The Effect of Direct Oral Anticoagulant Therapy (DOACs) on oral surgical procedures: a systematic review

Background Direct oral anticoagulants (DOACs) were developed to overcome the drawbacks of oral anticoagulants. However, not much has been discussed about 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. Methods A detailed literature search was performed to find potentially relevant studies using the Cochrane Library, Clinical Key, ClinicalTrials.gov, Google Scholar, Ovid, ScienceDirect, and Scopus. Every article available for free in English literature for the past 10 years, between 2012 and 2022, was searched. Results A total of 2792 abstracts were selected through a search strategy across various search engines. Based on inclusion and exclusion criteria, eleven 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 a few studies recommending DOAC administration with the bare minimum reported complications and others finding no statistically significant difference between discontinuation or continuation of drugs, especially across basic dental procedures. Conclusion Within the limitations of the study, it can be concluded that minor oral surgical procedures are safe for 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. Supplementary Information The online version contains supplementary material available at 10.1186/s12903-023-03427-8.

dental extractions, periodontal surgeries, alveoloplasty, dental implant surgery, and other pre-prosthetic surgeries for oral rehabilitation.However, the major drawback of oral anticoagulant therapy is the higher risk of hemorrhage after injuries or any surgical procedure [6].Due to the increased risk of postoperative bleeding or oral hematoma in patients on anticoagulant therapy, performing surgical procedures in such patients becomes a significant concern for a dentist [7].According to a study by Bump et al., fear of hemorrhages may elevate stress levels in cardiac patients, which may induce fibrinolytic activity [8].
To limit the risk of perioperative and postoperative bleeding associated with OAT, discontinuing anticoagulant treatment 2-3 days before oral surgical procedures is recommended [9,10].However, several studies suggest that discontinuing OAT for a short time may not be sufficient to stop perioperative complications and increase thromboembolic risk [2,6,[11][12][13][14][15].
Recently, DOACs have been developed to overcome the drawbacks of OAT.DOACs are categorized into Xa inhibitors and direct thrombin inhibitors.Among Xa inhibitors, Rivaroxaban acts rapidly by inhibiting the Xa activity of the prothrombinase complex within 2.5-4 h [16].Direct thrombin inhibitors such as Dabigatran inhibit the action of factor IIa in the coagulation pathway within 0.5-4 h [5,7,16,17].DOACs are known to have fewer drug-to-drug or drug-food interactions and a wide range of therapeutic windows that improve their safety.DOACs are more predictable than warfarin because of their simplified pharmacodynamics.They are more convenient, as they do not require periodic monitoring and are prescribed at 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 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 with Apixaban compared to 1.9% with warfarin during dental extractions, colonoscopy, and ophthalmologic surgery [24].
Little is known about the perioperative management of patients taking DOACs during oral surgical procedures.This systematic review aims to 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 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 Fig. 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 identify potentially relevant studies using the Cochrane Library, Clinical Key, ClinicalTrials.gov,Google Scholar, Ovid, ScienceDirect, and Scopus databases.Combined MeSH and accessible text search terms aimed to identify all anticoagulant agents, including synonyms, related terms, and variants, parenteral agents, "direct oral anticoagulants", "oral surgery", "dental extraction", and "dental implants", using PubMed and PubMed Central.Every article available for free in English literature for the past 10 years, between 2012 and 2022, was searched.Additionally, all related articles were scanned.Efforts were made to identify unpublished studies, especially the ones identified only in abstracts, but we could not reach the authors as not all details were 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 implant surgery, pre-prosthetic surgeries, or alveoloplasties were included in our study.Studies identified for inclusion in the previous systematic review were reviewed and considered for inclusion in the data synthesis.

Exclusion criteria
Case reports, case series, and literature reviews were excluded from our study.

Study selection criteria
The outcome parameters on which we focused mainly were preoperative and postoperative bleeding, local hemostasis, delayed bleeding due to DOACs, discontinuation of DOACs 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.Two reviewers screened independently and reviewed titles and abstracts for inclusion eligibility.They manually searched the references involving human subjects to identify relevant studies according to inclusion criteria.The same reviewers independently categorized the data, and the same two reviewers evaluated the data and results of the studies included in this assessment.

Outcome measures
The primary outcome was the frequency of postoperative bleeding, defined as any 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, the Newcastle-Ottawa Scale (NOS) was used to assess the quality of nonrandomized studies, as shown in Tables 1 and 2 [25].

Systematic review
Initially, a total of 2792 abstracts were selected through a search strategy across various search engines.They were screened and reviewed for the selected inclusion and exclusion criteria.Eleven clinical studies using DOACs as anticoagulants or studies comparing patients with and without DOACs under oral surgery procedures were found (Table 3).Due to the heterogeneity of the critical parameters, aggregation of statistical data was impossible.Therefore, not a meta-analysis but a descriptive analysis of the studies obtained was conducted.

