should be avoided if possible. The simultaneous use of dabigatran and non-steroidal anti-inflammatory agents FANS (specifically diclofenac) does not appear to result in a clinically significant interaction. 39 Most of the rivaroxaban is metabolized by CYP (3A4, 3A5, 2J2 etc.) before purging by the human body, and rivaroxaban is also a substrate of P-gp transporters. Therefore, it has been suggested to not prescribe rivaroxaban with other drugs that are strong inhibitors of both CYP3A4 and P-gp. 40 Drugs increasing OAT activity a) Anticoagulants biotrasformation inhibition (coumarinics) Clofiber Chloramphenicole Cimetidina Amiodarone Propafenone b) Displacement from proteinic plasmatic bindings Fenilbutazone Nonsteroidal anti-infiammatory drugs Sulfinpirazone c) Reduction of vitamin K bioavailability Tetracyclines d) Raised catabolism of coagulation factors Thyroid hormones Anabolic steroid e) Inhibition synthesis of dependent vitamin K factors Salicylates Quinidine Amiodarone Coadministration of rivaroxaban with ketoconazole (400 mg, once daily) led to significant increases in pharmacodynamic effects that may lead to an increased risk of bleeding. 39 The same effects possess systemic azoleantimycotics, such as itraconazole, voriconazole, and posaconazole (as well as human immunodeficiency virus protease inhibitors) this could be avoided in patients being treated with rivaroxaban. Fluconazole has less effect on rivaroxaban exposure and can be coadministered with attention. Clarithromycin is a strong CYP3A4 and moderate P-gp inhibitor, and has been suggested that it should be used with the maximum dose of 500 mg twice-daily, while the erythromycin maximum dose of 500 mg is three times per day. 42 With regard to anti-inflammatory drugs, Kubitza 42 concluded that there is no clinically relevant interaction between rivaroxaban and naproxen (500 mg/d). Clinical-diagnostic evaluation 26 MINERVA STOMATOLOGICA February 2015

8 Dental management in patients with anticoagulant therapy ISOLA Table II. Hematological laboratory tests. Test Normal values Increase Decrease Bleeding time 1-6 minute Von Willembrand disease aptt seconds Haemophilia A and B, epatopathies, vitamina K deficiency, Anticoagulants PT/INR s/ Epatopathies, vitamina K deficiency, anticoagulants, CID* Factor V % Epatopathies, CID* Factor VII % Epatopathies, vitamin K deficiency, CID* Factor VIII % Epatopathies Hemophilia A, Von Willembrand disease, CID* Factor IX % Hemophilia B *Disseminated intravascular coagulation. A careful evaluation of the compensation level that a patient has toward a given disease is required before carrying out a particular treatment on patients with haemoformance indicator measuring efficacy of the intrinsic coagulation pathway. In order to activate the intrinsic pathway, phospholipids (an activator), and calcium (CaCl 2 ) are mixed in plasma to delay clot formation (normal values: seconds). APTT is also used to monitor treatment effects with heparin. It usually increases in coagulative cascade disorders and because of clot factor deficiency. The prothombin time or quick time (PT) is a blood test that measures how long blood takes to clot after adding thromboplastin and calcium to the plasma citrate. It is an indicator of whether or not a given patient is under oral anticoagulant treatment. The reference range for PT is usually seconds (depending on the laboratory methods) corresponding to a prothombin activity of 100%. The more prolonged the PT is, the less coagulative is the plasma. Values above those considered as normal can be due to congenital defects, liver diseases and by anemias. Normal values range from 70% to 120%; lower values can be caused by vitamin K variations, drugs (i.e., corticosteroids) and by thrombosis. International Normalised Index (INR) is an index related to PT. It was introduced in 1987 to make the interpretation of performance concerning anticoagulant blood level univocal. Because of differences between batch sand manufactures of tissue factor, the INR was devised to standardize results. Each manufacturer gives an International Sensitivity Index (ISI) for any tissue factor they produce. The ISI value indicates how a particular batch of tissue factor compares to Table III. Cardiovascular disease requiring oral anticoagulant therapy. an internationally standardised sample. The ISI ranges usually between 0.9 and 1.2. The INR is the ratio of a patient s prothombin time to a normal control sample raised to the power of the ISI value for the control sample used (INR= PT patient / PT average of controls ). Conditions associated with a particularly elevated INR are: anticoagulant intake, hepatic insufficiency, vitamin K deficiency and uncorrected therapy with a high heparin dosage. In these conditions, INR values of 2-4 can be observed and are indicative of an excessive clot condition 43 (Table III). An additional useful parameter for evaluating the cardiovascular risk is fibrinogen, which at supra-physiological concentrations is a relevant indicator of increased risk. Dental implications Range INR* Prophylaxis/treatment of venous thrombosis 2-3 Treatment of pulmonary embolism 2-3 Prevention of systemic embolism 2-3 Recurrent systemic embolism 2-3 Acute myocardial infarction Valvular heart disease 2-3 Valvular replacement with tissue 2-3 Atrial fibrillation 2-3 Mechanical prosthetic heart valves (high risk) *INR: International Normalized Ratio. Vol No. 1 MINERVA STOMATOLOGICA 27

