Risk of bleeding with dentoalveolar surgery in patients taking direct oral anticoagulants or vitamin K antagonists: A systematic review and meta-analysis

Ke Dou; Yue Shi; Baoyi Yang; Zhiguo Zhao

doi:10.1016/j.jdsr.2025.08.002

. 2025 Aug 12;61:188–199. doi: 10.1016/j.jdsr.2025.08.002

Risk of bleeding with dentoalveolar surgery in patients taking direct oral anticoagulants or vitamin K antagonists: A systematic review and meta-analysis

Ke Dou ^a,^b, Yue Shi ^c, Baoyi Yang ^b, Zhiguo Zhao ^b,^⁎

PMCID: PMC12358962 PMID: 40831539

Abstract

Objective

The aim of the present study was to assess and compare the bleeding risks in patients undergoing dentoalveolar surgery who were on uninterrupted therapy with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs).

Methods

Electronic database searches were performed in PubMed, Embase, Web of Science, and CENTRAL through 28 September 2024, following PICOS criteria. Two reviewers independently performed literature screening, data extraction, and assessed the risk of bias. Data were pooled to estimate risk ratios (RR) with 95 % confidence intervals (CI) using a fixed-effects model. Between-study heterogeneity was assessed with the Q statistic and I². Subgroup analyses were conducted according to study characteristics, while sensitivity analyses were used to pinpoint potential sources of heterogeneity and evaluate the reliability of the results.

Results

29 studies enrolled a total of 29,212 patients. Meta-analysis demonstrated a reduced risk of bleeding in patients receiving DOACs compared to those treated with VKAs (RR = 0.79, 95 % CI: 0.68–0.92, I² = 0 %, P = 0.002). Subgroup analysis revealed a significantly reduced risk of bleeding with dabigatran compared to VKAs (RR = 0.40, 95 % CI: 0.23–0.67, I² = 0 %, P = 0.0006). However, no statistically significant differences were found between rivaroxaban (RR = 1.08, 95 % CI: 0.84–1.39, I² = 38 %, P = 0.54), apixaban (RR = 0.88, 95 % CI: 0.64–1.3, I² = 0 %, P = 0.46), edoxaban (RR = 0.70, 95 % CI: 0.45–1.11, I² = 60 %, P = 0.13) and VKAs. Combined analyses indicated an increased risk of bleeding with DOACs compared to controls (RR = 3.23, 95 % CI: 2.18–4.78, I² = 24 %, P < 0.0001), as well as increased bleeding risk with VKAs (RR = 3.35, 95 % CI: 2.31–4.85, I² = 0 %, P ＜ 0.0001).

Conclusions

Patients receiving DOACs or VKAs have an increased risk of bleeding during dentoalveolar surgery, but severe bleeding requiring hospitalization or causing irreversible damage is rare. Patients using DOACs appear to have a lower bleeding risk compared to those on VKAs. This difference is mainly observed in dabigatran etexilate, while it remains unclear in rivaroxaban, apixaban, and edoxaban. Current quality of evidence is very low, which should be interpreted with caution. Future studies with higher quality of evidence are required to strengthen the validity of these findings.

Keywords: Direct oral anticoagulants, Vitamin K antagonists, Bleeding, Dentoalveolar surgery, Meta-analysis

1. Introduction

As the population ages, oral anticoagulant therapy has become increasingly prevalent in the prevention and management of thrombotic complications [1]. Among the elderly, a substantial proportion are medically compromised and receiving anticoagulant therapy. Meanwhile, the demand for dental treatment among elderly patients is on the rise. As a result, treatment plans for these patients should consider the potential adverse effects of medications related to the procedures.

Oral anticoagulants are mainly prescribed to manage conditions such as atrial fibrillation, valvular heart disease, pulmonary embolism, and deep vein thrombosis. Vitamin K antagonists (VKAs), including warfarin, acenocoumarol, and phenprocoumon, have traditionally been the gold standard in anticoagulation therapy [2]. However, in recent years, direct oral anticoagulants (DOACs) have increasingly replaced VKAs as a preferred alternative. Compared to VKAs, direct oral anticoagulants (DOACs) such as apixaban, dabigatran, edoxaban, and rivaroxaban offer benefits like fewer side effects, shorter half-lives, no need for regular blood tests, and reduced interactions with food and other medications [3], [4].

