The Effect of Direct Oral Anticoagulant Therapy (DOACs) On Oral Surgical Procedures: A Systematic Review

The Effect of Direct Oral Anticoagulant Therapy (DOACs) On Oral Surgical Procedures: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Effect of Direct Oral Anticoagulant Therapy (DOACs) On Oral Surgical Procedures: A Systematic Review Ghassan Darwish This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2343060/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Oct, 2023 Read the published version in BMC Oral Health → Version 1 posted 13 You are reading this latest preprint version Abstract Purpose : Direct oral anticoagulants (DOACs) were developed to overcome the drawbacks of oral anticoagulants. However, not much has been discussed on the perioperative management of patients on DOACs during oral surgical procedures. Thus, we aim to determine the risk of perioperative and postoperative bleeding during oral surgical procedures in patients on DOACs. Methodology : A detailed literature search was performed to find potentially relevant studies using Cochrane Library, Clinical Key, ClinicalTrials.gov, Google Scholar, Ovid, ScienceDirect, and Scopus. Every article available for free in the English literature for the past 5 years, between 2018 -2022 was searched. Results : A total of 1091 abstracts were selected through search strategy across various search engines. Based on inclusion and exclusion criteria, eight clinical studies using DOACs as anticoagulants or studies comparing patients with and without DOACs under oral surgery procedures were found. The results were inconsistent and varied with few studies recommending DOACs administration with bare minimum reported complications and remaining finding no statistically significant difference between discontinuation or continuation of drugs, especially across basic dental procedures. Conclusion : Within the limitation of the study, it can be concluded that minor oral surgical procedures are safe to perform in patients on DOAC therapy. However, the continuation or discontinuation of DOACs in patients undergoing oral surgical procedures remains controversial and requires further studies to extrapolate the results. Direct oral anticoagulants Dental extraction Oral surgery Figures Figure 1 Introduction The use of anticoagulants has become the prevalent form of treatment in contemporary medicine. They are commonly recommended to lower the thromboembolism risk in subjects with a history of angina, atherosclerosis, atrial fibrillation, cerebrovascular accidents, deep vein thrombosis, peripheral artery disease, ischemic heart disease, myocardial infarction, and pulmonary embolism, thereby preventing the incidence of life-threatening events. Therapeutic anticoagulants are also prescribed in patients after angioplasty, stent placement, bypass surgery, and prosthetic heart valve placement to prevent thrombotic event. [ 1 , 2 , 3 , 4 ] Oral anticoagulants mainly include heparin, warfarin, and direct or new oral anticoagulants (DOACs/NOACs). Heparin is administered intravenously. It mainly acts by interfering with the thrombin-antithrombin pathways, reducing fibrin formation. It has a short shelf life. [ 5 ] Whereas warfarin, the 4-hydroxycoumarin derivative is administered orally. It is widely used as the standard drug for oral anticoagulant therapy (OAT). [ 2 ] It acts by inhibiting the function of vitamin K-dependent clotting factors such as II, VII, IX, X, and proteins C and S. The major drawback of oral anticoagulant therapy is the higher risk of hemorrhage after injuries or any surgical procedure. [ 6 ] In addition to this, OATs are commonly prescribed to elder patients who are more susceptible to dental diseases such as dental caries, periodontitis, or pericoronitis. [ 6 ] Such patients may be required to undergo oral surgical procedures such as dental extractions (surgical or non-surgical), periodontal surgeries, alveoloplasty, dental implant surgery, and other pre-prosthetic surgeries for oral rehabilitation. Due to the risk of increased postoperative bleeding in patients on anticoagulant therapy, performing surgical procedures in such patients becomes a major concern for a dentist. [ 7 ] Besides, a complication such as oral hematoma formation is common which can lead to postoperative trismus or may obstruct the upper airway. According to a study by Bump et al, fear of hemorrhages may elevate the stress levels in cardiac patients which may in turn induce a fibrinolytic activity. [ 8 ] To limit the risk of peri- and post-operative bleeding associated with OAT, discontinuing the anticoagulant treatment 2–3 days before oral surgical procedures is recommended. [ 9 , 10 ] However, discontinuing OAT for short time may not be sufficient to stop perioperative complications and can also increase the thromboembolic risk. [ 2 , 6 , 11 ] Several researches have reported episodes of thromboembolic events when warfarin was interrupted before an oral surgical procedure. [ 12 , 13 , 14 ] Another study by Garcia et al reported an increased risk of thromboembolism by 0.7% and an increased risk of bleeding by 1.7% within 30-days of the follow-up period with short-term discontinuation of oral anticoagulants. [ 15 ] In recent years DOACs were first developed to overcome the drawbacks of oral anticoagulants. Among Xa inhibitors, Rivaroxaban is a drug that is taken once daily in different doses of 10mg, 15mg, or 20mg. It acts rapidly within 2.5-4 hours and has a shelf life of 5–9 hours. [ 16 ] They mainly act by inhibiting the Xa activity of the prothrombinase complex. Another category of a drug such as dabigatran act by inhibiting the action of factor IIa in the coagulation pathway. [ 5 , 7 , 17 ] It is recommended twice daily in 110mg or 150 mg doses. It quickly acts with 0.5-4hours and has a shelf life of 12–15 hours. [ 16 ] DOACs are known to have fewer drug-to-drug or drug-food interactions. They have shorter half-lives and a wide range of therapeutic window that improves their safety. DOACs are more predictable compared to warfarin due to their simplified pharmacodynamics. They are more convenient to use as they do not require periodic monitoring and are prescribed in fixed doses. [ 18 , 19 , 20 ] Besides, DOACs have gained popularity among cardiologists as the drug of choice to prevent stroke and thromboembolism. [ 21 , 22 ] Shah et al in their study reported a significant reduction in the number of transient ischemic attacks and systemic emboli events with rivaroxaban compared to warfarin. [ 23 ] In another study by Costantinides et al, 1.6% of the risk of bleeding was observed in apixaban compared to 1.9% with warfarin during dental extractions, colonoscopy, and ophthalmologic surgery. [ 24 ] Although guidelines on the management of patients on OATs during oral surgical procedures are well described in the literature. But not much has been discussed on the perioperative management of patients on DOACs during oral surgical procedures. Through this systematic review, we aim to de determine the risk of perioperative and postoperative bleeding during oral surgical procedures in patients on DOACs. We also aim to assist dental professionals in making an informed clinical decision about continuing or discontinuing the DOACs before any oral surgical procedures. Materials And Methods This systematic review was developed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement as shown in Figure 1. The Patient, Intervention, Comparison, and Outcome (PICO) format was used to find the focused primary question; which was “To determine the risk of perioperative and postoperative bleeding during oral surgical procedures in patients on DOACs.” A detailed electronic literature search was performed to find potentially relevant studies using Cochrane Library, Clinical Key, ClinicalTrials.gov, Google Scholar, Ovid, ScienceDirect, and Scopus. Combined MeSH and free text search terms aimed to identify all anticoagulant agents, including synonyms, related terms and variants, parenteral agents, “Direct oral anticoagulants”, “Oral surgery”, “dental extraction”, “dental implants” using PubMed and PubMed Central. Every article available for free in the English literature for the past 5 years, between 2018 -2022 was searched. Additionally, all related articles were also scanned. Efforts were made to identify unpublished studies, especially the ones identified only in abstracts, but were not able to reach authors as all details were not available. Inclusion criteria : All prospective, retrospective, cohort, and RCTs (Randomized control trials) or studies comparing the patients on DOACs with patients without any anticoagulants that underwent oral surgical procedures such as extraction, periodontal surgery, dental implants surgery, pre-prosthetic surgeries, or alveoloplasties were included in our study. Studies identified for inclusion from the previous systematic review were reviewed and considered for inclusion in the data synthesis Exclusion criteria : Case reports and reviews of the literature were excluded from our study. Study selection criteria : The outcome parameters on which we focused mainly were preoperative and post-operative bleeding, local hemostasis, delayed bleeding due to DOACs, its discontinuation during the procedure, and comparison with patients without anticoagulants. Based on our inclusion and exclusion criteria, all the titles and abstracts of the articles searched were scrutinized based on their relevance and eligibility for inclusion. Full texts were reviewed according to the inclusion criteria and articles were finally selected for systematic review. Independent screening and review of titles and abstracts for inclusion eligibility were conducted by 2 reviewers. One reviewer independently extracted data for review by the second reviewer, who verified the information, with discrepancies resolved by discussion. Outcome measures: The main outcome was the frequency of postoperative bleeding, defined as any kind of bleeding occurring immediately after surgical procedures or up to 7 days after surgery. The primary independent variable was