mez-Moreno Gerardo Go Antonio Aguilar-Salvatierra ndez-Cejas Esther Ferna Rafael Arcesio Delgado-Ruiz Aleksa Markovic Jose Luis Calvo-Guirado
Dental implant surgery in patients in treatment with the anticoagulant oral rivaroxaban
Authors’ affiliations: Gerardo G omez-Moreno, Department of Special Care in Dentistry, Pharmacological Research in Dentistry, Director of Master in Periodontology and Implant Dentistry, Faculty of Dentistry, University of Granada, Granada, Spain Antonio Aguilar-Salvatierra, Department of Pharmacological Research in Dentistry, Faculty of Dentistry, University of Granada, Granada, Spain Esther Fern andez-Cejas, Department of Pharmacological Research in Dentistry Group, Faculty of Dentistry, University of Granada, Granada, Spain Rafael Arcesio Delgado-Ruiz, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA Aleksa Markovic, Department of Clinic of Oral Surgery, Faculty of Stomatology, University of Belgrade, Belgrade, Serbia Jose Luis Calvo-Guirado, International Research Cathedra UCAM, Universidad Cat olica San Antonio, Murcia, Spain
Key words: bleeding, dental implants, rivaroxaban, tranexamic acid
Corresponding author: Prof. Gerardo G omez-Moreno, DDS, MSc, PhD Facultad de Odontologıa Campus Universitario de Cartuja Colegio M aximo s/n E-18071 Granada Spain Tel.: +34 958 244085 Fax: +34 958 240908 e-mail: [email protected]
Conclusions: Dental implant surgery in patients taking the anticoagulant oral rivaroxaban can be
Date: Accepted 25 May 2015 To cite this article: G omez-Moreno G, Aguilar-Salvatierra A, Fern andez-Cejas E, Delgado-Ruiz RA, Markovic A, Calvo-Guirado JL. Dental implant surgery in patients in treatment with the anticoagulant oral rivaroxaban. Clin. Oral Impl. Res. 27, 2016, 730–733 doi: 10.1111/clr.12653
730
Abstract Objectives: The aim of this study was to evaluate the incidence of bleeding complications after dental implant placement in patients in treatment by the anticoagulant oral rivaroxaban without interrupting its administration or modifying dosage. Materials and methods: About 57 patients were divided into two groups: 18 had been in treatment by rivaroxaban for over 6 month before implant surgery and a control group consisted of 39 healthy subjects. All subjects received dental implants in different positions, without interrupting or modifying rivaroxaban dosage. Patients were treated in an outpatient setting. Non-absorbable sutures were used, and all patients were given gauze impregnated with tranexamic acid 5%, to bite on for 30–60 min. Results: One rivaroxaban patient presented moderate bleeding the day after surgery, and two control patients presented moderate bleeding the day after and on the second day. Bleeding was managed with gauzes impregnated with tranexamic acid. No statistically significant differences (P = 0.688) were found in relation to bleeding episodes between the groups, with a relative risk = 0.919 based on the pooled groups and 95% confidence interval of 0.078–10.844. performed safely in outpatients departments applying local hemostatic measures without the need to modify or interrupt anticoagulant medication.
Oral anticoagulants are a group of drugs used to treat many cardiovascular diseases, such as the prophylaxis of systemic embolism (whose risk is increased in patients with atrial fibrillation or who have undergone orthopedic surgery) (G omez-Moreno et al. 2010). Vitamin K antagonists, which include warfarin and acenocoumarol, have a low therapeutic index as their pharmacological management is difficult and requires continuous monitoring; they also have multiple interactions with other drugs and foods (Spyropoulos & Douketis 2002). Many of the patients being treated with warfarin present inadequate anticoagulation. Despite efforts to create care protocols and appropriate usages of the available anticoagulants, in clinical practice, the outcomes are far from desirable. Given this situation, this is a need for new anticoagulant agents that are effective, safe and easy to use. For several years, there were few pharmacological innovations in the field of anticoagulants, but recently the emergence
of new oral anticoagulants has generated high expectations, especially with regard to direct thrombin inhibitors (dabigatran) and activated factor X (Fxa) inhibitors (rivaroxaban), which offer similar efficacy to traditional drugs but have fewer side effects. For patients treated with these new anticoagulants, implant insertion surgery is made safer and easier and does not require special monitoring. Rivaroxaban is an oral anticoagulant drug and direct inhibitor of FXa clotting (G omezMoreno et al. 2005). It is a derivative of oxazolidone that inhibits free factor Xa by attaching to the prothrombinase complex. This inhibition disrupts the intrinsic and extrinsic pathways of coagulation cascade, inhibiting the formation of thrombin and thrombus. Rivaroxaban has no direct effect on platelet aggregation. Clinical trials of rivaroxaban have shown that anticoagulation is predictable and so there is no need to adjust dosage or monitor patients. It has more than 80% bioavailability after oral administration,
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
G omez-Moreno et al Dental implants in patients taking rivaroxaban
it is metabolized by the liver, and 66% is excreted in the urine. The purpose of this oral anticoagulant is to replace vitamin K antagonists for the prevention of venous thromboembolism and arterial embolism in patients with atrial fibrillation. This FXa inhibitor has been evaluated in several phase III trial studies, to study its use in secondary thromboprophylaxis in major orthopedic surgery (Eriksson et al. 2008; Kakkar et al. 2008; Lassen et al. 2008); rivaroxaban was shown to be significantly more effective than the treatment with enoxaparin. The aim of this study was to evaluate the incidence of bleeding complications after dental implant placement in patients in treatment by oral rivaroxaban without interrupting its administration or modifying dosage.
