Oral anticoagulants are used to prevent and treat thromboembolic events. Some dental procedures may result in a soft- or hard-tissue injury with consequent bleeding,1 in particular in individuals using anticoagulants.1-3
Atrial fibrillation and other diseases require that individuals receive oral anticoagulant therapy (OAT) to reduce the risk of stroke, morbidity, and mortality.4-7 A recent study from the Valencia region of Spain demonstrated that the percentage of individuals aged 18 years or older receiving OAT is 1.3%.6 The prevalence increases progressively with age, reaching 6.9% among individuals aged 80 years or older.6
Vitamin K antagonists (VKA) are the most commonly used oral anticoagulants. The use of VKA reduces stroke rates by 30% in high-risk individuals.8 Warfarin is the most commonly used medication among VKAs and has a long half-life (48 hours).4,5,9 Therefore, the pharmacological action of this anticoagulant after discontinuation of therapy may last between two and five days.4
The efficacy and safety of these medications depend on the maintenance of the patient within the therapeutic value of the international normalized ratio (INR), which must be compatible with the patient's pathology. In an individual who does not receive OAT, the INR usually has a value of 1.0, while among those who receive OAT, the value ranges between 2.0 and 3.0.6,9
Alternatively, the new oral anticoagulants (NOACs), such as dabigatran (a thrombin inhibitor), as well as rivaroxaban, apixaban, and edoxaban (factor Xa inhibitors), have been used.10 New oral anticoagulants have a short onset of action and achieve their maximum plasma level between one and four hours. Also, they present a short half-life ranging from five to 17 hours.11,12 Because NOACs are short-lived, some authors have stated that these medications could be discontinued for one or two days.12 However, other authors have stated that clinicians are reluctant to discontinue these medications; therefore, an assertive protocol for the management of individuals undergoing therapy with NOACs during tooth extractions remains uncertain.11,12 In a retrospective study with individuals who had undergone tooth extractions without discontinuation of NOAC treatment, a significant increase in postoperative bleeding was observed.11
More recently, the literature has reported that the use of OAT should be reduced or even suspended before tooth extractions.13 The literature reports that OAT could be replaced with heparin (low molecular weight heparin has smaller molecules, making it less cell-bound). The OAT could also be continued with emphasis on local hemostasis methods, such as the use of adjuvants and regulators1,2; alternatively, the OAT could be continued without changes in its regimen and without local hemostasis, taking into consideration INR values.2
The critical question is whether to continue, modify, or discontinue OAT before any dental treatment. The suspension or reduction of anticoagulant doses before dental procedures may expose these individuals to the risk of thromboembolism.14 In contrast, maintenance of the OAT increases the risk of bleeding during or after the procedure.2,15
Results from other reports show that dental procedures may be performed if the INR values are within the acceptable therapeutic range, which is below 4.0.16 Conversely, some authors have suggested that these procedures are safe in individuals receiving anticoagulation therapy whose INR values range between 3.5 and 4.2, since effective local hemostatic measurements are provided.16 A meta-analysis on individuals treated with warfarin showed that the risk of bleeding increased for individuals with an INR greater than 3.0, but the authors of another study reported that even INR values up to 5.5 are acceptable.17 In these cases, alternative protocols to avoid difficulties in controlling bleeding are highly recommended.16,18,19
Different authors confirm that tooth extraction in patients receiving OAT may be performed safely without changing the regimen if local hemostatic measures are used.14,20 Among the hemostatic agents used to control bleeding in individuals receiving OAT, the literature has highlighted oxidized cellulose, resorbable gelatin sponges, collagen sponges, fibrin glue, cyanoacrylate glue, platelet-rich plasma gel, calcium alginate, and topical thrombin.17,19,21 Local interventions, such as sutures, sealants, adhesives, ligating clips, vasoconstrictor agents, or a combination of these measures, have also been used to control bleeding.21 Hemostatic interventions also include antifibrinolytic agents. The importance of antifibrinolytic mouthwash solutions in the prevention of post-extraction bleeding has been observed in several articles.22-24
Epsilon-aminocaproic acid and tranexamic acid (TXA) are the most commonly used antifibrinolytic agents. Tranexamic acid and epsilon-aminocaproic acid work by blocking the interaction of plasminogen with fibrin, precluding the degradation of the fibrin clot.23,24 Antifibrinolytic agents are used to mitigate bleeding in surgical procedures because they stabilize and inhibit the breakdown of blood clots.23
Systematic reviews on the effectiveness of local hemostatic protocols for the prevention of bleeding in individuals receiving OAT who underwent tooth extraction have been reported in the literature, but no meta-analysis with pooled data has been found.25 The multiple interventions, heterogeneity of the studies, and the quality of the documents make quantitative analysis complex. Moreover, the prevention of bleeding in individuals receiving OAT undergoing other dental procedures, such as periodontal procedures or endodontic surgery, has been poorly documented.21,25 Different systematic reviews and meta-analyses have assessed VKAs and warfarin,25,26 but there is a shortage of information concerning NOACs. Recently, a systematic review and meta-analysis was carried out with studies assessing individuals receiving OAT with both VKAs and NOACs. However, only TXA and epsilon-aminocaproic acid were evaluated, and the effectiveness of TXA was demonstrated compared to placebo in patients receiving VKAs, but no results are available for individuals receiving NOACs.24 The results of the systematic reviews reported are diverse; one of them indicates greater effectiveness of TXA,25 but the other suggests greater effectiveness of Histoacryl glue.26 Therefore, this systematic review aims to compare the effectiveness of different hemostatic protocols for the prevention of bleeding during oral procedures among individuals receiving OAT (VKAs or NOACs).