Dentoalveolar surgery is a common dental procedure, encompassing tooth extractions, implant placement, and alveolar bone reconstruction. Anticoagulant therapy is a significant risk factor in dentoalveolar surgery [5]. Effective control of postoperative bleeding is crucial for anticoagulated patients undergoing these procedures. Close collaboration among cardiologists, general practitioners, and oral surgeons is essential to assess the patient's overall condition prior to surgery, minimizing the risk of thromboembolic events and ensuring prompt hemostatic management for postoperative bleeding [6]. Improper management of anticoagulation therapy during the perioperative period can complicate invasive procedures by increasing the risk of thrombosis or bleeding.

Current evidence suggests that routine discontinuation of anticoagulant therapy prior to dentoalveolar surgery is no longer recommended [7]. Strong evidence indicates that local hemostatic techniques can effectively control bleeding in patients taking VKA therapy, provided that their INR remains within the therapeutic range (≤ 4.0), without requiring interruption of treatment [8], [9].

The bleeding risk associated with DOACs and VKAs has been a subject of ongoing debate. One study suggests that DOACs may increase the risk of gastrointestinal bleeding, while another reports that the bleeding rate after single tooth extraction is similar in patients taking DOACs compared to those on VKAs [7], [10]. However, with the variety of DOACs available, direct comparisons between these agents and VKAs remain limited. A recent systematic review indicates that the risk of bleeding may be lower for patients on uninterrupted DOAC than VKA therapy, but the effect size of the risk is unclear [11]. This meta-analysis aims to evaluate the bleeding risk in patients undergoing dentoalveolar surgery on DOACs versus VKAs, in order to determine if there is a significant difference in bleeding risk between the two anticoagulants. This will assist clinicians in making informed decisions and optimizing bleeding risk management during dentoalveolar surgery in these patients.

2. Materials and methods

2.1. Study design and literature search

This systematic review was registered with PROSPERO (CRD42024608201) and conducted following the PRISMA guidelines [12]. As publicly available databases were utilized in this analysis, institutional ethical approval was not required. Electronic database searches were performed in PubMed, Embase, Web of Science, and CENTRAL through 28 September 2024. The literature screening, data extraction, and risk of bias assessment were performed by two independent reviewers, who also conducted a manual search to complement the results. Searches were conducted using a combination of controlled vocabularies (MeSH, Emtree) and free-text keywords such as "direct oral anticoagulants", "vitamin K antagonists", "bleeding" and "dentoalveolar surgery". The manual search was performed by systematically reviewing the reference lists of key articles, including relevant systematic reviews, clinical guidelines, and primary research studies identified through our initial database search. We focused on sources that were likely to contain studies that were not captured through the electronic databases alone, ensuring a comprehensive review of the literature. A detailed search queries are presented in the Supplementary Information.

2.2. Eligibility criteria

In accordance with the Population, Intervention, Comparison, Outcomes, and Study (PICOS) framework, the inclusion criteria were defined as follows:

(P)The study population was adult patients treated with DOACs or VKAs and scheduled to undergo dentoalveolar bone surgery; (I) (Intervention/Exposure) was the continuation of DOACs or VKAs medication during the perioperative period; (C) Controls were different types of oral anticoagulants and patients who are not taking anticoagulant medication; (O) Study outcomes were patient-reported bleeding events after tooth extraction or follow-up examinations by health care professionals; (S) Study design included randomised controlled trials, clinical controlled trials, prospective or retrospective cohort studies and case-control studies.

The following studies were excluded from the analysis:

1)
Studies that did not provide concrete data for patients treated with DOACs and VKAs. 2) Studies where the use of DOACs or VKAs was interrupted during the perioperative period. 3) Studies that did not report relevant outcomes. 4) Review articles and case reports.