Materials and methods Ethical guidelines
The study design followed guidelines established in the Declaration of Helsinki (revised 2002 version) for research involving human subjects. Possible secondary effects of surgery were managed according to the current prevailing norms in private practice. Each patient gave his/her informed consent to take part in the study. Patients
Eighteen patients (12 men and 6 women) in treatment by oral rivaroxaban anticoagulant, with ages ranging from 46 to 73 years (mean age 64.4 7.84 years), were recruited from private clinics; all had requested endosseous dental implant placement. The control group was made up of 39 healthy patients without primary or secondary coagulation disorders, comparable for age, sex, extent and site of the surgical implant procedures. Inclusion criteria were as follows: subjects who had been in treatment by rivaroxaban therapy for over six months before the start of the study, aged 8, any patients with a history of microvascular or macrovascular complications arising from diabetes, metabolic bone disorders, a history of renal failure, radiation treatment to the head or neck region, current chemotherapy, pregnancy, drug or alcohol abuse, poor oral hygiene, periodontal disease, a bleeding index >20% and smokers. Surgical protocol
All surgical procedures were performed in an outpatient setting in private dental practice early in the morning to enable resolution of any bleeding complication arising through the day. Oxygen saturation, blood pressure and cardiac electric activity were monitored throughout surgery. Following a single-blind protocol, one practitioner performed all implant surgeries, unaware of the group assignment of each individual patient; in this way, the implant surgical procedure did not vary and post-operative recommendations were the same in all cases. All surgery procedure was performed under local anesthesia following the manufacturers’ protocol. The local anesthetic used was articaine with 0.5 mg of epinephrine (Ultracainâ 0.5%; Normon S.L., Barcelona, Spain). Sulcus incisions were made at the buccal and lingual part of the teeth; a crestal incision was made with scalpel blade 15, raising a full-thickness mucoperiosteal flap. Each implant bed was prepared following the manufacturer’s instruction for the placement of Straumannâ Implant Standard PLUS
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
(Straumann AG, Basel, Switzerland) 8, 10 or 12 mm in length and 3.3 or 4.1 mm in diameter. All implants were placed with a submerged protocol and topped with a closure screw to avoid loading during the healing process. In the maxillary posterior areas were not necessary sinus floor augmentation procedures in patients with rivaroxaban. In the control group (seven participants) in the presence of a residual bone height of 5–8 mm, two lateral and five crestal sinus floor augmentation procedures were carried out using the lateral or crestal approach, with an organic bovine bone matrix (Bio-Oss; Geistlich Pharma AG, Wolhusen, Switzerland) as the graft material. Table 1 shows the positions and number of implants placed in the rivaroxaban treatment group and the control group. In the rivaroxaban group, the maximum number of dental implants placed in anterior sector was three and two in posterior sector, which minimized the risk of bleeding. After implant insertion, flaps were sutured with non-absorbable polyvinylidene fluoride sutures (PVDF 4-0; Lab. Arag o, Barcelona, Spain). Post-operative care and follow-up
When sutured, each patient was given sterile gauzes impregnated with tranexamic acid 5% (Amchafibrinâ 500 mg tablets 5 ml; Rottapharm Madaus S.L., Barcelona, Spain), which he/she was asked to bite on for 30–60 min. Afterward, the patient was examined again to ensure that hemorrhaging had stopped. When this had been established, the patient was given a packet of sterile gauzes and an ampoule of tranexamic acid and sent home. All patients were instructed to apply external ice packs to the surgical area for 6–8 h postoperatively. They were advised to avoid mouthwashes for the first 24 h after surgery, to avoid aspiration movement, manipulation of the surgical area and to avoid tongue contact with the area. Patients carrying removable dental prostheses were advised not to wear their dentures for 2–3 weeks after implant surgery. Table 1. Position and number of dental implants placed in patients in treatment by rivaroxaban and control patients
Implant positions
Number of implants in patients with rivaroxaban
Number of implants in control patients
Posterior maxilla Anterior maxilla Posterior mandible Anterior mandible Total
17 8 12 6 43
32 13 23 11 79
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G omez-Moreno et al Dental implants in patients taking rivaroxaban
To prevent post-operative infection, each patient was prescribed amoxicillin 1 g/8 h to be taken three times a day for 7 days and 1 g paracetamol every 8 h as an analgesic, if required. Post-operative visits were scheduled on days 3 and 8, and the sutures were removed 8 days after surgery. Patients were evaluated for the presence of swelling, pain, local infection, bleeding, peri-implant tissue status, inflammation signs and healing time by the same clinician who had performed the implant surgery. Semi-quantitative evaluation of post-operative hemorrhaging was performed over the eight-day period following implant insertion (Bacci et al. 2011): (i) no bleeding; (ii) slight bleeding, understood as slight oozing from the wound incision controlled with compressive gauze only; (iii) moderate bleeding, understood as large clots disrupting the surgical area and requiring additional hemostatic measures; and (iv) severe hemorrhaging, requiring major medical management. Patients were requested to record the moments when bleeding occurred. Statistical analysis
Data analysis was performed with IBM SPSS Statistics 20.0 software (New York, NY, USA). Fisher’s exact test was used to calculate the differences in prevalence of postoperative bleeding between the rivaroxaban group and the control group. Two-tailed P values ≤ 0.05 were considered to be statistically significant.