9 ISOLA Dental management in patients with anticoagulant therapy Table IV. Management of oral anticoagulant therapy concerning surgery procedures related to the risk of thromboembolism of the patient. Before surgery Patient with relatively low risk Patient with relatively high risk Keep oral anticoagulant therapy Keep oral anticoagulant therapy If the day before surgery the INR value is over 2, give 2-3 day before surgery interrupt oral anticoagulant patient 1.5 mg of vitamin K by intravenous injection therapy and replace it with low molecular weight heparin by subcutaneous injection* Intraoperatory precautions If value of INR is a little more than 1.5 it is possible to perform the operation otherwise postpone it Carry out a low trauma surgical technique Use adequate hemostatic protection such as tranexamic acid, fibrin sponges Stitch the wound effectively so that clot can be protected After surgery Patient with relatively low risk Patient with relatively high risk Verify if clot formation has occurred** Verify if clot formation has occurred** Prescribe antibiotics if there is an infection of the clot Prescribe antibiotics if there is an infection of the clot If the patient has interrupted OAT therapy initially take the anticoagulant with heparin for at least 48 hours until the patient s INR value have stabilised * The substitute therapy has to be started the sooner the INR value. ** The use a gauze split can be useful to make extra-alveolar compression easier. dynamic dysfunctions. The compensation level is also related to the kind of surgical operation that a patient will undergo (Table IV). The evaluation of the risk firstly begins with a careful preoperation anamnesis, aimed at identifying, for example, the intake of drugs able to alter arterial pressure. Particular attention has to be paid also on possible previous cardiovascular illnesses which can easily recur (as often happens for patients suffering from ischemic heart disease), especially in patients with oncological diseases. 44 Typical symptoms of a severe heart disease can be easily observed: dyspnea, with cyanotic signs and paroxysmal episodes of heart palpitation. An evaluation of pressure values is also highly recommended. In fact, if abnormal high values are found, the use of vasoconstrictors contained in the anesthetic has to be avoided. An excessive use of vasoconstrictors may cause, even if rarely, ischemic or anginoid crisis owing to the increase of induced pressure values. The management of patients undergoing surgery under local anesthesia requires patients being kept calm and that scheduled appointments should last no more than minutes. If a patient suffers from hypertension, the prescription of steroids or antidepressants has to be avoided as these drugs can trigger hypertensive crisis. Patients at risk of heart ischemia attacks need a close collaboration between the dentist and the general practitioner or, even, a cardiologist and emergency drugs always have to be immediately available. The main contraindication of cardiovascular diseases is, for example, the use of general anesthesia. In hypertensive patients anesthetic drugs such as halothane can cause a sudden pressure decline provoked by the augmentation of the effect of hypothensive drugs taken by patients. In these cases, admission to hospital is advisable especially for complex dental operations, 45 for which a correct and careful anesthesiological management is needed. Warfarin Operation surgery precautions As analysed above, dentists are frequently called to face the important problem of deciding for the discontinuation of the oral anticoagulant therapy in view of a dental operation. No unanimous consensus exists in international literature and conflicting indications can be also found. In a recent 28 MINERVA STOMATOLOGICA February 2015

10 Dental management in patients with anticoagulant therapy ISOLA work, Bulik 46 is in favor of a discontinuation of anticoagulant therapy, but only if details of the therapy are known and a careful evaluation of INR has been made before surgery. Jimenez et al. 47 have studied the effect of an oral anticoagulant treatment in a group of patients scheduled for an oral operation surgery or dental extraction. Based on their experience, the crucial point to avoid bleeding problems is to keep an optimal dosage of the oral anticoagulant drug stable. When anticoagulants have to be discontinued, they can be replaced by low weight heparin and antifibrinolitic agents can be used for hemostasis control. The use of Coumadin instead of heparin for dental surgery has been evaluated by a study by Mutzbauer 48 who found that the risk of hemorrhagic problems during the period following dental surgery is by far inferior to the possibility of thrombosis or embolism caused by the interruption of anticoagulants without adequate replacement with heparin. In another study, through analysis of patient data deriving from INR, Ward and Smith 49 have evaluated the use of Coumadin use in oral surgery. In those patients in whom oral anticoagulant therapy was interrupted with a preventive aim, the risk of thrombo-embolism was considerably increased. Based on the experience of Jacobson et al., 50 it can be deduced that the main goal of the pre-operation stage is essentially to reduce the INR target to acceptable values of at least of 2/1.9 in patients stabilized on oral anticoagulant therapy. In accordance with the indications of these authors, two types of patients can be identified on the basis of INR values: those with a low risk of bleeding (INR about 2), who can continue therapy, and those with a high risk of bleeding (INR over 2/2.5) for whom the discontinuation of anticoagulant therapy is indicated. The opinion of a cardiologist should be heard to correctly evaluate whether or not an anticoagulant treatment should be replaced by heparin. If the decision to continue the treatment is taken, the authors suggest the assumption of tranexamic acid (Ugurol, Rottapharm SPA, Monza, Italy) two hours before surgery to be continued for three days after the operation. In this way the control of bleeding can be achieved with no interruption of the oral anticoagulant therapy. A number of studies have considered the possibility of discontinuing anticoagulant therapy when drugs able to increase the Coumadin effect, such as glucosamine (Dona, Rottapharm SPA), anti-inflammatory and anti-rheumatic drugs are taken. 