2.3. Data extraction

Data extraction from each included study was performed independently by two reviewers using Excel 2021 software. The characteristics extracted for the systematic review included the following: author, publication year, study type, indication for anticoagulation, study groups, sample size, average age of participants, male-to-female ratio, bleeding episodes, INR, intra-operative hemostasis technique. Any disagreements between the two reviewers were settled by consulting a third reviewer for clarification. If necessary, the study authors were contacted to retrieve missing data or to provide further details. Dentoalveolar surgery refers to surgical procedures involving the dentoalveolar bone and surrounding tissues, typically including tooth extraction, dentoalveolar bone reconstruction, dental implant placement, and other related restorative interventions.

2.4. Quality assessment

The methodological quality of the included studies was assessed using the ROBINS-1 tool [13]. The methodological rigor of the included studies was evaluated across seven domains: confounding, selection of participants, classification of interventions, departure from intended interventions, missing data, measurement of outcomes, and selection of overall results. Each study was assigned a risk-of-bias rating categorized as low, moderate, serious, or critical based on these criteria. The certainty of evidence derived from our meta-analytic synthesis was systematically appraised using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework [14]. Following established protocols for inter-rater reliability enhancement, independent evaluations were conducted by three investigators with adjudication of discrepancies through consensus-based deliberation.

2.5. Data analysis

Meta-analysis was performed on groups containing at least three studies. The relative risk (RR) for combined effect sizes was calculated using Review Manager version 5.4 (The Nordic Cochrane Center, Copenhagen, Denmark) [15]. The Q test and I² statistic were applied to evaluate the heterogeneity across the studies. The Q test determined whether there was between-study heterogeneity, while the I² statistic measured its extent. I² values > 50 % indicated moderate heterogeneity, and values > 75 % were considered substantial. The choice between fixed-effects and random-effects models was determined by heterogeneity assessment. Sensitivity analysis was carried out to evaluate how individual studies influenced the overall estimate and to assess the reliability of the results. Subgroup analyses were conducted to explore and identify potential factors contributing to the observed heterogeneity among the studies. Prior to performing the analysis, the presence of publication bias was evaluated using funnel plots and Egger's test. A p-value of less than 0.05 was considered indicative of statistical significance. We also performed subgroup analyses to compare the risks between specific DOACs and VKAs. Begg's funnel plot and Egger's regression test were used to assess the potential for publication bias.

3. Results

3.1. Search results and studies selection

A total of 2982 articles were identified through both computerized and manual search methods based on our defined strategy. The process of study selection is detailed in Fig. 1. Subsequently, after a thorough examination of titles and abstracts, an additional 1572 articles were excluded based on relevance and inclusion criteria. Following a review of titles and abstracts, 1352 additional articles were excluded. After reviewing the full texts, 29 articles were excluded from the analysis. This included 16 studies without a control group, 8 with incomplete data, and 4 that were not available in full. In addition, due to duplicate patient samples, we excluded 1 article. Finally, a total of 29 studies fulfilled the inclusion criteria, encompassing a total of 29,212 patients.

Fig. 1 — Flowchart of literature search. Forest plot of bleeding outcomes between patients under DOACs vs. VKAs.

3.2. Basic characteristics and quality assessment

Table 1 presents a summary of the key characteristics of the studies that were included in the analysis, offering an overview of their essential details. The meta-analysis incorporated 29 eligible studies [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], consisting of 13 cohort studies, 14 case-control studies, and 2 cross-sectional studies. The quality assessments were provided in Supplemental Table 1. GRADE classification of quality of evidence for meta-analysis were provided in Supplemental Table 2. The level of evidence is low or very low. Fig. 2 showed the forest plots, while Fig. 3 displayed the funnel plots.

Table 1.

General characteristics of included studies.