the type of anticoagulants taken by the patients; the secondary independent variable was the postoperative bleeding event. Quality assessment: For the clinical studies, Newcastle-Ottawa Scale (NOS) was used to assess the quality of nonrandomized studies as shown in Table 2 and 3. [25] Results Systematic review Initially, a total of 1091 abstracts were selected through search strategy across various search engines. They were screened and reviewed for the selected in- and exclusion criteria. Eight clinical studies using DOACs as anticoagulants or studiescomparing patients with and without DOACs under oral surgery procedures were found. (Table 1). Due to the heterogeneity of the key parameters, aggregation of statistical data was not possible. Therefore, not a meta-analysis but a descriptive analysis of obtained studies was conducted. Study design Around eight articles have been included in this review with all studies being in English. Majority studies are retrospective cohort study (five) [26,27,28,29,30] with remaining one being retrospective clinical study [31] and two being case control. [32,33] The studies are published in last five years. Around four studies have been published in 2018 [26,27,28,32] with remaining two in 2020 [29,31] and another two in 2022. [30,33] Study characteristics The patient sample ranged from 12 to 120 with a mean of 69 across total eight studies. The patient population consisted of 215 males and 168 females across six studies. The mean age across all the studies was 67.78 ranging from 20 to 91 years. Rivaroxaban was the most frequently used anticoagulant DOAC type (33%, n = 183) across majority of the studies followed by Dabigatran and Apixaban. The studies were majorly retrospective cohort studies with two studies case-control. (For details, refer to Table 1) Oral surgical procedures Most of the obtained studies were principally focused on tooth extraction especially across four studies. Therefore, generalization of all data to the whole field of oral surgery is difficult. However, there were other reports on more extended oral surgical procedures such as varied procedures like alveolplasties, tuberosity reduction, high bleeding risks surgeries, implant surgeries, bone grafting, maxillary sinus floor elevation etc. (for details, see Table 1). DOACs The type of DOACs used across different patients were Apixaban, Dabigatran, Rivaroxaban, Edoxaban as illustrated in table 1. DOACs were majorly continued across studies prior to dental procedures as shown in table 1. In case of discontinuation of DOACs prior to dental procedures across varied studies, the time period of discontinuation ranged from 1- 3 days. Test and control groups Two studies were case control among total eight studies. Dabigatran was the DOAC drug of choice across one study with 29 cases administered with the drug and 42 without any DOACs. Rivaroxaban and Apixaban were the drugs of choice across second study with 37 patients administered and 40 being control group. Post-Operative Scenario The post-operative measures across varied studies with different surgical procedures included compression, haemostatic agent application (Majorly tranexamic acid) along with sutures. The patients were majorly followed up after three days or a week across the studies. The complications varied from post-operative immediate bleeding, delayed bleeding, swelling, major clots etc. across studies. (For details see table 1) Follow-up Time There was a broad variety in follow-up appointments and regimens. Whereas some authors instructed their patients to contact them post 7th postoperative day, others conducted frequent clinical follow-up examinations after 1 day followed by clinical examination on 3 rd day, 7 th day, 14 th day and after a month. No follow up was reported across two studies. Analysis of General Outcome parameters Post-operative bleeding events In six publications, data about postoperative local bleedings were reported. Inconsistency was reported in postoperative bleeding across all eight studies. Among case control studies, both studies reported non stoppage of DOACs during dental implant surgery and maxillary sinus elevation procedures. [32.33] They inferred safe administration of implant surgery and maxillary sinus floor augmentation procedures in patients taking DOACs with bare-minimum postoperative bleeding. Across the remaining six retrospective studies, 2 studies exhibited no episodes of post-operative bleeding. [26,29] Whereas 5 studies exhibited bare minimum post-operative bleeding recommending continuation of DOACs during dental procedures. [27,30,31,32,33] The post-operative bleeding incidence was pronounced only in cases of comorbidities or complex surgical procedures. [28] Delayed bleeding episodes Four studies reported no delayed bleeding. [27,29,30,33] The incidence of delayed bleeding was minimal with frequency exhibited after 2-7 days or across patients with comorbidities. DOAC vs interruption of DOACs The results were inconsistent and varied with few studies recommending DOACs administration with bare minimum reported complications and remaining finding no statistically significant difference between discontinuation or continuation of drugs especially across basic dental procedures. The reported complication of post-operative bleeding was associated with co-morbidities or in case of complex dental treatments like implant placement. Discussion Several studies have proposed recommendations for managing patients on DOACs during minor oral surgical procedures. However, inconsistencies in the guidelines have led to unnecessary discontinuity of DOACs, even in patients with a higher risk of thromboembolism. Thus, the present systematic review aims to evaluate the risk of perioperative and postoperative bleeding during minor oral surgical procedures in patients on DOACs and assist the dental professional in making an informed decision on the continuity or discontinuity of DOACs before oral surgery. The present study included six clinical studies that utilized DOACs as anticoagulant therapy [ 26 , 27 , 28 , 29 , 30 , 31 ] and two studies that compared patients on DOACs with patients without anticoagulants (control) during minor oral surgical procedures. [ 32 , 33 ] Of eight studies, five were retrospective cohort studies, one was a retrospective clinical study, and other two were case-control studies. The mean age across all studies was 67.78. Krammer et al., in their systematic review, referred to the term "minor oral surgery" to a variety of surgical procedures such as single tooth or multiple teeth extractions, dental implants, and maxillary sinus floor augmentation, the elevation of mucoperiosteal flaps, alveoloplasties, limited oral soft tissue surgeries, and complicated osteotomies. Therefore, our review included studies with similar minor oral surgical procedures based on Krammer's criteria. [ 6 ] This systematic review showed that Rivaroxaban was the most commonly used DOAC (33%, n = 183), followed by Dabigatran and Apixaban during oral surgical procedures. Among eight studies, three by Cocero et al., Gomez-Moreno et al., and Cappare et al. continued the DOAC therapy in patients undergoing oral surgical procedures. [ 27 , 32 , 33 ] On the contrary, five studies by Miller et al., Kwak et al., Kim et al., Galleti et al., and Woolcombe et al. continued the DOACs therapy in some patients and discontinued the therapy in others for a period varying from 12–120 hours before the oral surgery. [ 26 , 28 , 29 , 31 , 30 ] Miller et al. and Kim et al observed no evidence of postoperative bleeding in their studies. [ 26 , 29 ] Meanwhile, Cocero et al., Gomez-Moreno et al., Cappare et al., Kwak et al., Galleti et al., and Woolcombe et al. reported a few patients with postoperative bleeding. [ 27 , 28 , 31 , 30 , 32 ] However, the incidence of bleeding was also reported in control (individuals without DOACs therapy) groups as mentioned in studies by Gomez-Moreno et al. and Cappare et al. [ 32 , 33 ] This suggests the invasiveness of dental procedures may also have a role in the risk of bleeding. According to a study published by Campbell et al., procedures that involve periosteal incisions may increase the risk of postoperative bleeding. [ 34 ] On the contrary, a study by Clemm et al. demonstrated that the procedure's invasiveness had no significant impact on the postoperative bleeding risk. [ 35 ] According to current Scottish Dental Clinical Effectiveness Programme (SDCEP) guidelines, patients undergoing invasive dental procedures such as extraction of 1–3 teeth or incision and drainage with a low risk of bleeding should continue their DOAC regime. [ 36 ] Conversely, dental procedures associated with a high risk of bleeding, such as multiple teeth extractions, flap raising procedures, biopsies, and gingival re-contouring, should miss or delay their morning DOAC dose on the day of treatment to reduce the high risk of bleeding. Besides, dentists prefer to undertake the procedure when peak DOAC concentrations have subsided, i.e., 4–6 hours after the last dose. Among the studies that reported postoperative bleeding, the study by Cocero et al. involved 100 patients on DOACs (Dabigatran, Apixaban, and Rivaroxaban) who underwent tooth extractions. DOAC therapy continued in these patients. Of the 100 patients, 36 patients without any comorbidities reported no bleeding. [ 27 ] Whereas among the remaining 64 patients with comorbidities, one reported moderate bleeding, and three reported mild delayed bleeding. Delayed bleeding was attributed to the intake of one or two doses of DOACs. The authors concluded that postoperative bleeding was mainly observed in patients with comorbidities and patients that underwent extraction of multiple adjoining multi-rooted teeth. Another study by Moreno et al included 71 patients for dental implant placement. Of 71 patients, 29 were on DOACs therapy (Dabigatran test group), and 42 were healthy subjects (control group). [ 32 ] The DOACs therapy was not interrupted during the treatment. This study reported two patients in each group with postoperative