51 In certain cases with abnormally high INR values consequent to a combination of the above drugs, a decrease in the Coumadin dosage may result in a change of the INR within the therapeutic range. In the review of Wahl, 52 a population of 950 patients treated with anticoagulant therapy were analysed. Twelve patients (1.3%) were tested for coagulation and 3 of these (0.31%) exhibited INR values requiring the discontinuation of anticoagulant therapy. Among other 526 patients in whom therapy was discontinued, 5 of them had thromboembolism problems causing 4 deaths at the end of the study. Even Kamien 53 shares the same view of Walh. To summarize, most studies suggest continuing anticoagulant therapy to avoid serious thrombo-embolic consequences during dental surgery. On the other hand, the possible occurrences of bleeding, can easily be controlled by dentists with no additional risks. Dabigatran and rivaroxaban The development of a new oral direct thrombin inhibitor has resolved many problems concerning vitamin K antagonists, leading to dabigatran s recent popularity. However, as with any new medication, practitioners must take care with regard to the various types of potential problems. One area of concern with these medications is the treatment of hemorrhage complications. Recently, Griffiths and Scully 54 have highlighted that dabigatran and rivaroxaban are quickly absorbed and have short half-lives compared to warfarin so, in the case of excessive anticoagulant activity, discontinuing the drug is usually sufficient. There is no need for routine coagulation monitoring Vol No. 1 MINERVA STOMATOLOGICA 29

11 ISOLA Dental management in patients with anticoagulant therapy in the same way as warfarin using the INR value. Most dental situations such as the removal of a small number of teeth would be comparable to treating a patient with an INR 4, relying on local measures to obtain hemostasis pressure with sterile pads (moistened with water, normal saline or 5% tranexamic acid solution), absorbable oxidised cellulose sponges, and sutures. A Cochrane review of 14 studies 55 (over 25,000 patients) comparing direct thrombin inhibitors with low-molecular-weight Heparin and vitamin K antagonists demonstrated no statistically significant difference in the risk of bleeding events. Another study 56 showed that on 4500 patients undergoing medical invasive procedures during suspension of TAO (10% of these patients required dental procedures) showed similar results of perioperative bleeding in cases of minor surgery in association with both dosages of dabigatran (110 and 150 mg) and with warfarin. 56 On the contrary, the incidence of major postoperative bleeding was 4.6% with warfarin, 3.8% with dabigatran 110 mg and 5.1% with dabigatran 150 mg. 56 In case of minor bleeding, good results have been obtained in different studies with the administration of vitamin K for mild INR value elevation and with the administration of prothrombin complex concentrates in cases of acute hemorrhage. 57 On the subjects that received heparin, good results have been obtained with protamine sulphate. 58 The tests used to determine anticoagulation levels in patients with dabigatran include activated PTT, thrombin time and carin clotting time; INR is less helpful, as dabigatran has a poor effect on INR levels. Activated PTT provides a qualitative indication of anticoagulation by dabigatran but is not suitable for the precise quantification of effect, especially at high concentrations. 20 At this time, only a few studies have investigated the incidence of bleeding events among patients receiving a direct thrombin inhibitor and requiring dental extractions. For moderate or severe bleeding, treatments include mechanical compression, fluid replacement, hemodynamic support by oral application (if there is a recent ingestion of dabigatran) and hemodialysis. 59 For life-threatening bleeding, treatment includes administration of prothrombin complex concentrates in addition to supportive measures. A proven effective for a proper strategy for dabigatran in an emergency or during severe hemorrhage situations is still lacking. 60 All of the reviewed studies involving dabigatran showed a risk of hemorrhage statistically similar to that of warfarin when INR was between 2 and 3; for patients who are undergoing dental procedures or minor oral surgery procedures, such as simple extractions, it can be assumed that the risk of a major bleeding event, in case of treatment with dabigatran, will be low. 59 For patients who require many surgical extractions or significant oral maxillofacial surgical procedures, caution must be exercised considering the discontinuation of the direct thrombin inhibitor before the procedure, with the timing determined by renal function of the patient. Davis et al. 59 indicated that all patients receiving such a new class of medications and undergoing dental extractions receive local hemostatic measures, including suturing, gelatin sponge, cellulose mesh and oral 4.8% tranexamic acid rinse for 2 to 5 days after surgery. For patients who require extensive oral surgery in whom it is safe to stop anticoagulant medication, renal function must be used to determine the appropriate duration of discontinuation. 20 The suspension of dabigatran was also suggested in cases of a standard risk of bleeding 24 hours before the procedure for patients with creatinine clearance above 50 mg/ml, 2 days beforehand for those with creatinine clearance between 30 and 50 mg/ml and 2 to 5 days beforehand for those with creatinine clearance less than 30 mg/ml. 20, 59 For procedures with a high risk of bleeding, discontinuation should occur 2 to 4 days, before the procedure for patients with creatinine clearance above 50 mg/ml and more than 5 days beforehand for those with creatinine clearance less than 30 mg/ ml. 20, MINERVA STOMATOLOGICA February 2015