Results In all participants, the peri-implant tissue status was good, inflammation signs were not observed, and the healing time was normal. Three patients in treatment by rivaroxaban presented slightly prolonged PT, but this did not correspond clinically to any bleeding episode. All control subjects presented normal PT values. During the postoperative follow-up period, one rivaroxaban group patient (a male aged 57 years) suffered moderate bleeding the day after surgery in the area of an implant placed in the region of 16. To control bleeding, the patient bit on gauze soaked in tranexamic acid for 1 h in the region of the surgery and was indicated to repeat this procedure as a preventative measure three times a day for the next four days. The bleeding was brought under control within the hour, and no surgical intervention, additional sutures or any other hemostatic measures were required.
732 |
Clin. Oral Impl. Res. 27, 2016 / 730–733
In the control group, one male patient aged 63 years experienced moderate bleeding the day after implant surgery at 15 and one female aged 52 suffered moderate bleeding in the surgical zone of an implant placed at 46. In both cases, bleeding was managed within 50 min in the same way as the former rivaroxaban group patient applying the same preventative measures. After performing statistical analysis, no statistically significant differences were identified (P = 0.688) in relation to bleeding episodes between the group in treatment by rivaroxaban and the control group, with a relative risk of 0.919 based on the pooled groups and 95% confidence interval of 0.078–10.844 (Table 2).
Discussion As far as the authors are aware, no research has been published on oral surgical procedures among patients in treatment by the new anticoagulants such as rivaroxaban. Nevertheless, it can be assumed that rivaroxaban patients who are to undergo surgery or other invasive procedures are subject to higher risks of hemorrhage (Mingarro-de-Le on et al. 2014). For this reason, surgical interventions may require temporary interruption of rivaroxaban administration, assessing the risk of thromboembolic phenomena that suspending anticoagulant treatment might occasion. For this reason, it is important to investigate oral surgical procedures in this patient group in order to assess the possibility of bleeding, particularly as there is no antidote for any of the new oral anticoagulants. These new oral anticoagulants have overtaken vitamin K antagonists such as warfarin because they do not require laboratory monitoring (Firriolo & Hupp 2012). But patients treated with the new anticoagulants also need coagulation tests to assess the chances of unexpected thrombotic or hemorrhage complications, particularly in the case of emergency or programmed surgery (Fakhri et al. 2013). At the start of the present study, patients underwent PT tests to provide an indication of anticoagulation in relation to drug administration, as normal PT values
exclude significant rivaroxaban levels with most reagents. Although rivaroxaban may prolong prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) slightly, these tests do not appear to be clinically useful for assessing the anticoagulant effect produced by the drug, and they do not correlate well with the risk of hemorrhaging with which the drug may be associated (Castellone & Van Cott 2010). The present study observed that three patients taking rivaroxaban showed slightly prolonged PT but none experienced hemorrhaging after implant insertion. At the plasma concentrations obtained with normal rivaroxaban doses, routine hemostasia tests are not very sensitive. Currently, the chromogenic test used to evaluate antifactor Xa activity in plasma is the preferred laboratory test for monitoring the anticoagulant effect of rivaroxaban that correlates with the drug’s plasma concentration (Firriolo & Hupp 2012). However, no routine laboratory test for monitoring coagulation should be required for patients receiving rivaroxaban, except in special circumstances such as renal failure, obesity or severely underweight patients. The main inconvenience of the test is its economic cost and so it is not normally available in laboratories, where provision of this service is not regarded as essential. Firriolo & Hupp indicate that in patients with normal renal function, in treatment by rivaroxaban, and in the absence of any other risk of hemostasis disorders, it does not appear necessary to interrupt rivaroxaban administration before conventional dental treatments, including simple dental extractions (Firriolo & Hupp 2012). When it can be foreseen that oral or maxillofacial surgical procedures might occasion excessive bleeding and/or hemostasis problems, rivaroxaban should be suspended at least 24 h before the proposed surgery; the risk of hemorrhage will depend on the type and complexity of the surgical procedure, the presence and degree of any renal impairment, and the presence of other risks for impaired hemostasis. Medication should recommence 24–48 h after surgery. No studies have been found that establish a clear approach to dealing with patients in