bleeding. Cappare et al. conducted a study on 77 patients involving maxillary sinus elevation procedures. [ 33 ] Among 77 patients, 37 patients on DOACs therapy (Rivaroxaban/Apixaban) were included as the test group, and the remaining 40 were healthy subjects (control group). The authors continued the DOAC therapy in the test group during the procedure. Authors reported four patients in the test group and three patients in the control group with postoperative bleeding. In addition, a single case of delayed bleeding was also evident in the test group. Postoperative bleeding was easily managed using local measures. Both Moreno et al. and Cappare et al. concluded that no statistically significant difference in postoperative bleeding was evident in each group. [ 32 , 33 ] Kwak et al. conducted a study in 120 patients (153 cases) on DOAC therapy (Dabigatran, Rivaroxaban, Apixaban, Edoxaban) that included performing both high bleeding risk (e.g., scaling, curettage, extraction, and implant surgery) and low bleeding risk (e.g., impression taking, root canal treatment, crown preparation, and resin filling) dental procedures. [ 28 ] Of 153 cases performed, DOAC therapy was discontinued in 103 cases and continued in 50. Postoperative bleeding was reported in nine cases (2 scaling, three simple extractions, three-implant surgery, and one resin filling) which were mainly categorized as high bleeding-risk dental procedures. Thus, authors recommended at least 24 hours of discontinuation of DOAC therapy in patients undergoing high bleeding risk procedures especially implant surgeries. The incidence of postoperative bleeding in this study was reported to be 5.8% (9 of 153 cases) which was lower than the rate reported by Mauprivez et al. and Levy et al., who reported ~ 16% postoperative bleeding. In another study by Galleti et al., 12 patients on DOACs (Rivaroxaban) underwent dental implant and prosthetic rehabilitation procedures. [ 31 ] Patients were asked to interrupt their daily dose of Rivaroxaban 1 day before the treatment. Of 12 patients, three (25%) reported minor bleeding after the procedure, which was managed using local hemostatic measures. The study concluded that multiple implant placements could be performed without significant bleeding complications with the discontinuation of DOACs before the surgery. Lastly, a study by Woolcombe et al. conducted a study that included 98 patients on DOAC therapy (Rivaroxaban, Apixaban, Edoxaban, dabigatran) that underwent 119 dentoalveolar procedures in adherence with the Scottish Dental Clinical Effectiveness Programme (SDCEP) guidance. Postoperative bleeding was observed in 17 (14.3%) procedures. [ 30 ] Of 17 procedures, 5 (4.2%) reported minor postoperative bleeding, 1 (0.8%) required consultation in the oral surgery unit, and 11 (9.2%) procedures required the use of re-suturing and hemostatic packing and topical use of an antifibrinolytic agent to arrest the bleeding. Bleeding in 11 patients (11 procedures) was attributed to the unsuitability of six patients in applying the specific SDCEP instructions; four patients had heart failure, which was not reported in the medical history, and the rest of the patients reported comorbidities (liver disease and kidney disease) and simultaneous intake of Clopidogrel. Although the study by Kim et al. did not experience any postoperative bleeding. [ 29 ] However, blood clots were reported in 3 patients, and delayed bleeding was reported in 1 patient. Three of four patients were asked to discontinue the DOAC therapy before surgery. Since all four complications were self-limiting, no intervention was required. In addition, four patients in the study by Galleti et al. experienced post-surgery swelling, which was manageable and subsided over time. [ 31 ] Overall, no significant complications were reported in patients on DOAC therapy that underwent minor oral surgical procedures. In some cases, postoperative bleeding was trivial and did not require any intervention. [ 30 ] Some studies required local hemostatic measures such as mechanical compression using gauze pads, additional sutures, tranexamic acid wraps, or other local hemostatic agents to arrest bleeding. [ 27 , 32 , 33 , 28 , 30 , 31 ] However, none of the studies' patients required any hospitalization for systemic administration of antifibrinolytics or replacement therapy. Although SDCEP guidelines recommend delaying or missing the DOAC dose in procedures with a high risk of bleeding, studies by Cocerno et al., Moreno et al., and Cappare et al. continued DOAC therapy in patients undergoing high bleeding risk procedures such as extractions, implant surgery, and maxillary sinus elevation procedures respectively, and reported bare minimum evidence of postoperative bleeding. [ 28 , 32 , 33 ] Nevertheless, a sufficient gap was maintained between the last dose of DOAC and the dental procedure to minimize the risk of postoperative bleeding. In the present systematic review, data on the continuation or discontinuation of DOACs before dental treatment remains controversial, some authors suggested continuing DOAC therapy in low-bleeding risk procedures, some preferred discontinuation of DOAC therapy at least one day before the surgery, and others performed the oral surgical procedures 4–6 hours after the last dose of DOACs. Irrespective of the controversy, our systematic review demonstrated that minor oral surgical procedures are safe for postoperative bleeding in patients with DOAC therapy. However, dentists should decide on patients' continuity or discontinuity of the DOAC therapy based on the severity of the dental procedures performed, the risk of thromboembolism, and the presence of comorbidities in the patient. The results of our study were comparable to the literature review by Lanau et al., who evaluated the potential bleeding risk of DOACs and concluded that these drugs are safe to use while undergoing dental treatment. [ 37 ] However, the results of our study needed to be aligned with the results of systematic and metanalysis by Bensi et al. [ 17 ] They concluded that DOACs have three times higher risk of postoperative bleeding after oral surgical procedures than anticoagulants such as warfarin or enoxaparin. There are a few limitations to our study. For instance, only a limited number of studies fulfilled the inclusion criteria, and none included were randomized controlled trials. Since only a few studies were included in this review to evaluate the outcomes, the results of our study cannot be considered conclusive. Further, randomized controlled clinical trials are required to extrapolate the results. Future directions involve the development of inexpensive antidotes that can be effective in cases of extensive bleeding. Conclusion Within the limitation of the study, it can be concluded that minor oral surgical procedures are safe to perform in patients on DOAC therapy. In addition, the possible postoperative bleeding can be easily managed using local measures. However, the continuation or discontinuation of DOACs in patients undergoing oral surgical procedures remains controversial and requires further studies to extrapolate the results. Declarations Ethics approval and consent to participate: Not applicable Consent for publication: Not applicable. Availability of data and material: All data generated or analysed during this study are included in the supplementary information file. Competing interests: Declare no competing interests. Funding: No funding. Authors' contributions: The author GD collected and analyzed the data, wrote the manuscript, revised and edited. Acknowledgements: Not applicable. Authors' information: GD is Assistant Professor & Consultant at Department of Oral and Maxillofacial Surgery, Pain Control & Anesthesia Course Director, Dental Admission & Registration Director at Faculty of Dentistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. References De Caterina R. The current role of anticoagulants in cardiovascular medicine. J Cardiovasc Med (Hagerstown). 2009 Aug;10(8):595–604. Madrid C, Sanz M. What influence do anticoagulants have on oral implant therapy? A systematic review. Clin Oral Implants Res. 2009;20(Suppl 4):96–106. Bajkin BV, Vujkov SB, Milekic BR, Vuckovic BA. Risk factors for bleeding after oral surgery in patients who continued using oral anticoagulant therapy. J Am Dent Assoc. 2015;146(6):375–81. Cannon PD, Dharmar VT. Minor oral surgical procedures in patients on oral anticoagulants–a controlled study. Aust Dent J. 2003;48(2):115–8. 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Implant Placement in Patients under Treatment with Rivaroxaban: A Retrospective Clinical Study. Int J Environ Res Public Health. 2020;17(12):4607. Published 2020 Jun 26. Gómez-Moreno G, Fernández-Cejas E, Aguilar-Salvatierra A, de Carlos F, Delgado-Ruiz RA, Calvo-Guirado JL. Dental implant surgery in patients in treatment by dabigatran. Clin Oral Implants Res. 2018;29(6):644–8. Capparè P, Tetè G, Alfieri O, Pantaleo G, Montemezzi P. Postoperative Bleeding in Patients Under Direct Oral Anticoagulation After Maxillary Sinus Floor Augmentation: A Case-Control Study. Int J Oral Maxillofac Implants. 2022;37(2):365–72. Campbell JH, Alvarado F, Murray RA. Anticoagulation and minor oral surgery: should the anticoagulation regimen be altered? J Oral Maxillofac Surg. 2000;58(2):131–6. Clemm R, Neukam FW, Rusche B, Bauersachs A, Musazada S, Schmitt CM. Management of anticoagulated patients in implant therapy: a clinical comparative study. Clin Oral Implants Res. 2016;27(10):1274–82. Scottish Dental Clinical Effectiveness Programme. Management of Dental Patients Taking Anticoagulants or Antiplatelet Drugs. 