12 Dental management in patients with anticoagulant therapy ISOLA It is important to remember the mechanism of action and potential interaction of dabigatran with other drugs, especially with analgesics. Operation planning A clinical evaluation and careful operation planning are the essential conditions to obtain a high clinical surgery standard 61 (Table IV, Figure 3). Preoperation medical examination is needed to collect anamnestic details and an informed consent, and to evaluate patients at thrombo-embolic risk. The following aspects should be taken into consideration: 1. patients general conditions; 2. cardiovascular status; 3. details on the surgery which patients will undergo. Many of the procedures performed in the primary care setting are relatively noninvasive and would not require measurement of the INR. Such procedures would include prosthodontics (construction of dentures), scaling/polishing and some conservation work (fillings, crowns, bridges). Potentially invasive procedures performed in primary care would include: endodontics (root canal treatment), local anesthesia (infiltrations, inferior alveolar nerve block, mandibular blocks), extractions (single and multiple), minor oral surgery and periodontal surgery. In all of these conditions, cardiovascular diseases and coagulation disorders must be part of the preoperation evaluation. If hemochrome, coagulation factors and INR values are strongly altered, then a dental operation can be contraindicated. Possible problems of hemorrhage or thrombosis should be discussed with the patient s general practitioner. Any decision concerning discontinuation of anticoagulant therapy should be the result of this collaboration between the dentist and the physician. Concerning possible risks deriving from INR values, a table has been elaborated with the most common dental treatments 62 (Table V). In a subgroup of patients, replacement of anticoagulant drugs with low molecular weight heparin must be considered. INR has to be assessed in these patients at risk 4-12 hours before surgery. The risk of bleeding should thus be minimized. The possible risk of thrombosis associated with temporarily discontinuing anticoagulants prior to dental surgery is small but potentially serious. In a review by Wahl, 1% patients undergoing a lot of dental procedures and in whom anticoagulants were withdrawn specifically for surgery, had serious embolic complications of which four were fatal. 63 Moreover, some foods can strengthen oral anticoagulant action; a diet with excessive levels of vegetables (with a high content of Vitamin K), eaten during oral anticoagulant treatment, can cause a prothrombin activity higher than is expected 64 (Table V). Even if vegetable intake is not reduced, it is necessary to adapt anticoagulant treatment to eating habits. Foods with a high vitamin K content are lettuce, spinach, broccoli and cabbage, while pasta, potatoes, peas, tomatoes, white and red meat and liver exhibit low vitamin K content. Figure 3. Algorithm of a careful operation planning method for patients receiving OAT therapy. Vol No. 1 MINERVA STOMATOLOGICA 31

13 ISOLA Dental management in patients with anticoagulant therapy Table V. Safety of outpatient dental treatment for patients receiving OAT therapy. Treatment type Optimal range of INR Normal target INR range High values of INR < <3-3.5 >3.5 Examination, rx, study models Simple restorative dentistry, supragingival prophylaxis Complex restorative dentistry, scaling and root planning, endodontics Probably safe IR± Simple extractions, curettage, gingivoplasty Local measures Local measures Multiple extractions, removal of single bony impaction Local measures Local measures Local measures Gingivectomy, apicoectomy, minor periodontal flap surgery, placement of single implant Probably safe **IR+ Probably safe IR± Probably safe IR± Full mouth/full-arch extractions Probably safe IR± Local measures Extensive flap surgery, extraction of multiple bony impactions, multiple implant placement Probably safe IR± IR± Open-fracture reduction, orthognathic surgery Not advised Not advised Not advised Not advised Not advised Not advised Silver indicates that it is safe to proceed in a routine manner (local factors such as periodontitis / gingival inflammation can increase the severity of bleeding; the clinician should consider all factors when making a risk assessment). Darkgray, use caution, but in many instances the procedure can be safely performed with judicious use of local measures. Gray, procedure not advises at current INR level; refer to physician for adjustment. IR±: insufficient research to draw a conclusion. : Increased need for use of local measures such as sutures, oxidized cellulose, microfibrillar collagen hemostat, topical thrombin and tranexamic acid. : Should not be performed a dental surgery on a patient receiving anticoagulant therapy; this is a hospital procedure. **IR+: insufficient research, but similar to other procedures for which research data is available. From Herman WW et al. 62 However, there is also a small possible risk of major bleeding in patients undergoing oral surgery if anticoagulants