Table 2. Patients in treatment by rivaroxaban and control patients who suffered bleeding episodes after implant placement surgery Patients
No bleeding
Slight bleeding
Moderate bleeding*
Severe bleeding
Rivaroxaban patients Control patients
17 37
0 0
1 2
0 0
*Relative risk = 0.919; P = 0.688; 95% confidence interval 0.078–10.844.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
G omez-Moreno et al Dental implants in patients taking rivaroxaban
treatment by rivaroxaban who are to receive dental implants. In a systematic review of oral anticoagulant treatment by warfarin (Madrid & Sanz 2009), it is assumed that dental implant placement has a low risk of bleeding (minor surgery) and so does not require suspension or modification of the dose. When dental implant placement is compared with simple extraction in terms of primary wound closure, implant placement allows primary flap closure, which probably results in better hemostasis and a potentially lower incidence of bleeding (Bacci et al. 2011). In this way, these authors observed that by applying local hemostasis in dental implant surgery, it was possible to prevent bleeding complications in patients in treatment by warfarin without interrupting or modifying the dose, allowing these surgical procedures to be performed on an outpatient basis (Bacci et al. 2011). In the present study, implant surgery was performed in patients with normal renal function without interrupting or modifying rivaroxaban doses, applying local hemostasis that consisted of non-absorbable sutures, and compression with sterile gauzes soaked in 5% tranexamic acid in the surgical area for 30–
60 min; no significant differences were found between rivaroxaban patients and healthy control subjects. Only one rivaroxaban patient presented moderate bleeding the day after surgery, which was brought under control by applying gauze soaked in tranexamic acid solution; in this case, the patient reported that he had played some sport that morning that had coincided with the bleeding episode. The local application of tranexamic acid has been shown to stabilize clot formation in various oral surgical settings (Ramstr€ om et al. 1993; Ferrieri et al. 2007; Nkenke et al. 2007; Rodrıguez-Cabrera et al. 2011). The efficacy of this means of hemorrhage management is based on its inhibiting action on the plasminogen activation process, which reduces the fibrinolytic activity of human plasma. Patients were prescribed with the antibiotic amoxicillin to prevent post-operative infection; macrolide antibiotics (especially erythromycin and clarithromycin) were avoided because of their potential pharmacological interaction with rivaroxaban. Paracetamol was only prescribed if the patient was in pain and NSAIDs (non-steroid anti-inflammatory drugs), and opioid analgesics were avoided as these can prolong bleeding with some of the
new anticoagulants. In cases of prolonged bleeding after surgery, patients are recommended to contact their doctor, discontinue rivaroxaban, transfuse with packed red cells or fresh frozen plasma, and administer prothrombin complex concentrate or recombinant activated clotting factor VII (rFVIIa), if available (Firriolo & Hupp 2012). In conclusion, the present study found no statistically significant difference in the number of bleeding complications between rivaroxaban patients and a systemically healthy control group. Although the study had a small patient sample, this suggests that dental implant surgery in patients in treatment by the anticoagulant oral rivaroxaban can be performed safely in an outpatient setting applying local hemostatic measures; there is no need to interrupt or modify the coagulant dose.
Conflict of interest The authors declare that they have no conflict of interest.
References Bacci, C., Berengo, M., Favero, L. & Zanon, E. (2011) Safety of dental implant surgery in patients undergoing anticoagulation therapy: a prospective case-control study. Clinical Oral Implants Research 22: 151–156. Castellone, D.D. & Van Cott, E.M. (2010) Laboratory monitoring of new anticoagulants. American Journal of Hematology 85: 185–187. Eriksson, B.I., Borris, L.C., Friedman, R.J., Haas, S., Huisman, M.V., Kakkar, A.K., Bandel, T.J., Beckmann, H., Muehlhofer, E., Misselwitz, F. & Geerts, W. & RECORD1 Study Group. (2008) Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. The New England Journal of Medicine 358: 2765–2775. Fakhri, H.R., Janket, S.J., Jackson, E.A., Baird, A.E., Dinnocenzo, R. & Meurman, J.H. (2013) Tutorial in oral antithrombotic therapy: biology and dental implications. Medicina Oral Patologia Oral y Cirugia Bucal 18: e461–e472. Ferrieri, G.B., Castiglioni, S., Carmagnola, D., Cargnel, M., Strohmenger, L. & Abati, S. (2007) Oral surgery in patients on anticoagulant treatment without therapy interruption. Journal of Oral and Maxillofacial Surgery 65: 1149–1154. Firriolo, F.J. & Hupp, W.S. (2012) Beyond warfarin: the new generation of oral anticoagulants and their implications for the management of dental patients. Oral Surgery, Oral Medicine,