2015. Available online at http://www.sdcep.org.uk/wp-content/uploads/2015/09/SDCEP-Anticoagulants-Quick-Reference-Guide.pdf (accessed March 2017). Lanau N, Mareque J, Giner L, Zabalza M. Direct oral anticoagulants and its implications in dentistry. A review of literature. J Clin Exp Dent. 2017;9(11):e1346–54. Published 2017 Nov 1. Tables Table 1 is available in the Supplementary Files section Table 2: Newcastle Ottawa Bias Assessment for Case-control studies Selection Comparability Outcome Authors & Year Is the study Definition Adequate? (1) Representativeness of the cases (1) Selection of Controls (1) Definition of Controls (1) Comparability of samples and controls (2) Assessment of exposure (1) Same method of ascertainment for all samples (1) No response rate (1) Total quality score (9) Gomez-moreno et al 2018 1 1 1 1 2 1 1 1 9 Cappare et al 2022 1 1 1 1 2 1 1 1 9 Table 3: Newcastle Ottawa Bias Assessment for Cohort studies Selection Comparability Outcomes Authors & year Representativeness of the exposed cohort (1) Selection of the non-exposed cohort (1) Ascertainment of exposure (1) Demonstration that outcome of interest was not present at start of study (1) Study controls for age and gender (or analysis separated by gender) (2) Assessment of outcome (self-harm or suicidality) (1) Was follow-up long enough for outcomes to occur? (1) Adequacy of follow up of cohorts (1) Total quality score Miller et al 2018 1 1 1 1 2 1 1 1 9 Cocero N et al 2018 1 1 1 1 2 1 1 1 9 Kwak et al 2018 1 1 1 1 2 1 1 1 9 Kim et al 2020 1 1 1 1 2 1 1 1 9 Galleti et al 2020 1 1 1 1 2 1 1 1 9 Woolcombe et al 2022 1 1 1 1 2 1 1 1 9 Additional Declarations No competing interests reported. Supplementary Files Supplementaryfile1.docx Table1.docx Cite Share Download PDF Status: Published Journal Publication published 11 Oct, 2023 Read the published version in BMC Oral Health → Version 1 posted Editorial decision: Major revision 18 Apr, 2023 Reviews received at journal 09 Apr, 2023 Reviewers agreed at journal 31 Mar, 2023 Reviews received at journal 20 Mar, 2023 Reviewers agreed at journal 20 Mar, 2023 Reviews received at journal 02 Mar, 2023 Reviewers agreed at journal 23 Feb, 2023 Reviewers agreed at journal 17 Feb, 2023 Reviewers invited by journal 16 Feb, 2023 Editor assigned by journal 16 Feb, 2023 Editor invited by journal 18 Jan, 2023 Submission checks completed at journal 18 Jan, 2023 First submitted to journal 04 Dec, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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They are commonly recommended to lower the thromboembolism risk in subjects with a history of angina, atherosclerosis, atrial fibrillation, cerebrovascular accidents, deep vein thrombosis, peripheral artery disease, ischemic heart disease, myocardial infarction, and pulmonary embolism, thereby preventing the incidence of life-threatening events. Therapeutic anticoagulants are also prescribed in patients after angioplasty, stent placement, bypass surgery, and prosthetic heart valve placement to prevent thrombotic event. \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOral anticoagulants mainly include heparin, warfarin, and direct or new oral anticoagulants (DOACs/NOACs). Heparin is administered intravenously. It mainly acts by interfering with the thrombin-antithrombin pathways, reducing fibrin formation. It has a short shelf life.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e Whereas warfarin, the 4-hydroxycoumarin derivative is administered orally. It is widely used as the standard drug for oral anticoagulant therapy (OAT).\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e It acts by inhibiting the function of vitamin K-dependent clotting factors such as II, VII, IX, X, and proteins C and S. The major drawback of oral anticoagulant therapy is the higher risk of hemorrhage after injuries or any surgical procedure.\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e In addition to this, OATs are commonly prescribed to elder patients who are more susceptible to dental diseases such as dental caries, periodontitis, or pericoronitis.\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e Such patients may be required to undergo oral surgical procedures such as dental extractions (surgical or non-surgical), periodontal surgeries, alveoloplasty, dental implant surgery, and other pre-prosthetic surgeries for oral rehabilitation. Due to the risk of increased postoperative bleeding in patients on anticoagulant therapy, performing surgical procedures in such patients becomes a major concern for a dentist.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e Besides, a complication such as oral hematoma formation is common which can lead to postoperative trismus or may obstruct the upper airway. According to a study by Bump et al, fear of hemorrhages may elevate the stress levels in cardiac patients which may in turn induce a fibrinolytic activity.\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTo limit the risk of peri- and post-operative bleeding associated with OAT, discontinuing the anticoagulant treatment 2\u0026ndash;3 days before oral surgical procedures is recommended. \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e However, discontinuing OAT for short time may not be sufficient to stop perioperative complications and can also increase the thromboembolic risk. \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e Several researches have reported episodes of thromboembolic events when warfarin was interrupted before an oral surgical procedure. \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e Another study by Garcia et al reported an increased risk of thromboembolism by 0.7% and an increased risk of bleeding by 1.7% within 30-days of the follow-up period with short-term discontinuation of oral anticoagulants.\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn recent years DOACs were first developed to overcome the drawbacks of oral anticoagulants. Among Xa inhibitors, Rivaroxaban is a drug that is taken once daily in different doses of 10mg, 15mg, or 20mg. It acts rapidly within 2.5-4 hours and has a shelf life of 5\u0026ndash;9 hours.\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e They mainly act by inhibiting the Xa activity of the prothrombinase complex. Another category of a drug such as dabigatran act by inhibiting the action of factor IIa in the coagulation pathway. \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e It is recommended twice daily in 110mg or 150 mg doses. It quickly acts with 0.5-4hours and has a shelf life of 12\u0026ndash;15 hours.\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e DOACs are known to have fewer drug-to-drug or drug-food interactions. They have shorter half-lives and a wide range of therapeutic window that improves their safety. DOACs are more predictable compared to warfarin due to their simplified pharmacodynamics. They are more convenient to use as they do not require periodic monitoring and are prescribed in fixed doses. \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e Besides, DOACs have gained popularity among cardiologists as the drug of choice to prevent stroke and thromboembolism. \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e Shah et al in their study reported a significant reduction in the number of transient ischemic attacks and systemic emboli events with rivaroxaban compared to warfarin.\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e In another study by Costantinides et al, 1.6% of the risk of bleeding was observed in apixaban compared to 1.9% with warfarin during dental extractions, colonoscopy, and ophthalmologic surgery.\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e Although guidelines on the management of patients on OATs during oral surgical procedures are well described in the literature. But not much has been discussed on the perioperative management of patients on DOACs during oral surgical procedures. Through this systematic review, we aim to de determine the risk of perioperative and postoperative bleeding during oral surgical procedures in patients on DOACs. We also aim to assist dental professionals in making an informed clinical decision about continuing or discontinuing the DOACs before any oral surgical procedures.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eThis systematic review was developed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement as shown in Figure 1. The Patient, Intervention, Comparison, and Outcome (PICO) format was used to find the focused primary question; which was \u0026ldquo;To determine the risk of perioperative and postoperative bleeding during oral surgical procedures in patients on DOACs.\u0026rdquo;\u003c/p\u003e\n\u003cp\u003eA detailed electronic literature search was performed to find potentially relevant studies using Cochrane Library, Clinical Key, ClinicalTrials.gov, Google Scholar, Ovid, ScienceDirect, and Scopus. Combined MeSH and free text search terms aimed to identify all anticoagulant agents, including synonyms, related terms and variants, parenteral agents, \u0026ldquo;Direct oral anticoagulants\u0026rdquo;, \u0026ldquo;Oral surgery\u0026rdquo;, \u0026ldquo;dental extraction\u0026rdquo;, \u0026ldquo;dental implants\u0026rdquo; using PubMed and PubMed Central. Every article available for free in the English literature for the past 5 years, between 2018 -2022 was searched.\u0026nbsp;Additionally, all related articles were also scanned.\u0026nbsp;Efforts were made to identify unpublished studies, especially the ones identified only in abstracts, but were not able to reach authors as all details were not available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e: All prospective, retrospective, cohort, and RCTs (Randomized control trials) or studies comparing the patients on DOACs with patients without any anticoagulants that underwent oral surgical procedures such as extraction, periodontal surgery, dental implants surgery, pre-prosthetic surgeries, or alveoloplasties were included in our study. Studies identified for inclusion from the previous systematic review were reviewed and considered for inclusion in the data synthesis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e: Case reports and reviews of the literature were excluded from our study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy selection criteria\u003c/strong\u003e: The outcome parameters on which we focused mainly were preoperative and post-operative bleeding, local hemostasis, delayed bleeding due to DOACs, its discontinuation during the procedure, and comparison with patients without anticoagulants. Based on our inclusion and exclusion criteria, all the titles and abstracts of the articles searched were\u0026nbsp;scrutinized based on their relevance and eligibility for inclusion. Full texts were reviewed according to the inclusion criteria and articles were finally selected for systematic review. Independent screening and review of titles and abstracts for inclusion eligibility were conducted by 2 reviewers. One reviewer independently extracted data for review by the second reviewer, who verified the information, with discrepancies resolved by discussion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures:\u003c/strong\u003e The main outcome was the frequency of postoperative bleeding, defined as any kind of bleeding occurring immediately after surgical procedures or up to 7 days after surgery. The primary independent variable was the type of anticoagulants taken by the patients; the secondary independent variable was the postoperative bleeding event.