are not suspended before surgery. Many randomised studies supporting this theory have been published. Devani et al. 65 in a randomized study of 65 patients under treatment with warfarin who underwent a total of 133 dental extractions divided the sample into 2 groups: 32 patients who discontinued the drug 2-3 days before surgery (reduced average INR ) and 32 patients who have instead continued OAT (with an average of INR preoperative 2.7). All patients received local measures ( Surgi- cel packing and sutures) to control postoperative bleeding. None of the patients had any immediate postoperative bleeding and only one patient from each group had mild delayed hemorrhage, which was controlled with hemostatic local measures. Evans et al. 66 compared 109 patients in suspension and discontinuation of OAT. The mean INR for the group taking anticoagulants at the time of dental surgery was 2.5 for the group that continued therapy and 1.6 for the group that discontinued therapy. The rate of bleeding was higher in the group continuing anticoagulation (26%) than in the control group (14%) but the difference 32 MINERVA STOMATOLOGICA February 2015

14 Dental management in patients with anticoagulant therapy ISOLA was not significant. Therefore, these studies show that the risk of significant bleeding in patients on oral anticoagulants and with a stable INR in the therapeutic range 2-4 is low. The risk of thrombosis if anticoagulants are discontinued may be increased and these studies suggest that oral anticoagulants should not be discontinued in the majority of patients requiring outpatient dental treatment. The surgical skills of primary care dentists and the difficulty of surgery, particularly when INR levels approach 4, is also important when assessing the risk of bleeding. Individuals in whom the INR is unstable should be discussed with their anticoagulant management team. Concerning the surgical phase, this should be as brief as possible and the least traumatic possible. Bleeding should be always the subject of a continuous and careful evaluation, especially in the immediate post-surgical period. Thus, padding with sterile gauzes, compression of vessels, diathermocoagulation and ligature of vessels are all useful tools. 67 For bleeding of little importance it is sufficient to take tranexamic acid or put fibrin sponges in the hemorrhagic site. 68 Patients should be observed for at least 30 minutes to make sure that wound hemostasis has occurred. In the postsurgical period patients have to keep an ice pack close to the surgical site and then follow a liquid diet avoiding hot food for at least a day. The current American College of Chest Physicians guidelines recommend the use of tranexamic acid mouthwashes (or epsilon amino caproic acid [EACA] mouthwashes) without the interruption of anticoagulant therapy in anticoagulated patients undergoing dental surgery. 69 The recommendations in patients undergoing dental extractions state that patients bleeding may be minimised by the use of oxidised cellulose ( Surgicel ) or collagen sponges with the association of sutures. The anti-biotic and anti-inflammatory prophylaxis for bacteriemia, edema and postsurgical pain must be carefully discussed with the physician before the surgery. 70 It is suggested to check patients for seven con- secutive days after the dental operation to make sure that wound has healed. 71 In case of replacement with heparin, 8 hours after surgery, patients should take at the same time their usual anticoagulant treatment and heparin, until achievement of normal INR values. Thereafter, oral anticoagulant therapy should be regularly continued without risks. In patients undergoing dental surgery it has been suggested from literature studies to prescribed antibiotics to prevent endocarditis. Antibiotics commonly prescribed include amoxicillin, ampicillin, clindamycin and azithromycin. 72 Moderate doses of an antibiotic are unlikely to have any significant effect upon the INR. Individuals who are prescribed multiple doses of antibiotics should have the INR measured two to three days before starting treatment. For patients with stable OAT warfarin (INR 2-4) for the use of a single dose of antibiotic (such as prophylaxis for endocarditis) should not necessitate changing their usual OAT. With regard to anti-inflammatory drugs, non-steroidal anti-inflammatory drugs are avoided in patients receiving oral anticoagulants because of their antiplatelet action and the risk of over anticoagulation and hemorrhage. Cyclo oxygenase-2 (COX-2) selective inhibitors are perceived to be little safer than non-steroidal anti-inflammatory drugs in patients receiving warfarin (because it has also been shown recently that COX assumption is associated with gingival hemorrhage). 73 Use of plasma derivates At present, many papers in the literature do not recommend suspending anticoagulant therapy with the aim of replacing it with heparin before minor surgery to avoid serious thromboembolic complications. Different reports have suggested the use of human fibrin glue as a valid hemostatic agent. 74 Rakocz et al. 75 suggest to use fibrin glue to prevent hemorrhage in patients with bleeding disorders, but the high cost of this kind of treatment and potential infectious Vol No. 1 MINERVA STOMATOLOGICA 33