Study	Year	Location	Study type	Indication for anticoagulation	Studygroups	Sample size	Mean age (years)	Male gender(%)	Bleeding episodes	INR	Intra-operative hemostasis technique
Bacci et al. [16]	2010	Italy	Prospective case-control study	AF, PV, MI, DVT, VHD, Stroke	Warfarin	451	63.5	55	7	1.8–4	Fibrin sponges; Silk sutures; Gauzes saturated with tranexamic acid
Bacci et al. [16]	2010	Italy	Prospective case-control study	AF, PV, MI, DVT, VHD, Stroke	Control	448	66.4	45	4	1.8–4
Bacci et al. [17]	2011	Italy	Prospective case-control study	AF, MI, PV, DVT, VHD, Stroke	Warfarin	50	56.2 ± 8.9	75	2	1.8–2.98	Suturing; Pressure pack of tranexamic acid
Bacci et al. [17]	2011	Italy	Prospective case-control study	AF, MI, PV, DVT, VHD, Stroke	Control	109	NR	NR	3	0.98–1.21	Suturing; Pressure pack of tranexamic acid
Hanken et al. [18]	2015	Germany	Retrospective cohort study	VHD, MI, DVT, Stent, Apoplex, Others	Rivaroxaban	50	76.7 ± 11.3	35	6	NR	Fibrin glue; Suturing; Pressure
Hanken et al. [18]	2015	Germany	Retrospective cohort study	VHD, MI, DVT, Stent, Apoplex, Others	Control	285	64.2 ± 10.3	48	2	NR	Fibrin glue; Suturing; Pressure
Gomez-Moreno et al.a [19]	2015	Spain	Prospective case-control study	AF, DVT, VHD	Dabigatran	29	66.7 ± 9.15	65.5	2	NR	Suturing; Pressure pack of tranexamic acid
Gomez-Moreno et al.a [19]	2015	Spain	Prospective case-control study	AF, DVT, VHD	Control	42	66.7 ± 9.15	65.5	2	NR	Suturing; Pressure pack of tranexamic acid
Gomez-Moreno et al.b [20]	2015	Spain	Prospective case-control study	AF, VHD, DVT, PE	Rivaroxaban	18	64.4 ± 7.8	66.7	1	NR	Suturing; Pressure pack of tranexamic acid
Gomez-Moreno et al.b [20]	2015	Spain	Prospective case-control study	AF, VHD, DVT, PE	Control	39	64.4 ± 7.8	66.7	2	NR	Suturing; Pressure pack of tranexamic acid
Clemm et al. [21]	2015	Germany	Prospective cohort study	AF, MI, DVT, PE, CP	VKAs	16	NR	NR	1	2.62 ± 0.52	Suturing; Electrocautery
					DOACs	8			0
					Antiplatelets	40			0
					Control	271			2
Miclotte et al. [22]	2016	Belgium	Prospective case-control study	AF, DVT, PE	DOACs	26	76	57	12	NR	Suturing; Tranexamic acid pack
Miclotte et al. [22]	2016	Belgium	Prospective case-control study	AF, DVT, PE	Control	26	72	50	5	NR	Suturing; Tranexamic acid pack
Mauprivez et al. [23]	2016	France	Prospective cohort study	AF, DVT, PE, IHD, Stroke	DOACs	31	70.3 ± 2.1	45.2	5	2.28 ± 0.1	Gelatin sponge; Suturing
Mauprivez et al. [23]	2016	France	Prospective cohort study	AF, DVT, PE, IHD, Stroke	Warfarin	20	70.6 ± 2.8	55	4	2.28 ± 0.1	Gelatin sponge; Suturing
Caliskan et al. [24]	2017	Turkey	Prospective case-control study	AF, VHD, DVT, PE, IHD, Stroke	DOACs	21	60.8 ± 11.8	57	1	1.81 ± 1.3	Suturing; Oxidized cellulose
Caliskan et al. [24]	2017	Turkey	Prospective case-control study	AF, VHD, DVT, PE, IHD, Stroke	Warfarin	22	60.7 ± 10.4	73	3	2.33 ± 0.5	Suturing; Oxidized cellulose
Yagyuu et al. [25]	2017	Japan	Retrospective cohort study	NR	DOACs	41	72.3 ± 7.1	52.8	4	1.17 ± 0.12	NR
Yagyuu et al. [25]	2017	Japan	Retrospective cohort study	NR	Warfarin	50	73.7 ± 15.6	63	5	1.63 ± 0.39	NR
Andrade et al. [26]	2018	Brazil	Prospective case-control study	AF	Warfarin	12	67a	52	0	2–3	Suturing
Andrade et al. [26]	2018	Brazil	Prospective case-control study	AF	Dabigatran	25	71a	41	5	2–3	Suturing
Lababidi et al. [27]	2018	Australia	Retrospective cohort study	AF, VHD, DVT, PE	DOACs	38	72 ± 2	46.5	4	NR	Hemostatic agent; Suturing; Ttranexamic acid mouthwash
Lababidi et al. [27]	2018	Australia	Retrospective cohort study	AF, VHD, DVT, PE	Warfarin	50	71 ± 1.5	52	9	2.2–4	Hemostatic agent; Suturing; Ttranexamic acid mouthwash
Yoshikawa et al. [28]	2019	Japan	Prospective cohort study	AF, IHD, DVT, VHD, Stroke	DOACs	119	74.6 ± 10.1	68.9	4	NR	Suturing; Oxidized cellulose
Yoshikawa et al. [28]	2019	Japan	Prospective cohort study	AF, IHD, DVT, VHD, Stroke	Warfarin	248	71.6 ± 10.1	65.7	23	2.08 ± 0.47	Suturing; Oxidized cellulose
Berton et al. [29]	2019	Italy	Prospective cohort study	AF, DVT, PE, Stroke	DOACs	65	76 ± 9.2	52.3	12	NR	Oxidized cellulose sponges; Tranexamic acid pack