Study characteristics
The patient sample across all eleven studies was 1,000, with a minimum of 12 and a maximum of 337 patients.The patient population consisted of 399 males and 339 females across eight studies.The mean age across all the studies was 57.4,ranging from 20 to 91 years.Rivaroxaban was the most frequently used anticoagulant DOAC type (26.5%, n = 265) across most studies, followed by Dabigatran and Apixaban (for details, refer to Table 3).

Oral surgical procedures
Most of the studies obtained were principally focused on tooth extraction, especially across the seven studies.
Therefore, generalizing all the 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, highbleeding-risks surgeries, implant surgeries, bone grafting, maxillary sinus floor elevation, etc. (for details, see Table 3).

DOACs
The types of DOACs used across different patients were Apixaban, Dabigatran, Rivaroxaban, and Edoxaban, as illustrated in Table 3. DOACs were mostly continued across studies prior to dental procedures, as shown in Table 3.In cases of discontinuation of DOACs prior to dental procedures across varied studies, the period of discontinuation ranged from 1-3 days.

Test and control groups
Among eleven studies, four were case-control.In one study, Rivaroxaban was the drug of choice, with 18 cases administered with the drug and 39 without any drug.Meanwhile, Dabigatran was the DOAC drug of choice in the study, with 29 cases administered with the drug and 42 without any DOACs.Rivaroxaban and Apixaban were the drugs of choice in the remaining two studies (Table 3).

Postoperative scenario
The postoperative measures across varied studies with different surgical procedures included compression, hemostatic agent application (mostly tranexamic acid), and sutures.In one of the studies, moderate bleeding was managed either by contacting a physician in the emergency department or through re-intervention.The patients were mainly followed up after three days or a week across the studies.The complications varied from postoperative immediate bleeding to delayed bleeding, swelling, major clots, etc., across studies (for details, see Table 3).

Follow-up time
There was a wide variety of follow-up appointments and regimens.Whereas some authors instructed their patients to contact them after the 7th postoperative day, others conducted frequent clinical follow-up examinations after 1 day, followed by clinical examinations on the 3 rd , 7 th , 10 th , and 14 th days, and after a month.No followup was reported across the two studies.

Postoperative bleeding events
In eight studies, data about postoperative local bleeding was reported.Inconsistency was reported in postoperative bleeding across all eleven studies.Among case-control studies, three reported non-stoppage of DOACs during dental extractions, dental implant surgery, and maxillary sinus elevation procedures [33,35].They inferred the 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 cohort studies, two exhibited no postoperative bleeding episodes [27,30].Overall, five studies exhibited the bare minimum of postoperative bleeding, recommending the continuation of DOACs during dental procedures [28,[31][32][33]35].The postoperative bleeding incidence was pronounced only in cases of comorbidities or complex surgical procedures [29].

Delayed bleeding episodes
Four studies reported no delayed bleeding [28,30,31,35].The incidence of delayed bleeding was minimal, with frequency exhibited after 2-7 days or across patients with comorbidities.However, in one study, four of the seven cases of delayed bleeding were moderate, requiring contact with a physician or a re-intervention [34].

DOAC vs. interruption of DOACs
The results were inconsistent and varied, with a few studies recommending DOAC administration with the bare minimum reported complications and others finding no statistically significant difference between discontinuation or continuation of drugs, especially across basic dental procedures.The reported postoperative bleeding complication was associated with comorbidities or complex dental treatments like implant placement.