15 ISOLA Dental management in patients with anticoagulant therapy diseases are restrictive factors. Another author 76 has demonstrated that the use of fibrin glue could be the cause of the risk of viral infections. Platelets are a physiological deposit of numerous growth factors such as plateletderived growth factor, transforming growth factor β, insulin-like growth factors I and II, and epithelial growth factor and glycosaminoglycan such as hyaluronic acid For this reason, some studies proposed an autologous platelet concentrate to enhance these healing processes in cardiovascular surgical patients with hemorrhagic risk. Moreover, other studies also showed that the use of platelet-rich plasma (PRP) gel in postextractive sockets, in patients who did not suspend anticoagulant oral therapy, showed good results for preventing postoperative bleeding. 81 The potential objectives of PRP in medicine it could be to gather the platelets from an anticoagulant therapy patient s blood harvest and to re-inject these platelet suspensions into a damaged site to promote healing through the massive release of platelet growth factors. 82 Indeed, PRP suspension is activated by bovine thrombin that permit to organize a fibrin gel. 83 Platelet-rich fibrin (PRF) is another type of platelet concentrate (more compact than PRP gels and with a different matrix organization) 84 that was developed with the aim of obtaining a dense autologous platelet-fibrin gel without the use of an anticoagulant and activator. The PRF procedure was developed and perfected by many authors 85 and in the biomaterial classification it is commonly scheduled as a leukocyte- and platelet-rich fibrin (L-PRF) biomaterial. In order to obtain PRF, blood could be collect in tubes without an anticoagulant and immediately centrifuged for 12 minutes; then a strong PRF clot layer will appear in the middle of the solution, between the red blood cells and the acellular plasma. It was shown that the healing properties of PRF are related to its platelet and leukocyte content and a production of a dense fibrin scaffold. 86 PRF is also useful in clinical practice as a filling material for the treatment of alveo- lar socket preservation technique in regenerated bone ridges and these properties could be interesting in patients with general pathologies associated with delayed healing or coagulation. 87 Conclusions Analysis of the literature does not allow conclusive and well defined guidelines to be drawn with regard to the correct treatment of patients under oral anticoagulant therapy. In particular, the question on whether or not anticoagulant therapy has to be discontinued in view of dental surgery still remains open. In general, it can be suggested that anticoagulant therapy can be continued in patients undergoing a dental operation. However, in order to obtain better stomatognathic performances that result in a clinical success, 88 the following categories of patients could need special attention: patients with artificial heart valve, with atrial fibrillation and patients suffering from deep vein thrombosis requiring surgery. 89 Sharing therapeutic strategies, both in pediatric and elderly patients, that comprise an analysis of the molecular pathway of gingival tissues and a strict collaboration with a physician is recommended in the attempt to reduce the risk of complication. Particularly, the following aspects merit a deep consideration: the evaluation of bleeding risk in relation to INR; 2. the choice of the least traumatic surgical technique; 3. a careful observation of the hemostasis of the surgical area in the postoperation period. By applying these simple rules it is possible to reduce the various risks and complications discussed above. If the general practitioner decides to discontinue therapy, the use of hemostatic drugs such as tranexamic acid and fibrin sponges that probably are a protection from hemostasis are recommended. In any case, dentists should monitor INR and give patients and/or their caregivers detailed information concerning 34 MINERVA STOMATOLOGICA February 2015

16 Dental management in patients with anticoagulant therapy ISOLA the degree of gravity of the dental operation. Additionally, patients should be provided with a list of foods containing vitamin K and drugs that can interfer with the anticoagulants. Each patient at risk should have an individual medical record where clinical and laboratory data are collected as carefully as possible. Altogether these precautions will contribute to ensure that the patient is better safeguarded from the risk of further complications and also that the dentist is safeguarded from possible future medicallegal problems. For patients taking one of new oral anticoagulants, there is a lack of data and the relative experience regarding their dental treatment management prior to undergoing dental procedures which are likely to involve significant bleeding. 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Trends Biotechnol 2010;28: Piancino MG, Isola G, Merlo A, Dalessandri D, Debernardi C, Bracco P. Chewing pattern and muscular activation in open bite patients. J Electromyogr Kinesiol 2012;22: Jafri SM, Mehta TP. Periprocedural management of anticoagulation in patients on extended warfarin therapy. Semin Thromb Hemost 2004;30: Perillo L, Isola G, Esercizio D, Iovane M, Triolo G, Matarese G. Differences in craniofacial characteristics in Southern Italian children from Naples: a retrospective study by cephalometric analysis. Eur J Paediatr Dent 2013;14: Portelli M, Matarese G, Militi A, Cordasco G, Lucchese A. A proportional correlation index for space analysis in mixed dentition derived from an Italian population sample. Eur J Paediatr Dent 2012;13: Perillo L, Padricelli G, Isola G, Femiano F, Chiodini P, Matarese G. Class II malocclusion division 1: a new classification method by cephalometric analysis. Eur J Paediatr Dent 2012;13: Ferrieri GB, Castiglioni S, Carmagnola D, Cargnel M, Strohmenger L, Abati S. Oral surgery in patients on anticoagulant treatment without therapy interruption. J Oral Maxillofac Surg 2007;65: Buffoli B, Dalessandri M, Favero G, Mensi M, Dalessandri D, Di Rosario F et al. AQP1 expression in human gingiva and its correlation with periodontal and peri-implant tissue. Acta Histochem 2014;116: Conflicts of interest. The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. Received on November 26, Accepted for publication on December 11, Vol No. 1 MINERVA STOMATOLOGICA 37