What is the effectiveness of hemostatic protocols for the prevention of bleeding during oral procedures among individuals receiving anticoagulation therapy?
This systematic review will consider studies with participants 18 years of age or older who receive OAT such as VKA and NOAC, and who need oral procedures including i) dental procedures, such as dental extractions, periodontal surgeries, or endodontic surgeries; ii) soft-tissue surgery (biopsies); or iii) procedures on bone tissues, such as alveolar bone flange surgeries. Articles evaluating extraoral procedures will be excluded.
Studies in which the effectiveness of hemostatic protocols for the prevention of bleeding, such as TXA, epsilon or local antifibrinolytic solutions, oxidized cellulose, gel foam, resorbable gelatin sponges, collagen sponges or fleeces, fibrin glue, cyanoacrylate glue, platelet-rich plasma gel, topical thrombin, calcium alginate, and mechanical means such as suture, ligating clips, gauze pressure, and vasoconstrictor agents will be evaluated. Studies with insufficient information to determine the effectiveness of the hemostatic protocol assessed will be excluded.
The comparisons presented in the review can be i) patients with OAT and hemostatic intervention versus patients with OAT and without hemostatic intervention or gauze pressure; ii) patients with OAT and hemostatic intervention versus patients with OAT and placebo; iii) patients with OAT and hemostatic intervention versus patients with OAT and another type of hemostatic intervention.
This systematic review will consider studies in which the effectiveness in preventing intraoperative and postoperative bleeding was evaluated as a primary outcome. The secondary outcomes to be assessed in this systematic review will be the adverse effects of hemostatic protocols and the type of anticoagulant therapy to which participants had been submitted.
Types of studies
Randomized controlled clinical trials will be included without restriction on the language or date of publication. Meeting abstracts, literature reviews, expert opinions, and editorials will be excluded.
This systematic review will be conducted in accordance with the JBI methodology for systematic reviews of effectiveness.27 The protocol was registered in PROSPERO: CRD42019136744.
A preliminary search was conducted in PubMed. Text words in the titles/abstracts and keywords of the references retrieved will be used to tailor the search strategy for each electronic database. The search strategy for PubMed is displayed in Appendix I.
Computerized searches will be performed in the following electronic databases: MEDLINE (PubMed, Ovid), Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), LILACS (Latin American and Caribbean Literature in Health Sciences), and Scopus. Unpublished studies will be searched in the ProQuest Dissertations and Theses database and in ClinicalTrials.gov. Searches in Google Scholar and OpenGrey limited to the first 100 hits will also be conducted. The reference lists of the included articles will be screened to identify references that might be missed during the searches in the electronic databases.
The references retrieved in the searches will be uploaded to EndNote Basic (Clarivate Analytics, PA, USA), and duplicates removed. To select the studies, two independent review authors will assess the titles/abstracts of the references retrieved. References whose titles/abstracts meet the eligibility criteria will be included. For the references whose titles/abstracts contain insufficient information for a decision on inclusion or exclusion, the full texts will be retrieved. The same two review authors will evaluate the full texts. References whose full texts meet the eligibility criteria will also be included. Detailed information of the included studies will be imported to the JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; JBI, Adelaide, Australia). The full text of studies that do not fit the eligibility criteria will be excluded. The results of the search will be reported in full in the final systematic review and presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.28 Discrepancies between review authors during study selection will be resolved via a senior researcher.
Assessment of methodological quality
The assessment of the methodological quality of the included studies will be obtained by two review authors and discrepancies will be resolved via a senior researcher. The assessment of the methodological quality will be carried out using the JBI appraisal checklist for randomized controlled trials.27 Each item may be awarded “yes” (low risk of bias), “no” (high risk of bias), or “unclear” (unclear risk of bias).
All included studies will be submitted to data extraction.