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality assessment:\u003c/strong\u003e For the clinical studies, Newcastle-Ottawa Scale (NOS) was used to assess the quality of nonrandomized studies as shown in Table 2 and 3.\u003csup\u003e[25]\u003c/sup\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSystematic review\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInitially, a total of 1091 abstracts were selected through search strategy across various search engines. They were screened and reviewed for the selected in- and exclusion criteria. Eight clinical studies\u0026nbsp;using DOACs as anticoagulants or studiescomparing patients with and without DOACs under oral surgery procedures were found.\u0026nbsp;(Table 1). Due to the heterogeneity of the key parameters, aggregation of statistical data was not possible. Therefore, not a meta-analysis but a descriptive analysis of obtained studies was conducted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAround eight articles have been included in this review with all studies being in English. Majority studies are retrospective cohort study (five) \u003csup\u003e[26,27,28,29,30]\u003c/sup\u003e with remaining one being retrospective clinical study\u003csup\u003e\u0026nbsp;[31]\u003c/sup\u003e and two being case control. \u003csup\u003e[32,33]\u003c/sup\u003e The studies are published in last five years. Around four studies have been published in 2018\u003csup\u003e[26,27,28,32]\u003c/sup\u003e with remaining two in 2020\u003csup\u003e[29,31]\u003c/sup\u003e and another two in 2022.\u003csup\u003e\u0026nbsp;[30,33]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient sample ranged from 12 to 120 with a mean of 69 across total eight studies. The patient population consisted of 215 males and 168 females across six studies. The mean age across all the studies was 67.78 ranging from 20\u0026nbsp;to 91\u0026nbsp;years.\u0026nbsp;Rivaroxaban was the most frequently used anticoagulant DOAC type (33%, n = 183) across majority of the studies followed by Dabigatran and Apixaban. The studies were majorly retrospective cohort studies with two studies case-control. (For details, refer to Table 1)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOral surgical procedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMost of the obtained studies were principally focused on tooth extraction especially across four studies. Therefore, generalization of all data to the whole field of oral surgery is difficult. However, there were other reports on more extended oral surgical procedures such as varied procedures like alveolplasties, tuberosity reduction, high bleeding risks surgeries, implant surgeries, bone grafting, maxillary sinus floor elevation etc. (for details, see Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDOACs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe type of DOACs used across different patients were Apixaban, Dabigatran, Rivaroxaban, Edoxaban as illustrated in table 1. DOACs were majorly continued across studies prior to dental procedures as shown in table 1. In case of discontinuation of DOACs prior to dental procedures across varied studies, the time period of discontinuation ranged from 1- 3 days.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTest and control groups\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo studies were case control among total eight studies. Dabigatran was the DOAC drug of choice across one study with 29 cases administered with the drug and 42 without any DOACs. Rivaroxaban and Apixaban were the drugs of choice across second study with 37 patients administered and 40 being control group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePost-Operative Scenario\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe post-operative measures across varied studies with different surgical procedures included compression, haemostatic agent application (Majorly tranexamic acid) along with sutures. The patients were majorly followed up after three days or a week across the studies. The complications varied from post-operative immediate bleeding, delayed bleeding, swelling, major clots etc. across studies. (For details see table 1)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up Time\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was a broad variety in follow-up appointments and regimens. Whereas some authors instructed their patients to contact them post 7th postoperative day, others conducted frequent clinical follow-up examinations after 1 day followed by clinical examination on 3\u003csup\u003erd\u003c/sup\u003e day, 7\u003csup\u003eth\u003c/sup\u003e day, 14\u003csup\u003eth\u003c/sup\u003e day and after a month. No follow up was reported across two studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnalysis of General Outcome parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePost-operative bleeding events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn six publications, data about postoperative local bleedings were reported. Inconsistency was reported in postoperative bleeding across all eight studies. Among case control studies, both studies reported non stoppage of DOACs during dental implant surgery and maxillary sinus elevation procedures.\u003csup\u003e\u0026nbsp;[32.33]\u003c/sup\u003e They inferred safe administration of implant surgery and maxillary sinus floor augmentation procedures in patients taking DOACs with bare-minimum postoperative bleeding. Across the remaining six retrospective studies, 2 studies exhibited no episodes of post-operative bleeding.\u003csup\u003e\u0026nbsp;[26,29]\u003c/sup\u003e Whereas 5 studies exhibited bare minimum post-operative bleeding recommending continuation of DOACs during dental procedures.\u003csup\u003e\u0026nbsp;[27,30,31,32,33]\u003c/sup\u003e The post-operative bleeding incidence was pronounced only in cases of comorbidities or complex surgical procedures.\u003csup\u003e[28]\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDelayed bleeding episodes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour studies reported no delayed bleeding.\u003csup\u003e\u0026nbsp;[27,29,30,33]\u003c/sup\u003e The incidence of delayed bleeding was minimal with frequency exhibited after 2-7 days or across patients\u0026nbsp;with comorbidities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDOAC vs interruption of DOACs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results were inconsistent and varied with few studies recommending DOACs administration with bare minimum reported complications and remaining finding no statistically significant difference between discontinuation or continuation of drugs especially across basic dental procedures. The reported complication of post-operative bleeding was associated with co-morbidities or in case of complex dental treatments like implant placement.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSeveral studies have proposed recommendations for managing patients on DOACs during minor oral surgical procedures. However, inconsistencies in the guidelines have led to unnecessary discontinuity of DOACs, even in patients with a higher risk of thromboembolism. Thus, the present systematic review aims to evaluate the risk of perioperative and postoperative bleeding during minor oral surgical procedures in patients on DOACs and assist the dental professional in making an informed decision on the continuity or discontinuity of DOACs before oral surgery.\u003c/p\u003e \u003cp\u003eThe present study included six clinical studies that utilized DOACs as anticoagulant therapy\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e and two studies that compared patients on DOACs with patients without anticoagulants (control) during minor oral surgical procedures.\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e Of eight studies, five were retrospective cohort studies, one was a retrospective clinical study, and other two were case-control studies. The mean age across all studies was 67.78. Krammer et al., in their systematic review, referred to the term \"minor oral surgery\" to a variety of surgical procedures such as single tooth or multiple teeth extractions, dental implants, and maxillary sinus floor augmentation, the elevation of mucoperiosteal flaps, alveoloplasties, limited oral soft tissue surgeries, and complicated osteotomies. Therefore, our review included studies with similar minor oral surgical procedures based on Krammer's criteria.\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e This systematic review showed that Rivaroxaban was the most commonly used DOAC (33%, n\u0026thinsp;=\u0026thinsp;183), followed by Dabigatran and Apixaban during oral surgical procedures.