Oral Pathology and Oral Radiology 113: 431– 441. G omez-Moreno, G., Aguilar-Salvatierra, A., MartınPiedra, M.A., Guardia, J., Calvo-Guirado, J.L., Cabrera, M., L opez-Gallardo, C. & Castillo, T. (2010) Dabigatran and rivaroxaban, new oral anticoagulants. New approaches in dentistry. Journal of Clinical and Experimental Dentistry 2: e14– e18. G omez-Moreno, G., Cutando-Soriano, A., Arana, C. & Scully, C. (2005) Hereditary blood coagulation disorders: management and dental treatment. Journal of Dental Research 84: 978–985. Kakkar, A.K., Brenner, B., Dahl, O.E., Eriksson, B.I., Mouret, P., Muntz, J., Soglian, A.G., Pap, A.F., Misselwitz, F., Haas, S. & RECORD2 Investigators. (2008) Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 372: 31–39. Lassen, M.R., Ageno, W., Borris, L.C., Lieberman, J.R., Rosencher, N., Bandel, T.J., Misselwitz, F., Turpie, A.G. & RECORD3 Investigators. (2008) Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. The New England Journal of Medicine 358: 2776–2786. Madrid, C. & Sanz, M. (2009) What influence do anticoagulants have on oral implant therapy? A
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
systematic review. Clinical Oral Implants Research 20: 96–106. Mingarro-de-Le on, A., Chaveli-L opez, B. & Gavalda-Esteve, C. (2014) Dental management of patients receiving anticoagulant and/or antiplatelet treatment. Journal of Clinical and Experimental Dentistry 6: e155–e161. Nkenke, E., Eitner, S., Radespiel-Tr€ oger, M., Vairaktaris, E., Neukam, F.W. & Fenner, M. (2007) Patient-centred outcomes comparing transmucosal implant placement with an open approach in the maxilla: a prospective, non-randomized pilot study. Clinical Oral Implants Research 18: 197– 203. Ramstr€ om, G., Sindet-Pedersen, S., Hall, G., Blomb€ack, M. & Alander, U. (1993) Prevention of postsurgical bleeding in oral surgery using tranexamic acid without dose modification of oral anticoagulants. Journal of Oral and Maxillofacial Surgery 51: 1211–1216. Rodrıguez-Cabrera, M.A., Barona-Dorado, C., LecoBerrocal, I., G omez-Moreno, G. & MartınezGonzalez, J.M. (2011) Extractions without eliminating anticoagulant treatment: a literature review. Medicina Oral Patologia Oral y Cirugia Bucal 16: e800–e804. Spyropoulos, A.C. & Douketis, J.D. (2002) How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 120: 2954–2962.
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Dental implant surgery in patients in treatment with the anticoagulant oral rivaroxaban
Authors’ affiliations: Gerardo G omez-Moreno, Department of Special Care in Dentistry, Pharmacological Research in Dentistry, Director of Master in Periodontology and Implant Dentistry, Faculty of Dentistry, University of Granada, Granada, Spain Antonio Aguilar-Salvatierra, Department of Pharmacological Research in Dentistry, Faculty of Dentistry, University of Granada, Granada, Spain Esther Fern andez-Cejas, Department of Pharmacological Research in Dentistry Group, Faculty of Dentistry, University of Granada, Granada, Spain Rafael Arcesio Delgado-Ruiz, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA Aleksa Markovic, Department of Clinic of Oral Surgery, Faculty of Stomatology, University of Belgrade, Belgrade, Serbia Jose Luis Calvo-Guirado, International Research Cathedra UCAM, Universidad Cat olica San Antonio, Murcia, Spain
Key words: bleeding, dental implants, rivaroxaban, tranexamic acid
Corresponding author: Prof. Gerardo G omez-Moreno, DDS, MSc, PhD Facultad de Odontologıa Campus Universitario de Cartuja Colegio M aximo s/n E-18071 Granada Spain Tel.: +34 958 244085 Fax: +34 958 240908 e-mail: [email protected]
Conclusions: Dental implant surgery in patients taking the anticoagulant oral rivaroxaban can be
Date: Accepted 25 May 2015 To cite this article: G omez-Moreno G, Aguilar-Salvatierra A, Fern andez-Cejas E, Delgado-Ruiz RA, Markovic A, Calvo-Guirado JL. Dental implant surgery in patients in treatment with the anticoagulant oral rivaroxaban. Clin. Oral Impl. Res. 27, 2016, 730–733 doi: 10.1111/clr.12653
730
Abstract Objectives: The aim of this study was to evaluate the incidence of bleeding complications after dental implant placement in patients in treatment by the anticoagulant oral rivaroxaban without interrupting its administration or modifying dosage. Materials and methods: About 57 patients were divided into two groups: 18 had been in treatment by rivaroxaban for over 6 month before implant surgery and a control group consisted of 39 healthy subjects. All subjects received dental implants in different positions, without interrupting or modifying rivaroxaban dosage. Patients were treated in an outpatient setting. Non-absorbable sutures were used, and all patients were given gauze impregnated with tranexamic acid 5%, to bite on for 30–60 min. Results: One rivaroxaban patient presented moderate bleeding the day after surgery, and two control patients presented moderate bleeding the day after and on the second day. Bleeding was managed with gauzes impregnated with tranexamic acid. No statistically significant differences (P = 0.688) were found in relation to bleeding episodes between the groups, with a relative risk = 0.919 based on the pooled groups and 95% confidence interval of 0.078–10.844. performed safely in outpatients departments applying local hemostatic measures without the need to modify or interrupt anticoagulant medication.