Data of the included studies will be extracted using the standardized JBI data extraction tool.27 Data will be extracted by two review authors and any disagreements will be resolved via a senior researcher. These two evaluators will check the data extracted twice to verify accuracy. The following data will be extracted: last name of the first authors and date of publication of the study, country where the study was conducted, number of participants, characteristics of the participants (sex and age), type of anticoagulant used by participants, hemostatic protocols evaluated, outcomes evaluated, and comparisons of the effectiveness of the hemostatic protocols evaluated. In the case of missing data, the authors of the included studies will be contacted for further information.
JBI SUMARI and RevMan v5.3 (Copenhagen, The Nordic Cochrane Centre, Cochrane) will be used. Results of the meta-analysis will be provided in risk ratio for studies with dichotomous data and mean difference for studies with continuous data. Confidence intervals (95%) will also be provided. Statistical heterogeneity of the meta-analysis will also be evaluated by means of the I2 statistic. If the meta-analysis presents high statistical heterogeneity, the random effects model will be used; if the meta-analysis presents low statistical heterogeneity, the fixed effects model will be used.27 For meta-analysis with high statistical heterogeneity, sensitivity analysis will be performed, removing studies one by one, repeating the calculations to check for similar results and determining the possible influence of each study. A funnel plot will be generated: for meta-analysis of continuous outcomes, the assessment of funnel plot asymmetry will be performed with the Egger test; for the meta-analysis of dichotomous outcomes, the Harbord test will be employed for funnel plot asymmetry evaluation.30 The results will be displayed as forest plots. Subgroup analyses will be planned considering the characteristics of participants (according to age and INR), methodological quality, type of interventions, and the outcome measures of the studies. If possible, the authors will perform a meta-regression analysis to compare the effects of the interventions according to the risk of bias. If necessary, the authors will develop the network meta-analysis that allows the identification of the results. A Bayesian structure will be carried out through statistical packages in Software R v3.6.2 (R Core Team). The network description, network graph, evaluation of the convergence, assessment of inconsistencies, and results of the network meta-analysis will be delivered. If data pooling is unfeasible, a narrative synthesis presenting data in tables and figures will be carried out instead.
Assessing certainty in the findings
The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the certainty of evidence will be followed and a Summary of Findings will be created using GRADEpro (McMaster University, ON, Canada).29 For the outcomes assessed, GRADE evaluates the number of studies incorporated into the analysis, studies’ design, risk of bias, inconsistency, indirectness, imprecision, and publication bias. For risk of bias, inconsistency, indirectness, imprecision, and publication bias, the certainty of the evidence may be downgraded one or two levels. Based on this evaluation, the certainty of the evidence for each outcome may be very low, low, moderate, or high.
This study was supported by the Brazilian agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Appendix I: Search strategy
Search conducted October 2019.
1. Ripolles-De Ramon J, Muñoz-Corcuera M, Bravo-Llatas C, Bascones-Martinez A. Aplicacion de un gel de Acido tranexamico en pacientes tratados con anticoagulantes orales [Tranexamic acid gel in patients treated with oral anticoagulants]. Med Clin (Barc)
2014; 143 (11):484–488. Spanish.
2. Bajkin BV, Popovic SL, Selakovic SDJJ. Randomized, prospective trial comparing bridging therapy using low-molecular-weight heparin with maintenance of oral anticoagulation during extraction of teeth. J Oral Maxillofac Surg
2009; 67 (5):990–995.
3. Jiménez Y, Poveda R, Gavaldá C, Margaix M, Sarrión G. An update on the management of anticoagulated patients programmed for dental extractions and surgery. Med Oral Patol Oral Cir Bucal
2008; 1313 (33):176–179.
4. Kämmerer PW, Frerich B, Liese J, Schiegnitz E, Al-Nawas B. Oral surgery during therapy with anticoagulants—a systematic review. Clin Oral Investig
2015; 19 (2):171–180.
5. Eichhorn W, Burkert J, Vorwig O, Blessmann M, Cachovan G, Zeuch J, et al. Bleeding incidence after oral surgery with continued oral anticoagulation. Clin Oral Investig
2012; 16 (5):1371–1376.
6. Boned-ombuena A, Pérez-panadés J, López-maside A. Prevalencia de la anticoagulación oral y calidad de su seguimiento en el ámbito de la atención primaria: estudio de la Red Centinela Sanitaria de la Comunitat Valenciana [Prevalence of oral anticoagulation and quality of its management in primary healthcare: a study by the Health Sentinel Network of the Region of Valencia (Spain)]. Atención Primaria
2017; 49 (9):534–548. Spanish.
7. Rocha AL, Souza AF, Martins MAP, Fraga MG, Travassos DV, Oliveira ACB, et al. Oral surgery in patients under antithrombotic therapy: perioperative bleeding as a significant risk factor for postoperative hemorrhage. Blood Coagul Fibrinolysis
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8. Bartholomay E, Polli I, Borges A, Kalil C, Arroque A, Kohler I, et al. Prevalence of oral anticoagulation in atrial fibrillation. Clinics
2014; 69 (9):615–620.