\u003c/p\u003e \u003cp\u003eAmong eight studies, three by Cocero et al., Gomez-Moreno et al., and Cappare et al. continued the DOAC therapy in patients undergoing oral surgical procedures. \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e On the contrary, five studies by Miller et al., Kwak et al., Kim et al., Galleti et al., and Woolcombe et al. continued the DOACs therapy in some patients and discontinued the therapy in others for a period varying from 12\u0026ndash;120 hours before the oral surgery. \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e Miller et al. and Kim et al observed no evidence of postoperative bleeding in their studies. \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e Meanwhile, Cocero et al., Gomez-Moreno et al., Cappare et al., Kwak et al., Galleti et al., and Woolcombe et al. reported a few patients with postoperative bleeding. \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e However, the incidence of bleeding was also reported in control (individuals without DOACs therapy) groups as mentioned in studies by Gomez-Moreno et al. and Cappare et al. \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e This suggests the invasiveness of dental procedures may also have a role in the risk of bleeding. According to a study published by Campbell et al., procedures that involve periosteal incisions may increase the risk of postoperative bleeding.\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e On the contrary, a study by Clemm et al. demonstrated that the procedure's invasiveness had no significant impact on the postoperative bleeding risk.\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e According to current Scottish Dental Clinical Effectiveness Programme (SDCEP) guidelines, patients undergoing invasive dental procedures such as extraction of 1\u0026ndash;3 teeth or incision and drainage with a low risk of bleeding should continue their DOAC regime.\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e Conversely, dental procedures associated with a high risk of bleeding, such as multiple teeth extractions, flap raising procedures, biopsies, and gingival re-contouring, should miss or delay their morning DOAC dose on the day of treatment to reduce the high risk of bleeding. Besides, dentists prefer to undertake the procedure when peak DOAC concentrations have subsided, i.e., 4\u0026ndash;6 hours after the last dose. Among the studies that reported postoperative bleeding, the study by Cocero et al. involved 100 patients on DOACs (Dabigatran, Apixaban, and Rivaroxaban) who underwent tooth extractions. DOAC therapy continued in these patients. Of the 100 patients, 36 patients without any comorbidities reported no bleeding.\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e Whereas among the remaining 64 patients with comorbidities, one reported moderate bleeding, and three reported mild delayed bleeding. Delayed bleeding was attributed to the intake of one or two doses of DOACs. The authors concluded that postoperative bleeding was mainly observed in patients with comorbidities and patients that underwent extraction of multiple adjoining multi-rooted teeth.\u003c/p\u003e \u003cp\u003eAnother study by Moreno et al included 71 patients for dental implant placement. Of 71 patients, 29 were on DOACs therapy (Dabigatran test group), and 42 were healthy subjects (control group).\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e The DOACs therapy was not interrupted during the treatment. This study reported two patients in each group with postoperative bleeding. Cappare et al. conducted a study on 77 patients involving maxillary sinus elevation procedures.\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e Among 77 patients, 37 patients on DOACs therapy (Rivaroxaban/Apixaban) were included as the test group, and the remaining 40 were healthy subjects (control group). The authors continued the DOAC therapy in the test group during the procedure. Authors reported four patients in the test group and three patients in the control group with postoperative bleeding. In addition, a single case of delayed bleeding was also evident in the test group. Postoperative bleeding was easily managed using local measures. Both Moreno et al. and Cappare et al. concluded that no statistically significant difference in postoperative bleeding was evident in each group. \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eKwak et al. conducted a study in 120 patients (153 cases) on DOAC therapy (Dabigatran, Rivaroxaban, Apixaban, Edoxaban) that included performing both high bleeding risk (e.g., scaling, curettage, extraction, and implant surgery) and low bleeding risk (e.g., impression taking, root canal treatment, crown preparation, and resin filling) dental procedures.\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e Of 153 cases performed, DOAC therapy was discontinued in 103 cases and continued in 50. Postoperative bleeding was reported in nine cases (2 scaling, three simple extractions, three-implant surgery, and one resin filling) which were mainly categorized as high bleeding-risk dental procedures. Thus, authors recommended at least 24 hours of discontinuation of DOAC therapy in patients undergoing high bleeding risk procedures especially implant surgeries. The incidence of postoperative bleeding in this study was reported to be 5.8% (9 of 153 cases) which was lower than the rate reported by Mauprivez et al. and Levy et al., who reported\u0026thinsp;~\u0026thinsp;16% postoperative bleeding. In another study by Galleti et al., 12 patients on DOACs (Rivaroxaban) underwent dental implant and prosthetic rehabilitation procedures.\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e Patients were asked to interrupt their daily dose of Rivaroxaban 1 day before the treatment. Of 12 patients, three (25%) reported minor bleeding after the procedure, which was managed using local hemostatic measures. The study concluded that multiple implant placements could be performed without significant bleeding complications with the discontinuation of DOACs before the surgery.\u003c/p\u003e \u003cp\u003eLastly, a study by Woolcombe et al. conducted a study that included 98 patients on DOAC therapy (Rivaroxaban, Apixaban, Edoxaban, dabigatran) that underwent 119 dentoalveolar procedures in adherence with the Scottish Dental Clinical Effectiveness Programme (SDCEP) guidance. Postoperative bleeding was observed in 17 (14.3%) procedures.\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e Of 17 procedures, 5 (4.2%) reported minor postoperative bleeding, 1 (0.8%) required consultation in the oral surgery unit, and 11 (9.2%) procedures required the use of re-suturing and hemostatic packing and topical use of an antifibrinolytic agent to arrest the bleeding. Bleeding in 11 patients (11 procedures) was attributed to the unsuitability of six patients in applying the specific SDCEP instructions; four patients had heart failure, which was not reported in the medical history, and the rest of the patients reported comorbidities (liver disease and kidney disease) and simultaneous intake of Clopidogrel. Although the study by Kim et al. did not experience any postoperative bleeding.\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e However, blood clots were reported in 3 patients, and delayed bleeding was reported in 1 patient. Three of four patients were asked to discontinue the DOAC therapy before surgery. Since all four complications were self-limiting, no intervention was required. In addition, four patients in the study by Galleti et al. experienced post-surgery swelling, which was manageable and subsided over time.\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOverall, no significant complications were reported in patients on DOAC therapy that underwent minor oral surgical procedures. In some cases, postoperative bleeding was trivial and did not require any intervention.\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e Some studies required local hemostatic measures such as mechanical compression using gauze pads, additional sutures, tranexamic acid wraps, or other local hemostatic agents to arrest bleeding. \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e However, none of the studies' patients required any hospitalization for systemic administration of antifibrinolytics or replacement therapy.\u003c/p\u003e \u003cp\u003e Although SDCEP guidelines recommend delaying or missing the DOAC dose in procedures with a high risk of bleeding, studies by Cocerno et al., Moreno et al., and Cappare et al. continued DOAC therapy in patients undergoing high bleeding risk procedures such as extractions, implant surgery, and maxillary sinus elevation procedures respectively, and reported bare minimum evidence of postoperative bleeding.\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e Nevertheless, a sufficient gap was maintained between the last dose of DOAC and the dental procedure to minimize the risk of postoperative bleeding.\u003c/p\u003e \u003cp\u003eIn the present systematic review, data on the continuation or discontinuation of DOACs before dental treatment remains controversial, some authors suggested continuing DOAC therapy in low-bleeding risk procedures, some preferred discontinuation of DOAC therapy at least one day before the surgery, and others performed the oral surgical procedures 4\u0026ndash;6 hours after the last dose of DOACs. Irrespective of the controversy, our systematic review demonstrated that minor oral surgical procedures are safe for postoperative bleeding in patients with DOAC therapy. However, dentists should decide on patients' continuity or discontinuity of the DOAC therapy based on the severity of the dental procedures performed, the risk of thromboembolism, and the presence of comorbidities in the patient.\u003c/p\u003e \u003cp\u003eThe results of our study were comparable to the literature review by Lanau et al., who evaluated the potential bleeding risk of DOACs and concluded that these drugs are safe to use while undergoing dental treatment.\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e However, the results of our study needed to be aligned with the results of systematic and metanalysis by Bensi et al.\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e They concluded that DOACs have three times higher risk of postoperative bleeding after oral surgical procedures than anticoagulants such as warfarin or enoxaparin.