Berton et al. [29]	2019	Italy	Prospective cohort study	AF, DVT, PE, Stroke	Warfarin	65	76 ± 7.7	47.7	20	2–3	Oxidized cellulose sponges; Tranexamic acid pack
Sannino et al. [30]	2019	ltaly	Prospective case-control study	AF, MI, DVT, PE, PV, Stroke, Hypertension, TIA	Warfarin	40	NR	NR	11	< 3.5	Bome wax; Gelfoam; Suturing; Pressure pack of tranexamic acid
					Rivaroxaban	40			3
					Control	40			1
Rubino et al. [31]	2019	USA	Retrospective case-control study	AF, PE, DVT, ACS, NR	Warfarin	10	NR	NR	1	NR	NR
					DOACs	2			0
					Aspirin	122			0
					Clopidogrel	8			0
					Comibinations	34			1
Manor et al. [32]	2020	lsrael	Retrospective case-control study	NR	Warfarin	9	NR	NR	0	< 3	Suturing; Gelfoam; Pressure pack of tranexamic acid
					DOACs	2			0
					Aspirin	39			0
					Clopidogrel	1			0
					Comibinations	21			4
					Control	121			7
Brennan et al. [33]	2020	Australia	Prospective cohort study	AF, DVT, Other	Warfarin	21	71a	86	9	2–4	Suturing; Pressure pack of tranexamic acid
Brennan et al. [33]	2020	Australia	Prospective cohort study	AF, DVT, Other	DOACs	86	73a	63	31	2–4	Suturing; Pressure pack of tranexamic acid
Pippi et al. [34]	2020	Italy	Prospective case-control study	NR	VKAs	80	74.26 ± 9.83	62.2	15	1.18–4.38	Suturing; Compression; Gelatin sponge; Chitosan dressing; Collagen sponge
					DOACs	34			5	NR
					Antiplatelet	140			20	NR
Inokoshi et al. [35]	2021	Japan	Retrospective case-control study	AF, IHD, DVT, PE, VHD, Arrhythmias	DOACs	138	80 ± 6	49.3	22	NR	Hemostatic agent; Suturing
Inokoshi et al. [35]	2021	Japan	Retrospective case-control study	AF, IHD, DVT, PE, VHD, Arrhythmias	Warfarin	98	78.9 ± 6.5	49	17	< 3.5	Hemostatic agent; Suturing
Buchbender et al. [36]	2021	Germany	Prospective cohort Study	Hypertension, VHD, CHF, AHV	VKAs	17	73.29	53	1	1.5–3	Suturing; Tranexamic acid with bite swab and local wound compression
					DOACs	27		67	8
					Antiplatelet	51		69	16
					Control	100	62.01	58	2
Matarese et al. [37]	2021	Italy	Prospective cohort study	Hypertension, LD	DOACs	178	NR	NR	7	2–3	Suturing; Fibrin sponges; Compression
Matarese et al. [37]	2021	Italy	Prospective cohort study	Hypertension, LD	VKAs	120	NR	NR	14	2–3	Suturing; Fibrin sponges; Compression
Hiroshi et al. [38]	2022	Japan	Cross-sectional study	NR	Dabigatran	182	NR	65.4	6	< 3	Compression brace; Electrotome coagulation
					Rivaroxaban	88		70.5	7
					Warfarin	496		64.5	35
					Control	2321		48.5	49
Iwata et al. [39]	2022	Japan	Retrospective cohort study	Hypertension, Stroke, DVT, AF	Warfarin	287	72.1 ± 10.9	64	77	< 3	Suturing; Compression; Surgical splint; Hemostatic agent
Iwata et al. [39]	2022	Japan	Retrospective cohort study	Hypertension, Stroke, DVT, AF	DOACs	104	74.8 ± 8.8	63	27	< 3	Suturing; Compression; Surgical splint; Hemostatic agent
Ueda et al. [40]	2023	Japan	Retrospective case-control study	NR	Apixaban	74	83	19.5	16	< 3	Suturing; Gauze; oxidized regenerated cellulose; Surgical splint; Periodontal dressing material
					Edoxaban	66	83.5	7.7	6
					Rivaroxaban	65	81.1	19.4	18
					Warfarin	190	81.8	19.5	35
Nakamura et al. [41]	2023	Japan	Crosssectional study	Hypertension, LD, Stroke	Warfarin	2462	68.3 ± 14.3	44.8	52	NR	Suturing; Compression
					DOACs	2619			47
					Antiplatelet	10109			88
Ono et al. [42]	2023	Japan	Retrospective cohort study	Hypertension, Stroke, LD, TIA	Warfarin	1557	71.75a	66.2	35	NR	NR
Ono et al. [42]	2023	Japan	Retrospective cohort study	Hypertension, Stroke, LD, TIA	DOACs	3696	74.86a	60.2	71	NR	NR
Bajkin et al. [43]	2024	Serbia	Prospective cohort study	NR	VKAs	103	NR	NR	5	2.0–3.5	Suturing; Compression; Hemostatic agent
					DOACs	103			3
					Control	103			1
Kim et al. [44]	2024	Korea	Retrospective case-control study	NR	DOACs	246	77.4 ± 8.9	45	12	1.15 ± 0.5	Suturing; Compression; Absorbable hemostatic gelatin sponge
Kim et al. [44]	2024	Korea	Retrospective case-control study	NR	Control	47	74.5 ± 10.6	48	0	1.13 ± 0.55	Suturing; Compression; Absorbable hemostatic gelatin sponge