9. Almiñana-Pastor PJ, Segarra-Vidal M, López-Roldán A, Alpiste-Illueca FM. A controlled clinical study of periodontal health in anticoagulated patients: assessment of bleeding on probing. J Clin Exp Dent
2017; 9 (12):e1431–e1438.
10. Serrano-Sánchez V, Ripollés-de-Ramón J, Collado-Yurrita L, Vaello-Checa I, Colmenero-Ruiz C, Helm A, et al. New horizons in anticoagulation: direct oral anticoagulants and their implications in oral surgery. Med Oral Patol Oral Cir Bucal
2017; 22 (5):e601–e608.
11. Hanken H, Gröbe A, Heiland M, Smeets R, Kluwe L, Wikner J, et al. Postoperative bleeding risk for oral surgery under continued rivaroxaban anticoagulant therapy. Clin Oral Investig
2016; 20 (6):1279–1282.
12. Miclotte I, Vanhaverbeke M, Agbaje JO, Legrand P, Vanassche T, Verhamme P, et al. Pragmatic approach to manage new oral anticoagulants in patients undergoing dental extractions: a prospective case-control study. Clin Oral Investig
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13. Mulligan R, Weitzel KG. Pretreatment management of the patient receiving anticoagulant drugs. J Am Dent Assoc
1988; 117 (3):479–483.
14. Bajkin BV, Selakovic SD, Mirkovic SM, Sarcev IN, Tadic AJ, Milekic BR. Comparison of efficacy of local hemostatic modalities in anticoagulated patients undergoing tooth extractions. Vojnosanit Pregl
2014; 71 (12):1097–1101.
15. Dudek D, Marchionni S, Gabriele M, Iurlaro A, Helewski K, Toti P, et al. Bleeding rate after tooth extraction in patients under oral anticoagulant therapy. J Craniofac Surg
2016; 27 (5):1228–1233.
16. Branislav V, Sanja B, Bojana R, Biljana A. Risk factors for bleeding after oral surgery in patients who continued using oral anticoagulant therapy. JADA
2015; 146 (6):375–381.
17. Febbo A, Cheng A, Stein B, Goss A, Sambrook P. Postoperative bleeding following dental extractions in patients anticoagulated with warfarin. J Oral Maxillofac Surg
2016; 74 (8):1518–1523.
18. Carter G, Goss A, Lloyd J, Tocchetti R. Tranexamic acid mouthwash versus autologous fibrin glue in patients taking warfarin undergoing dental extractions: a randomized prospective clinical study. J Oral Maxillofac Surg
2003; 61 (12):1432–1435.
19. Pippi R, Santoro M, Cafolla A. The effectiveness of a new method using an extra-alveolar hemostatic agent after dental extractions in older patients on oral anticoagulation treatment: an intrapatient study. Oral Surg Oral Med Oral Pathol Oral Radiol
2015; 120 (1):15–21.
20. 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 (6):1149–1154.
21. Nagraj SK, Prashanti E, Aggarwal H, Lingappa A, Muthu MS, Krishanappa SKK, et al. Interventions for treating post-extraction bleeding. Cochrane Database Syst Rev
22. Carter G, Goss A. Tranexamic acid mouthwash–a prospective randomized study of a 2-day regimen vs 5-day regimen to prevent postoperative bleeding in anticoagulated patients requiring dental extractions. Int J Oral Maxillofac Surg
2003; 32 (5):504–507.
23. de Vasconcellos SJ, de A, de Santana Santos T, Reinheimer DM, Faria-e-Silva AL, de Melo M, de FB, Martins-Filho PRS. Topical application of tranexamic acid in anticoagulated patients undergoing minor oral surgery: a systematic review and meta-analysis of randomized clinical trials. J Craniomaxillofac Surg
2017; 45 (1):20–26.
24. Engelen ET, Schutgens RE, Mauser-bunschoten EP, Van Es RJ, Van Galen KP. Antifibrinolytic therapy for preventing oral bleeding in people on anticoagulants undergoing minor oral surgery or dental extractions. Cochrane Database Syst Rev
25. Ockerman A, Miclotte I, Vanhaverbeke M, Verhamme P, Poortmans L-L, Vanassche T, et al. Local haemostatic measures after tooth removal in patients on antithrombotic therapy: a systematic review. Clin Oral Investig
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26. Weltman NJ, Al-Attar Y, Cheung J, Duncan DPB, Katchky A, Azarpazhooh A, et al. Management of dental extractions in patients taking warfarin as anticoagulant treatment: a systematic review. J Can Dent Assoc
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30. Higgins J, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration. 2011 [cited 2019 Sep 5]. Available from: https://training.cochrane.org/handbook/current