\u003c/p\u003e \u003cp\u003eThere are a few limitations to our study. For instance, only a limited number of studies fulfilled the inclusion criteria, and none included were randomized controlled trials. Since only a few studies were included in this review to evaluate the outcomes, the results of our study cannot be considered conclusive. Further, randomized controlled clinical trials are required to extrapolate the results. Future directions involve the development of inexpensive antidotes that can be effective in cases of extensive bleeding.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWithin the limitation of the study, it can be concluded that minor oral surgical procedures are safe to perform in patients on DOAC therapy. In addition, the possible postoperative bleeding can be easily managed using local measures. However, the continuation or discontinuation of DOACs in patients undergoing oral surgical procedures remains controversial and requires further studies to extrapolate the results.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: Not applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and material: All data generated or analysed during this study are included in the supplementary information file.\u003c/p\u003e\n\u003cp\u003eCompeting interests: Declare no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding: No funding.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions: The author GD collected and analyzed the data, wrote the manuscript, revised and edited.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: Not applicable.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; information: GD is Assistant Professor \u0026amp; Consultant at Department of Oral and Maxillofacial Surgery, Pain Control \u0026amp; Anesthesia Course Director, Dental Admission \u0026amp; Registration Director at Faculty of Dentistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eDe Caterina R. 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A randomized controlled trial of dabigatran versus warfarin for periablation anticoagulation in patients undergoing ablation of atrial fibrillation. Pacing Clin Electrophysiol. 2013;36(2):172\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDvorackova S, Mala-Ladova K, Zimcikova E, et al. Spontaneous reports of adverse drug reactions related to oral anticoagulants in the Czech Republic. Int J Clin Pharm. 2021;43(4):948\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eZiakas PD, Kourbeti IS, Poulou LS, Vlachogeorgos GS, Mylonakis E. Medicare part D prescribing for direct oral anticoagulants in the United States: Cost, use and the \u0026quot;rubber effect\u0026quot;. PLoS ONE. 2018;13(6):e0198674.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eShah R, Patel MR. Primary and key secondary results from the ROCKET AF trial, and their implications on clinical practice. Ther Adv Cardiovasc Dis. 2017;11(3):105\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCostantinides F, Rizzo R, Pascazio L, Maglione M. Managing patients taking novel oral anticoagulants (NOAs) in dentistry: a discussion paper on clinical implications. \u003cem\u003eBMC Oral Health\u003c/em\u003e. 2016;16:5. Published 2016 Jan 28.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWells GA, Shea B, O\u0026rsquo;Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMiller SG, Miller CS. Direct oral anticoagulants: A retrospective study of bleeding, behavior, and documentation. Oral Dis. 2018;24(1\u0026ndash;2):243\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCocero N, Basso M, Grosso S, Carossa S. Direct Oral Anticoagulants and Medical Comorbidities in Patients Needing Dental Extractions: Management of the Risk of Bleeding. J Oral Maxillofac Surg. 2019;77(3):463\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKwak EJ, Nam S, Park KM, Kim SY, Huh J, Park W. Bleeding related to dental treatment in patients taking novel oral anticoagulants (NOACs): a retrospective study. Clin Oral Investig. 2019;23(1):477\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKim T, Finkelman M, Desai B, Farag A. Direct-acting oral anti-coagulants in dental practice: A Retrospective Observational Study (Part 1). Oral Dis. 2021;27(4):1052\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWoolcombe SA, Ball RE, Patel JP. Managing direct oral anticoagulants in accordance with the Scottish Dental Clinical Effectiveness Programme guidance for patients undergoing dentoalveolar surgery. Br Dent J. 2022;232(8):547\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGalletti G, Alfonsi F, Raffaele A, et al. Implant Placement in Patients under Treatment with Rivaroxaban: A Retrospective Clinical Study. Int J Environ Res Public Health. 2020;17(12):4607. Published 2020 Jun 26.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eG\u0026oacute;mez-Moreno G, Fern\u0026aacute;ndez-Cejas E, Aguilar-Salvatierra A, de Carlos F, Delgado-Ruiz RA, Calvo-Guirado JL. Dental implant surgery in patients in treatment by dabigatran. Clin Oral Implants Res. 2018;29(6):644\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCappar\u0026egrave; P, Tet\u0026egrave; G, Alfieri O, Pantaleo G, Montemezzi P. Postoperative Bleeding in Patients Under Direct Oral Anticoagulation After Maxillary Sinus Floor Augmentation: A Case-Control Study. Int J Oral Maxillofac Implants. 2022;37(2):365\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCampbell JH, Alvarado F, Murray RA. Anticoagulation and minor oral surgery: should the anticoagulation regimen be altered? J Oral Maxillofac Surg. 2000;58(2):131\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eClemm R, Neukam FW, Rusche B, Bauersachs A, Musazada S, Schmitt CM. Management of anticoagulated patients in implant therapy: a clinical comparative study. Clin Oral Implants Res. 2016;27(10):1274\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eScottish Dental Clinical Effectiveness Programme. Management of Dental Patients Taking Anticoagulants or Antiplatelet Drugs. 2015. Available online at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.sdcep.org.uk/wp-content/uploads/2015/09/SDCEP-Anticoagulants-Quick-Reference-Guide.pdf\u003c/span\u003e\u003c/span\u003e (accessed March 2017).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eLanau N, Mareque J, Giner L, Zabalza M. Direct oral anticoagulants and its implications in dentistry. A review of literature. J Clin Exp Dent. 2017;9(11):e1346\u0026ndash;54. Published 2017 Nov 1.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eTable 2: Newcastle Ottawa Bias Assessment for Case-control studies\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"756\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.523809523809524%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"39.682539682539684%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSelection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.492063492063492%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Comparability\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"30.952380952380953%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.349206349206349%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.523809523809524%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAuthors \u0026amp; Year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.698412698412698%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eIs the study Definition Adequate?\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.523809523809524%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRepresentativeness of the cases\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.73015873015873%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSelection of Controls\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.73015873015873%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDefinition of Controls\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.492063492063492%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eComparability of samples and controls\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.317460317460318%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAssessment of exposure\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.698412698412698%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSame method of ascertainment for all samples\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.936507936507937%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNo response rate\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.349206349206349%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTotal quality score\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.523809523809524%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGomez-moreno et al 2018\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.698412698412698%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.523809523809524%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.73015873015873%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.73015873015873%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.492063492063492%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.317460317460318%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.698412698412698%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.936507936507937%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.349206349206349%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"9.523809523809524%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCappare et al\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2022\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.698412698412698%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.523809523809524%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.73015873015873%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.73015873015873%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.492063492063492%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.317460317460318%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.698412698412698%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.936507936507937%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.349206349206349%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eTable 