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NR, not reported; VKAs, vitamin K inhibitors; DOACs, direct oral anticoagulants; INR, international normalized ratio; AF atrial fibrillation; IHD, ischemic heart disease; DVT, deep vein thrombosis; PE, pulmonary embolism; VHD, valvular heart disease; PV, Prosthetic valve; MI, myocardial infarction; AHV, artificial heart valves; CP, cardiovascular prophylaxis; TIA, transitory ischaemic attack; ACS, acute coronary syndrome; LD, liver disease.

a Median (Interquartile range).

Forest plots of (A) bleeding outcomes between patients under DOACs vs. VKAs, (B) bleeding outcomes between patients under different DOAC vs. VKAs, (C) bleeding outcomes between patients under DOACs vs. Control with subgroup analysis based on inclusion of patients on antiplatelet drugs (D) bleeding outcomes between patients under DOACs vs. Control, (E) bleeding outcomes between patients under VKAs vs. Control. Forest plot of bleeding outcomes between patients under different DOAC vs. VKAs Fig. 2 (Continued) Forest plot of bleeding outcomes between patients under DOACs vs. Control with subgroup analysis based on inclusion of patients on antiplatelet drugs Forest plot of bleeding outcomes between patients under DOACs vs. Control Fig. 2 (Continued) Forest plot of bleeding outcomes between patients under VKAs vs. Control Fig. 2 (Continued) Funnel plot of Forest plots of bleeding outcomes between patients under DOACs vs. VKAs Funnel plot of bleeding outcomes between patients under different DOAC vs. VKAs Funnel plot of bleeding outcomes between patients under DOACs vs. Control with subgroup analysis based on inclusion of patients on antiplatelet drugs.