Discussion
Several studies have proposed recommendations for managing patients on DOACs during minor oral surgical procedures.However, guidelines inconsistencies have led to unnecessary discontinuation 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 seven clinical studies that utilized DOACs as anticoagulant therapy [26][27][28][29][30][31][32] and four studies that compared patients on DOACs with patients without anticoagulants (control) during minor oral surgical procedures [33][34][35].Of the eleven studies, six were retrospective cohort studies, one was a retrospective clinical study, and the other four were case-control studies.The mean age across all studies was 57.4,ranging from 20 to 91 years.Krammer et al., in their systematic review, referred to the term "minor oral surgery" as a variety of surgical procedures such as single tooth or multiple tooth extractions, dental implants, 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 in the studies presently included that Rivaroxaban was the most commonly used DOAC, followed by Dabigatran and Apixaban during oral surgical procedures.
Among eleven studies, five by Gomez-Moreno et al., Hanken et [26,[33][34][35] This suggests the invasiveness of dental procedures may also play 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 [36].On the contrary, a study by Clemm et al. demonstrated that the procedure's invasiveness had no significant impact on the postoperative bleeding risk [37].
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, which NHS recommends and most guidelines [38][39][40].Conversely, patients undergoing dental procedures associated with a high risk of bleeding, such as multiple tooth extractions, flapraising 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 [41].Besides, dentists prefer to undertake the procedure when peak DOAC concentrations have subsided, i.e., 4-6 h after the last dose.Among the studies that reported postoperative bleeding, a study by Hanken et al. reported 52 oral procedures performed under anticoagulant therapy with Rivaroxaban.The postoperative bleeding complications of these procedures were compared with those of 285 oral procedures in healthy patients without anticoagulant or antiplatelet therapy.Among 52 oral procedures, two were performed under Rivaroxaban in combination with antiplatelet therapy as per the recommendation of treating cardiologists.Although dual therapy does not match our inclusion criteria, we included this study in our research because the number of patients on dual therapy was relatively low and may not have significantly impacted the study results.The authors concluded that postoperative bleeding complications after oral surgical procedures occurred more frequently in patients receiving DOAC therapy than in healthy patients.However, the bleeding was manageable [26].Another study by Miclotte et al. compared the difference in postoperative bleeding between 26 patients on DOACs and 26 healthy patients without any anticoagulant therapy undergoing dental extractions.DOAC therapy was discontinued for these patients on the day of the procedure.The study's results reported no significant difference in bleeding events between groups.However, patients on DOACs reported a high bleeding rate due to increased delayed bleeding [34].
Another 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 [28].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 who underwent extraction of multiple adjoining multi-rooted teeth.
Another study by Gomez Moreno et al. included 71 patients for dental implant placement.Of 71 patients, 29 were on DOAC therapy (the Dabigatran test group), and 42 were healthy subjects (the control group) [33].The DOAC 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 [35].Among 77 patients, 37 on DOAC therapy (Rivaroxaban/Apixaban) were included as the test group, and the remaining 40 were healthy subjects (the control group).The authors continued the DOAC therapy in the test group during the procedure.
The authors reported four patients in the test group and three 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 [33,35].
Kwak et al. conducted a study in 120 patients (153 cases) on DOAC therapy (Dabigatran, Rivaroxaban, Apixaban, and 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 [29].Of the 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 surgeries, and one resin filling), mainly categorized as high-bleeding-risk dental procedures.Thus, the authors recommended at least 24 h of discontinuation of DOAC therapy in patients undergoing high-bleedingrisk procedures, especially implant surgeries.The incidence of postoperative bleeding in this study was 5.8% (9 of 153 cases), 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 [32].Patients were asked to interrupt their daily dose of Rivaroxaban one 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, and Dabigatran) who underwent 119 dentoalveolar procedures in adherence with the Scottish Dental Clinical Effectiveness Programme (SDCEP) guidance.Postoperative bleeding was observed in 17 (14.3%)procedures [31].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, hemostatic packing, and topical use of an antifibrinolytic agent to arrest the bleeding.Bleeding in eleven patients (11 procedures) was attributed to the unsuitability of six patients for 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 [30].However, blood clots were reported in three patients, and delayed bleeding was reported in one patient.Three of the four patients were asked to discontinue DOAC therapy before surgery.Since all four complications were selflimiting, no intervention was required.In addition, four patients in the study by Galleti et al. experienced postsurgery swelling, which was manageable and subsided over time [32].
Overall, no significant complications were reported in patients on DOAC therapy who underwent minor oral surgical procedures.In some cases, postoperative bleeding was trivial and did not require any intervention [31].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 [26,28,29,[31][32][33]35]. None of the study's patients required hospitalization for systemic administration of antifibrinolytics or replacement therapy.However, a study by Miclotte et [26,29,33,35].Nevertheless, a sufficient gap was maintained between the last dose of DOAC and the dental procedure to minimize the risk of postoperative bleeding.Zeng et al., while comparing the effectiveness and safety outcomes of DOACs with warfarin in patients with atrial fibrillation, concluded that DOACs exerted superior effectiveness and were associated with a significant reduction in severe bleeding and intracranial hemorrhage [42].DOACs exert their action by reversibly inhibiting the action of coagulation factors, such as thrombin or factor Xa. Since the action of DOACs is concentration-dependent.So, as soon as DOACs are eliminated from the body, the activity of the coagulation factor will be restored, minimizing the risk of excess bleeding [43].
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; others performed the oral surgical procedures 4-6 h 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 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 those of 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 [44].However, the results of our study needed to be aligned with the results of a systematic meta-analysis by Bensi et al. [17] They concluded that DOACs have a 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 were randomized controlled trials.As 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 these results.Future directions involve the development of inexpensive antidotes that can be effective in cases of extensive bleeding.

Conclusion
Within the limitations of this study, it can be concluded that minor oral surgical procedures are safe to perform on patients receiving DOAC therapy.In addition, postoperative bleeding can be easily managed using local measures.However, continuing or discontinuing of DOACs in patients undergoing oral surgical procedures remains controversial and requires further studies to extrapolate the results.
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Table 1
Newcastle Ottawa bias assessment for case-

Table 2
Newcastle Ottawa bias assessment for cohort studies

Table 3
Summary of study design and study characteristics
al. reported moderate bleeding, managed either by contacting a physician in the emergency department or re-intervention.Although SDCEP guidelines recommend delaying or missing the DOAC dose in procedures with a high risk of bleeding, studies by Hanken et al., Gomez-Moreno et al., Cocerno et al., Moreno et al., and Cappare et al.