19 ISOLA Dental management in patients with anticoagulant therapy La terapia anticoagulante orale in pazienti sottoposti a interventi dentari: una review critica della letteratura e attuali prospettive L Organizzazione Mondiale della Sanità ha pubblicato dati allarmanti riguardo i tassi di mortalità dovuti a malattie coronariche e affezioni cerebrovascolari. In realtà, ogni anno, 17 milioni di persone nel mondo muoiono a causa di malattie cardiovascolari, in particolare infarti e ictus 1. Fumo, inattività fisica e dieta malsana sono alcune ben conosciute scorrette abitudini e ben definiti fattori di rischio per queste malattie. Nei paesi industrializzati a causa del miglioramento della qualità della vita fra le persone e l introduzione di specifici farmaci, il tasso di mortalità si è ridotto negli anni recenti 2, 3. Infezioni dentarie, osteomieliti, affezioni parodontali 4 e complicanze derivanti da interventi di chirurgia orale 5, 6, potrebbero essere tutti fonti di più estese infezioni batteriche nell organismo con conseguente produzione del lipopolisaccaride batterico 7 e da qui una conseguente reazione del sistema immunitario 8, 9. Il coinvolgimento patologico della risposta infiammatoria da parte degli altri organi e/o sistemi nei pazienti con vasculopatie è indubbiamente un critico fattore aggravante della loro condizione clinica 10. La salute orale, quindi, dovrebbe anche essere oggetto di attenzione come una rilevante condizione che indirettamente contribuisce alla diminuzione del rischio in pazienti con affezioni cardio-cerebrovascolari. Stress o farmaci possono influire sul sistema cardiovascolare andando ad attivare il sistema nervoso simpatico con il conseguente rilascio di catecolamine endogene e il susseguente effetto cromotropo e dromotropo positivo cardiaco che determina un aumento della pressione arteriosa e del consumo di O2; tutti questi effetti possono causare disfunzioni metaboliche o eventi ischemici che potenzialmente possono indurre qualche danno nel miocardio e/o nel cervello 11. Una stretta collaborazione tra il dentista e il medico curante potrebbe pertanto risultare un approccio ottimale affinché entrambi valutino correttamente l intera situazione clinica dirigendo le strategie terapeutiche con i migliori vantaggi e minori rischi per i pazienti con cardio-cerebro affezioni. I farmaci anticoagulanti Gli anticoagulanti sono un gruppo di farmaci usati per i disordini trombotici in pazienti a rischio. In particolare sono usati per impedire la trombosi venosa profonda, l embolia arteriosa periferica, ictus, l infarto miocardico e altre malattie. Tali farmaci sono classificati in: 1. anticoagulanti orali; 2. eparina; 3. eparina a basso peso molecolare. Anticoagulanti orali Questi farmaci hanno azione antagonista sugli effetti della vitamina K. La vitamina K è essenziale per la γ-carbossilazione dei fattori della coagulazione, la quale li rende incapaci a legare il Ca 2+, fattore essenziale per la loro costituzione 12. In assenza di tale vitamina K la cascata coagulativa non è efficiente (la vitamina K è difatti usata anche come un agente emostatico). Gli anticoagulanti orali antagonizzano la rigenerazione della vitamina K cosi inducendone una carenza funzionale 13 (Figura 1). Conseguentemente al fallimento dell attività biologica dei fattori della coagulazione dipendenti dalla vitamina K sopravviene una riduzione del processo di carbossilazione fino al 40% che determina una concomitante riduzione dei singoli fattori coagulativi approssimativamente del 50% 8, 14. Due principali farmaci anticoagulanti sono disponibili sul mercato, il Coumadin (Warfarin sodium, Bristol-Myers Squibb Srl, Roma, Italia) e il Sintrom (Acenocumarolo, Novartis Farma, Origgio, Varese, Italia). Una compressa di Coumadin di 5 mg ha lo stesso effetto anticoagulante di una da 2,5 mg di Sintrom. Entrambi i farmaci sono veramente efficaci e largamente usati quando il rischio trombotico risulta essere particolarmente elevato. Eparina L eparina è una sostanza biologica in genere di derivazione animale, ed è composta da una miscela di polisaccaridi lineari e complessi. L eparina è presente nelle cellule dei tessuti che contengono mastcellule e non si ritrova normalmente nel plasma. Prodotti della stessa derivazione dell eparina, quali eparansolfato e dermatansolfato sono presenti nella maggior parte delle cellule e nella MEC matrice; le molecole di eparansolfato che sono presenti nella superficie interna dell endotelio vasale vanno a interagire con l antitrombina circolante (e l eparina ne è un cofattore) assicurando così un meccanismo antitrombotico naturale 15. L eparina agisce attivando l antitrombina III la quale blocca i fattori della cascata coagulativa IIa, Xa e la trombina. Per avere un adeguato effetto e inibire la trombina e il fattore Xa deve possedere una concentrazione di almeno 0,1-1 U/ml. L eparina può essere usata esclusivamente per via parenterale (o in vitro per impedire la coagulazione del sangue in provetta o del plasma) con una concentrazione di almeno 5000 U/l fino ad arrivare alle U/l. Eparina a basso peso molecolare Le eparine a basso peso molecolare sono ottenute dalla stessa eparina ma ne differiscono sia per la 38 MINERVA STOMATOLOGICA February 2015