Funnel plots of (A) bleeding outcomes between patients under DOACs vs. VKAs, (B) bleeding outcomes between patients under different DOAC vs. VKAs, (C) bleeding outcomes between patients under DOACs vs. Control with subgroup analysis based on inclusion of patients on antiplatelet drugs (D) bleeding outcomes between patients under DOACs vs. Control, (E) bleeding outcomes between patients under VKAs vs. Control Funnel plot of bleeding outcomes between patients under VKAs vs. Control Funnel plot of bleeding outcomes between patients under VKAs vs. Control Fig. 3 (Continued).

3.3. DOACs vs. VKAs

A total of 23 studies (13,825 patients) compared bleeding risks between DOACs and VKAs. Pooled analysis revealed a statistically significant 21 % reduction in bleeding risk with DOACs ((RR = 0.79, 95 % CI: 0.68–0.92, P = 0.002), with negligible heterogeneity (I² = 0 %). Given the negligible heterogeneity observed across studies, a fixed-effects model was deemed appropriate for the primary analysis. The bleeding propensity was lower in patients receiving DOACs compared to those on VKAs. Subgroup analyses stratified by concomitant antiplatelet therapy demonstrated consistent trends. This indicates that concomitant antiplatelet therapy did not significantly affect the results. Subgroup analyses identified dabigatran as superior to VKAs (RR = 0.40, 95 % CI: 0.23–0.67, I² = 0 %, P = 0.0006), whereas rivaroxaban (RR = 1.08, 95 % CI: 0.84–1.39, I² = 38 %, P = 0.54), apixaban (RR = 0.88, 95 % CI: 0.64–1.3, I² = 0 %, P = 0.46), and edoxaban (RR = 0.70, 95 % CI: 0.45–1.11, I² = 60 %, P = 0.13) showed no significant differences. Sensitivity analyses confirmed robustness, and no publication bias was detected (Egger’s test P = 0.929＞0.05; symmetrical funnel plot).

3.4. DOACs vs. Control

10 studies (4091 patients) evaluated bleeding risks in DOAC users versus non-anticoagulated controls. Meta-analysis analyses indicated an increased risk of bleeding with DOACs compared to controls (RR = 3.23, 95 % CI: 2.18–4.78, P < 0.0001), with low heterogeneity (I² = 24 %). Since heterogeneity was less than 50 %, we used a fixed-effects model for our analysis. Sensitivity analyses supported result stability, and publication bias assessment revealed no selective reporting (Egger’s test P = 0.363＞ 0.05; symmetrical funnel plot).

3.5. VKAs vs. Control

7 studies (4565 patients) assessed bleeding risks between VKAs and controls. Similar to DOACs, VKAs indicated an increased risk of bleeding (RR = 3.35, 95 % CI: 2.31–4.85, P＜0.0001), with no heterogeneity (I² = 0 %). Due to the extremely low heterogeneity, we used a fixed-effects model for our analysis. Results remained stable in sensitivity analyses, and no publication bias was observed (Egger’s test P = 0.382 ＞ 0.05; symmetrical funnel plot).

4. Discussion

For an extended period, standardized guidelines on anticoagulant therapy for patients undergoing dental surgery were lacking. The question of whether anticoagulant therapy should be discontinued, dose-reduced, or continued during dentoalveolar surgery has remained a subject of ongoing debate. Anticoagulant therapy is essential in reducing the risk of thromboembolism, particularly in patients with a range of systemic conditions [45]. Traditionally, VKAs have been regarded as the cornerstone therapy for systemic anticoagulation. However, VKAs come with several limitations, such as the requirement for frequent adjustments to ensure the international normalized ratio (INR) stays within the desired therapeutic range. Additionally, VKAs are prone to numerous interactions with food and other drugs, have a delayed onset of action, and are often used alongside heparin, which further elevates the risk of bleeding complications [3], [4], [46]. In contrast, DOACs offer several advantages by targeting specific coagulation factors, thereby addressing many of the limitations of VKAs. DOACs demonstrate superior efficacy and safety profiles, including a faster onset of action, fewer food and drug interactions, and the convenience of not requiring routine monitoring [47]. These benefits position DOACs as a promising alternative in the management of thromboembolic diseases.