Oral anticoagulants are a group of drugs used to treat many cardiovascular diseases, such as the prophylaxis of systemic embolism (whose risk is increased in patients with atrial fibrillation or who have undergone orthopedic surgery) (G omez-Moreno et al. 2010). Vitamin K antagonists, which include warfarin and acenocoumarol, have a low therapeutic index as their pharmacological management is difficult and requires continuous monitoring; they also have multiple interactions with other drugs and foods (Spyropoulos & Douketis 2002). Many of the patients being treated with warfarin present inadequate anticoagulation. Despite efforts to create care protocols and appropriate usages of the available anticoagulants, in clinical practice, the outcomes are far from desirable. Given this situation, this is a need for new anticoagulant agents that are effective, safe and easy to use. For several years, there were few pharmacological innovations in the field of anticoagulants, but recently the emergence
of new oral anticoagulants has generated high expectations, especially with regard to direct thrombin inhibitors (dabigatran) and activated factor X (Fxa) inhibitors (rivaroxaban), which offer similar efficacy to traditional drugs but have fewer side effects. For patients treated with these new anticoagulants, implant insertion surgery is made safer and easier and does not require special monitoring. Rivaroxaban is an oral anticoagulant drug and direct inhibitor of FXa clotting (G omezMoreno et al. 2005). It is a derivative of oxazolidone that inhibits free factor Xa by attaching to the prothrombinase complex. This inhibition disrupts the intrinsic and extrinsic pathways of coagulation cascade, inhibiting the formation of thrombin and thrombus. Rivaroxaban has no direct effect on platelet aggregation. Clinical trials of rivaroxaban have shown that anticoagulation is predictable and so there is no need to adjust dosage or monitor patients. It has more than 80% bioavailability after oral administration,
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
G omez-Moreno et al Dental implants in patients taking rivaroxaban
it is metabolized by the liver, and 66% is excreted in the urine. The purpose of this oral anticoagulant is to replace vitamin K antagonists for the prevention of venous thromboembolism and arterial embolism in patients with atrial fibrillation. This FXa inhibitor has been evaluated in several phase III trial studies, to study its use in secondary thromboprophylaxis in major orthopedic surgery (Eriksson et al. 2008; Kakkar et al. 2008; Lassen et al. 2008); rivaroxaban was shown to be significantly more effective than the treatment with enoxaparin. The aim of this study was to evaluate the incidence of bleeding complications after dental implant placement in patients in treatment by oral rivaroxaban without interrupting its administration or modifying dosage.
Materials and methods Ethical guidelines
The study design followed guidelines established in the Declaration of Helsinki (revised 2002 version) for research involving human subjects. Possible secondary effects of surgery were managed according to the current prevailing norms in private practice. Each patient gave his/her informed consent to take part in the study. Patients
Eighteen patients (12 men and 6 women) in treatment by oral rivaroxaban anticoagulant, with ages ranging from 46 to 73 years (mean age 64.4 7.84 years), were recruited from private clinics; all had requested endosseous dental implant placement. The control group was made up of 39 healthy patients without primary or secondary coagulation disorders, comparable for age, sex, extent and site of the surgical implant procedures. Inclusion criteria were as follows: subjects who had been in treatment by rivaroxaban therapy for over six months before the start of the study, aged 8, any patients with a history of microvascular or macrovascular complications arising from diabetes, metabolic bone disorders, a history of renal failure, radiation treatment to the head or neck region, current chemotherapy, pregnancy, drug or alcohol abuse, poor oral hygiene, periodontal disease, a bleeding index >20% and smokers. Surgical protocol
All surgical procedures were performed in an outpatient setting in private dental practice early in the morning to enable resolution of any bleeding complication arising through the day. Oxygen saturation, blood pressure and cardiac electric activity were monitored throughout surgery. Following a single-blind protocol, one practitioner performed all implant surgeries, unaware of the group assignment of each individual patient; in this way, the implant surgical procedure did not vary and post-operative recommendations were the same in all cases. All surgery procedure was performed under local anesthesia following the manufacturers’ protocol. The local anesthetic used was articaine with 0.5 mg of epinephrine (Ultracainâ 0.5%; Normon S.L., Barcelona, Spain). Sulcus incisions were made at the buccal and lingual part of the teeth; a crestal incision was made with scalpel blade 15, raising a full-thickness mucoperiosteal flap. Each implant bed was prepared following the manufacturer’s instruction for the placement of Straumannâ Implant Standard PLUS
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