3: Newcastle Ottawa Bias Assessment for Cohort studies\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"710\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"33.80281690140845%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSelection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.211267605633802%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Comparability\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"29.577464788732396%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003cstrong\u003e\u0026nbsp;Outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.732394366197184%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"12.658227848101266%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAuthors \u0026amp; year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRepresentativeness of the exposed cohort\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.0014064697609%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSelection of the non-exposed cohort\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.29817158931083%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAscertainment of exposure\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.7355836849507735%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemonstration that outcome of interest was not present at start of study\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.189873417721518%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy controls for age and gender (or analysis separated by gender)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.70464135021097%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAssessment of outcome (self-harm or suicidality)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e\u003cstrong\u003eWas follow-up long enough for outcomes to occur?\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.829817158931084%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdequacy of follow up of cohorts\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal quality\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003escore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"12.658227848101266%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMiller et al\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2018\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.0014064697609%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.29817158931083%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.7355836849507735%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.189873417721518%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.70464135021097%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.829817158931084%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"12.658227848101266%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCocero N et al\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2018\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.0014064697609%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.29817158931083%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.7355836849507735%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.189873417721518%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.70464135021097%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.829817158931084%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"12.658227848101266%\"\u003e\n \u003cp\u003e\u003cstrong\u003eKwak et al\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2018\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.0014064697609%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.29817158931083%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.7355836849507735%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.189873417721518%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.70464135021097%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.829817158931084%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"12.658227848101266%\"\u003e\n \u003cp\u003e\u003cstrong\u003eKim et al\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2020\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.0014064697609%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.29817158931083%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.7355836849507735%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.189873417721518%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.70464135021097%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.829817158931084%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"12.658227848101266%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGalleti et al\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2020\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.0014064697609%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.29817158931083%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.7355836849507735%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.189873417721518%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.70464135021097%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.829817158931084%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"12.658227848101266%\"\u003e\n \u003cp\u003e\u003cstrong\u003eWoolcombe et al \u0026nbsp;2022\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.0014064697609%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.29817158931083%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.7355836849507735%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.189873417721518%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.70464135021097%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.829817158931084%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"8.860759493670885%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Direct oral anticoagulants, Dental extraction, Oral surgery","lastPublishedDoi":"10.21203/rs.3.rs-2343060/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2343060/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: Direct oral anticoagulants (DOACs) were developed to overcome the drawbacks of oral anticoagulants. However, not much has been discussed on the perioperative management of patients on DOACs during oral surgical procedures. Thus, we aim to determine the risk of perioperative and postoperative bleeding during oral surgical procedures in patients on DOACs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethodology\u003c/strong\u003e: A detailed literature search was performed to find potentially relevant studies using Cochrane Library, Clinical Key, ClinicalTrials.gov, Google Scholar, Ovid, ScienceDirect, and Scopus. Every article available for free in the English literature for the past 5 years, between 2018 -2022 was searched.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 1091 abstracts were selected through search strategy across various search engines. Based on inclusion and exclusion criteria, eight clinical studies using DOACs as anticoagulants or studies\u003cstrong\u003e \u003c/strong\u003ecomparing patients with and without DOACs under oral surgery procedures were found. The results were inconsistent and varied with few studies recommending DOACs administration with bare minimum reported complications and remaining finding no statistically significant difference between discontinuation or continuation of drugs, especially across basic dental procedures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Within the limitation of the study, it can be concluded that minor oral surgical procedures are safe to perform in patients on DOAC therapy. However, the continuation or discontinuation of DOACs in patients undergoing oral surgical procedures remains controversial and requires further studies to extrapolate the results.\u003c/p\u003e","manuscriptTitle":"The Effect of Direct Oral Anticoagulant Therapy (DOACs) On Oral Surgical Procedures: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-20 15:41:04","doi":"10.21203/rs.3.rs-2343060/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-04-18T11:47:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-04-09T20:11:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"410d4baa-1921-454c-affa-4ab3794f9746","date":"2023-03-31T08:37:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-03-20T21:51:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3c0ef711-8808-4258-9ec0-a47250443085","date":"2023-03-20T21:34:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-03-02T15:39:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"193d4a08-33aa-4f3b-a7da-1f79b44e07e4","date":"2023-02-23T16:30:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"38c8a75a-1156-458f-919b-103dbe8a5d08","date":"2023-02-17T06:17:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-02-16T19:43:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-02-16T19:34:21+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-01-18T14:08:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-01-18T14:01:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Oral Health","date":"2022-12-04T14:35:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cb4902ff-d784-41ab-99b1-52b287f39a8f","owner":[],"postedDate":"January 20th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T15:04:49+00:00","versionOfRecord":{"articleIdentity":"rs-2343060","link":"https://doi.org/10.1186/s12903-023-03427-8","journal":{"identity":"bmc-oral-health","isVorOnly":false,"title":"BMC Oral Health"},"publishedOn":"2023-10-11 15:01:49","publishedOnDateReadable":"October 11th, 2023"},"versionCreatedAt":"2023-01-20 15:41:04","video":"","vorDoi":"10.1186/s12903-023-03427-8","vorDoiUrl":"https://doi.org/10.1186/s12903-023-03427-8","workflowStages":[]},"version":"v1","identity":"rs-2343060","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2343060","identity":"rs-2343060","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}