20 Dental management in patients with anticoagulant therapy ISOLA farmacocinetica sia per la farmacodinamica. Dato il minor peso molecolare esse non esercitano il loro effetto anticoagulante con l inibizione della trombina, ma attraverso l inibizione del fattore Xa per opera dell antitrombina 16. Questi composti si trovano in commercio dal nome Clexane (Enoxaparina, Sanofi- Aventis, Origgio, Varese, Italia), Fluxum (Parnaparina, Alfa Wassermann, Alanno, Pescara, Italia) o Fraxiparina (Nadroparina, GlaxoSmithKline, Verona, Italia). I nuovi anticoagulanti orali L interesse nello sviluppo di nuovi farmaci anticoagulanti è attualmente in crescita a causa delle limitazioni rappresentate in campo medico dalla somministrazione dell eparina per via parenterale e per le interazioni di tale farmaco con farmaci antagonisti della vitamina K, quale il warfarin. A causa del relativo rischio di emorragia e dei problemi conseguenti a un uso della terapia con il warfarin, in campo medico e odontoiatrico la terapia anticoagulante con warfarin risulta essere sottoutilizzata nonostante delle chiare linee guida con le relative documentate indicazioni al trattamento. Gli inibitori diretti della trombina costituiscono una classe di farmaci che in popolare aumento per la prevenzione e il trattamento di diverse malattie come la tromboembolia venosa e per la prevenzione di ictus nei casi di fibrillazione atriale. Questa classe di farmaci rappresenta un nuovo campo di ricerca, con diversi studi che ne stanno esaminando la loro sicurezza nel trattamento di queste condizioni. Un grande interesse si è concentrato sullo sviluppo di nuovi farmaci negli ultimi anni: l antitrombina per via orale (anti-fattore IIa) e l anti-fattore Xa come potenziali sostituti per gli antagonisti della vitamina K per via orale. Attualmente, gli agenti anti-xa e anti-iia per via orale sono stati approvati dalla Food and Drug Administration (FDA) e altri sono in sviluppo clinico 17. Uno di questi farmaci è rappresentato dal dabigatran etexilato, un inibitore diretto della trombina somministrato per via orale, mentre gli inibitori del fattore Xa sono rappresentati dal rivaroxaban e dall apixaban. Dabigatran Il dabigatran è stato approvato dalla US FDA nel mese di ottobre 2010 per il trattamento della fibrillazione atriale non valvolare e già ad agosto 2011 presente in circa 1 milione di prescrizioni negli Stati Uniti d America 18. Il dabigatran è stato anche dimostrato essere efficace quanto il warfarin nella prevenzione e nel trattamento del tromboembolismo venoso ricorrente e nei casi di embolia polmonare 19. Il meccanismo di azione del dabigatran etexilato è quello di legarsi con il sito attivo della trombina (fattore IIa) in modo da non poter catalizzare la reazione del fibrinogeno in fibrina. A differenza del warfarin, il dabigatran etexilato inibisce direttamen- te sia la trombina libera che quella legata al coagulo di fibrina 20 (Figura 2). Questo farmaco prolunga il tempo di tromboplastina parziale attivata (aptt), il tempo di ecarina (ECT) e il tempo di trombina (TT) alle dosi terapeutiche di solito consigliate, avendo però allo stesso tempo scarso effetto sul tempo di protrombina (PT)/INR a concentrazioni plasmatiche clinicamente rilevanti 21. Questo farmaco ha minime interazioni farmacologiche e presenta risultati efficaci nell azione antitrombotica nel giro di poche ore dopo l ingestione. Il dabigatran etexilato viene di solito somministrato due volte al giorno con una biodisponibilità dopo somministrazione orale del 3-7%, presenta una abbastanza rapida insorgenza d azione, con concentrazioni plasmatiche massime 2-4 ore dopo l assunzione e un emivita terminale di ore (14-17 ore negli anziani) 22. La somministrazione due volte/die di dabigatran etexilato, permette di raggiungere le concentrazioni plasmatiche per 2 o 3 giorni. Come indicato da alcuni lavori, i principali effetti avversi associati con il dabigatran (>15% dei pazienti) sono stati sintomi gastro-simili, quali dispepsia e dolore addominale. Pochi eventi emorragici di lieve entità sono stati riportati nell 8-33% dei pazienti mentre gli eventi emorragici maggiori (ad esempio, emorragia gastrointestinale) nel <6% dei pazienti 23. Come emerso da diversi studi, il monitoraggio di routine della coagulazione non è necessario per i pazienti mantenuti con dabigatran 19, 24. Entrambi i test TT e ECT sono quelli più sensibili per quantificare gli effetti anticoagulanti dei farmaci dabigatran; van Ryn et al. 21 suggerisce che in caso di emergenza, l aptt e/o il TT sono i test più accessibili per il monitoraggio degli effetti anticoagulanti del dabigatran, poiché il test ECT, che viene eseguito su veleno di serpente, non è di larga disponibilità. Tuttavia, un altro studio 25 ha dimostrato che per monitorare l effetto anticoagulante degli inibitori diretti della trombina (compreso il dabigatran) anche il TT risulta essere troppo sensibile, con un tempo di laboratorio troppo lungo per ottenerne il risultato (>200 secondi). Pertanto, gli autori consigliano l uso dell aptt quando accessibile, come prova del dosaggio del tempo di coagulazione protrombinasi dipendente. Rivaroxaban e apixaban Il rivaroxaban è stato testato in un largo studio clinico multicentrico randomizzato a doppio cieco (RCT) nei pazienti con fibrillazione atriale per la gestione della prevenzione dell ictus. L assunzione del rivaroxaban una volta al giorno per via orale come inibitore diretto del fattore Xa è stata comparata agli antagonisti della vitamina K (warfarin) per la prevenzione di ictus e dell embolia nella fibrillazione atriale 26. Questo studio ha dimostrato come l incidenza dell emorragia cerebrale sia stata statisticamente ridotta nei pazienti in cui era stato somministrato il rivaroxaban rispetto a un gruppo di controllo (warfarin). Vol No. 1 MINERVA STOMATOLOGICA 39

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