(Straumann AG, Basel, Switzerland) 8, 10 or 12 mm in length and 3.3 or 4.1 mm in diameter. All implants were placed with a submerged protocol and topped with a closure screw to avoid loading during the healing process. In the maxillary posterior areas were not necessary sinus floor augmentation procedures in patients with rivaroxaban. In the control group (seven participants) in the presence of a residual bone height of 5–8 mm, two lateral and five crestal sinus floor augmentation procedures were carried out using the lateral or crestal approach, with an organic bovine bone matrix (Bio-Oss; Geistlich Pharma AG, Wolhusen, Switzerland) as the graft material. Table 1 shows the positions and number of implants placed in the rivaroxaban treatment group and the control group. In the rivaroxaban group, the maximum number of dental implants placed in anterior sector was three and two in posterior sector, which minimized the risk of bleeding. After implant insertion, flaps were sutured with non-absorbable polyvinylidene fluoride sutures (PVDF 4-0; Lab. Arag o, Barcelona, Spain). Post-operative care and follow-up
When sutured, each patient was given sterile gauzes impregnated with tranexamic acid 5% (Amchafibrinâ 500 mg tablets 5 ml; Rottapharm Madaus S.L., Barcelona, Spain), which he/she was asked to bite on for 30–60 min. Afterward, the patient was examined again to ensure that hemorrhaging had stopped. When this had been established, the patient was given a packet of sterile gauzes and an ampoule of tranexamic acid and sent home. All patients were instructed to apply external ice packs to the surgical area for 6–8 h postoperatively. They were advised to avoid mouthwashes for the first 24 h after surgery, to avoid aspiration movement, manipulation of the surgical area and to avoid tongue contact with the area. Patients carrying removable dental prostheses were advised not to wear their dentures for 2–3 weeks after implant surgery. Table 1. Position and number of dental implants placed in patients in treatment by rivaroxaban and control patients
Implant positions
Number of implants in patients with rivaroxaban
Number of implants in control patients
Posterior maxilla Anterior maxilla Posterior mandible Anterior mandible Total
17 8 12 6 43
32 13 23 11 79
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G omez-Moreno et al Dental implants in patients taking rivaroxaban
To prevent post-operative infection, each patient was prescribed amoxicillin 1 g/8 h to be taken three times a day for 7 days and 1 g paracetamol every 8 h as an analgesic, if required. Post-operative visits were scheduled on days 3 and 8, and the sutures were removed 8 days after surgery. Patients were evaluated for the presence of swelling, pain, local infection, bleeding, peri-implant tissue status, inflammation signs and healing time by the same clinician who had performed the implant surgery. Semi-quantitative evaluation of post-operative hemorrhaging was performed over the eight-day period following implant insertion (Bacci et al. 2011): (i) no bleeding; (ii) slight bleeding, understood as slight oozing from the wound incision controlled with compressive gauze only; (iii) moderate bleeding, understood as large clots disrupting the surgical area and requiring additional hemostatic measures; and (iv) severe hemorrhaging, requiring major medical management. Patients were requested to record the moments when bleeding occurred. Statistical analysis
Data analysis was performed with IBM SPSS Statistics 20.0 software (New York, NY, USA). Fisher’s exact test was used to calculate the differences in prevalence of postoperative bleeding between the rivaroxaban group and the control group. Two-tailed P values ≤ 0.05 were considered to be statistically significant.
Results In all participants, the peri-implant tissue status was good, inflammation signs were not observed, and the healing time was normal. Three patients in treatment by rivaroxaban presented slightly prolonged PT, but this did not correspond clinically to any bleeding episode. All control subjects presented normal PT values. During the postoperative follow-up period, one rivaroxaban group patient (a male aged 57 years) suffered moderate bleeding the day after surgery in the area of an implant placed in the region of 16. To control bleeding, the patient bit on gauze soaked in tranexamic acid for 1 h in the region of the surgery and was indicated to repeat this procedure as a preventative measure three times a day for the next four days. The bleeding was brought under control within the hour, and no surgical intervention, additional sutures or any other hemostatic measures were required.
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In the control group, one male patient aged 63 years experienced moderate bleeding the day after implant surgery at 15 and one female aged 52 suffered moderate bleeding in the surgical zone of an implant placed at 46. In both cases, bleeding was managed within 50 min in the same way as the former rivaroxaban group patient applying the same preventative measures. After performing statistical analysis, no statistically significant differences were identified (P = 0.688) in relation to bleeding episodes between the group in treatment by rivaroxaban and the control group, with a relative risk of 0.919 based on the pooled groups and 95% confidence interval of 0.078–10.844 (Table 2).
Discussion As far as the authors are aware, no research has been published on oral surgical procedures among patients in treatment by the new anticoagulants such as rivaroxaban. Nevertheless, it can be assumed that rivaroxaban patients who are to undergo surgery or other invasive procedures are subject to higher risks of hemorrhage (Mingarro-de-Le on et al. 2014). For this reason, surgical interventions may require temporary interruption of rivaroxaban administration, assessing the risk of thromboembolic phenomena that suspending anticoagulant treatment might occasion. For this reason, it is important to investigate oral surgical procedures in this patient group in order to assess the possibility of bleeding, particularly as there is no antidote for any of the new oral anticoagulants. These new oral anticoagulants have overtaken vitamin K antagonists such as warfarin because they do not require laboratory monitoring (Firriolo & Hupp 2012). But patients treated with the new anticoagulants also need coagulation tests to assess the chances of unexpected thrombotic or hemorrhage complications, particularly in the case of emergency or programmed surgery (Fakhri et al. 2013). At the start of the present study, patients underwent PT tests to provide an indication of anticoagulation in relation to drug administration, as normal PT values
exclude significant rivaroxaban levels with most reagents. Although rivaroxaban may prolong prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) slightly, these tests do not appear to be clinically useful for assessing the anticoagulant effect produced by the drug, and they do not correlate well with the risk of hemorrhaging with which the drug may be associated (Castellone & Van Cott 2010). The present study observed that three patients taking rivaroxaban showed slightly prolonged PT but none experienced hemorrhaging after implant insertion. At the plasma concentrations obtained with normal rivaroxaban doses, routine hemostasia tests are not very sensitive. Currently, the chromogenic test used to evaluate antifactor Xa activity in plasma is the preferred laboratory test for monitoring the anticoagulant effect of rivaroxaban that correlates with the drug’s plasma concentration (Firriolo & Hupp 2012). However, no routine laboratory test for monitoring coagulation should be required for patients receiving rivaroxaban, except in special circumstances such as renal failure, obesity or severely underweight patients. The main inconvenience of the test is its economic cost and so it is not normally available in laboratories, where provision of this service is not regarded as essential. Firriolo & Hupp indicate that in patients with normal renal function, in treatment by rivaroxaban, and in the absence of any other risk of hemostasis disorders, it does not appear necessary to interrupt rivaroxaban administration before conventional dental treatments, including simple dental extractions (Firriolo & Hupp 2012). When it can be foreseen that oral or maxillofacial surgical procedures might occasion excessive bleeding and/or hemostasis problems, rivaroxaban should be suspended at least 24 h before the proposed surgery; the risk of hemorrhage will depend on the type and complexity of the surgical procedure, the presence and degree of any renal impairment, and the presence of other risks for impaired hemostasis. Medication should recommence 24–48 h after surgery. No studies have been found that establish a clear approach to dealing with patients in
Table 2. Patients in treatment by rivaroxaban and control patients who suffered bleeding episodes after implant placement surgery Patients
No bleeding
Slight bleeding
Moderate bleeding*
Severe bleeding
Rivaroxaban patients Control patients
17 37
0 0
1 2
0 0
*Relative risk = 0.919; P = 0.688; 95% confidence interval 0.078–10.844.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
G omez-Moreno et al Dental implants in patients taking rivaroxaban
treatment by rivaroxaban who are to receive dental implants. In a systematic review of oral anticoagulant treatment by warfarin (Madrid & Sanz 2009), it is assumed that dental implant placement has a low risk of bleeding (minor surgery) and so does not require suspension or modification of the dose. When dental implant placement is compared with simple extraction in terms of primary wound closure, implant placement allows primary flap closure, which probably results in better hemostasis and a potentially lower incidence of bleeding (Bacci et al. 2011). In this way, these authors observed that by applying local hemostasis in dental implant surgery, it was possible to prevent bleeding complications in patients in treatment by warfarin without interrupting or modifying the dose, allowing these surgical procedures to be performed on an outpatient basis (Bacci et al. 2011). In the present study, implant surgery was performed in patients with normal renal function without interrupting or modifying rivaroxaban doses, applying local hemostasis that consisted of non-absorbable sutures, and compression with sterile gauzes soaked in 5% tranexamic acid in the surgical area for 30–
60 min; no significant differences were found between rivaroxaban patients and healthy control subjects. Only one rivaroxaban patient presented moderate bleeding the day after surgery, which was brought under control by applying gauze soaked in tranexamic acid solution; in this case, the patient reported that he had played some sport that morning that had coincided with the bleeding episode. The local application of tranexamic acid has been shown to stabilize clot formation in various oral surgical settings (Ramstr€ om et al. 1993; Ferrieri et al. 2007; Nkenke et al. 2007; Rodrıguez-Cabrera et al. 2011). The efficacy of this means of hemorrhage management is based on its inhibiting action on the plasminogen activation process, which reduces the fibrinolytic activity of human plasma. Patients were prescribed with the antibiotic amoxicillin to prevent post-operative infection; macrolide antibiotics (especially erythromycin and clarithromycin) were avoided because of their potential pharmacological interaction with rivaroxaban. Paracetamol was only prescribed if the patient was in pain and NSAIDs (non-steroid anti-inflammatory drugs), and opioid analgesics were avoided as these can prolong bleeding with some of the
new anticoagulants. In cases of prolonged bleeding after surgery, patients are recommended to contact their doctor, discontinue rivaroxaban, transfuse with packed red cells or fresh frozen plasma, and administer prothrombin complex concentrate or recombinant activated clotting factor VII (rFVIIa), if available (Firriolo & Hupp 2012). In conclusion, the present study found no statistically significant difference in the number of bleeding complications between rivaroxaban patients and a systemically healthy control group. Although the study had a small patient sample, this suggests that dental implant surgery in patients in treatment by the anticoagulant oral rivaroxaban can be performed safely in an outpatient setting applying local hemostatic measures; there is no need to interrupt or modify the coagulant dose.
Conflict of interest The authors declare that they have no conflict of interest.
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