Notably, a meta-analysis of randomized controlled trials demonstrated that DOACs can reduce the risk of major bleeding by 32–69 % compared to VKAs [48]. Ma et al. demonstrated that, based on pooled data from randomized controlled trials, apixaban exhibited the most favorable safety profile for non-major clinically relevant bleeding, followed by VKAs, dabigatran, and rivaroxaban [49]. Edoxaban was found to have the least favorable safety profile among the anticoagulants. For minor bleeding events, apixaban demonstrated the best safety profile, followed by edoxaban in second place, dabigatran in third, and VKAs exhibiting the highest risk. Chan et al. reported that, in patients with non-valvular atrial fibrillation, dabigatran was associated with a reduced risk of major bleeding, ischemic stroke, and intracranial hemorrhage compared to VKAs [50]. Furthermore, dabigatran was linked to a lower risk of both major bleeding and intracranial hemorrhage compared to rivaroxaban. Our research results identified that dabigatran as superior to VKAs in terms of postoperative bleeding, whereas rivaroxaban, apixaban, and edoxaban showed no significant differences. While dabigatran etexilate can locally inhibit thrombin at the surgical wound, the systemic anticoagulant effect is easier to control due to its short half-life and the support of reversal agents. In contrast, the Xa inhibitor factor has a wide range of effects and is difficult to reverse, making it more difficult to balance postoperative hemostasis [51].

At present, there is no agreement among dentists on whether oral anticoagulants should be withheld before performing dentoalveolar surgery. Some authors suggest that patients undergoing dentoalveolar surgery either not stop anticoagulation or only omit the morning dose on the day of surgery [17], [18], [22]. However, there is not enough robust evidence at present to confirm this view. The studies included in our review show that the incidence of bleeding following dentoalveolar surgery in patients on oral anticoagulants varies significantly across studies, ranging from 0 % to 46 % [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44]. This variability is likely due to the relatively small sample sizes of anticoagulant-treated patients in these monocentric studies, which has contributed to inconsistent recommendations across multiple guidelines, further complicating risk assessment. The American College of Surgeons advises stopping DOACs 24–48 h before tooth extraction and resuming them 24 h after the procedure [52]. In contrast, the European Heart Rhythm Association advises administering the final dose of DOACs 18–24 h before surgery in cases of minimal bleeding risk, with resumption 6 h postoperatively (with the possibility of omitting one dose for dabigatran or apixaban) [53]. A recent survey conducted across Germany, Switzerland, and Austria showed that 94 % of dentists continue to administer VKAs during single tooth extractions, whereas 62 % opt to discontinue DOACs for such procedures [54]. Similarly, a survey in Australia found that one-third of general dentists would pause DOAC treatment in patients undergoing tooth extractions [55]. This indicates that dentists remain cautious when conducting oral surgery on patients who are using oral anticoagulants.

Curto et al. classified dental procedures into two categories based on the associated risk of bleeding: low-risk and moderate-to-high-risk procedures [56]. Low-risk procedures typically involve uncomplicated tooth extractions, oral surgeries that are completed in less than 45 min. These procedures are generally considered to have a lower likelihood of complications, making them safer for patients, including those on anticoagulant therapy. In contrast, procedures involving the removal of more than three teeth or lasting over 45 min are considered moderate to high risk. They suggested that for these higher-risk procedures, specialist consultation is recommended to determine whether discontinuation of anticoagulants is warranted. For procedures categorized as low-risk, it is generally unnecessary to stop dabigatran use. Additionally, apixaban can be continued at its standard dosage the day after the procedure without increasing the risk of bleeding complications. In contrast, for intermediate- to high-risk procedures, dabigatran and apixaban should be withheld for at least 48 h and 24 h, respectively. In patients with compromised renal function, it may be necessary to extend the duration of anticoagulant discontinuation to reduce the risk of bleeding. Additionally, bridging therapy with low-molecular-weight heparin (LMWH) should be considered to maintain appropriate anticoagulation during this period.

A study by Manor et al. found that dual therapy with antiplatelet and anticoagulant agents did not increase the incidence of postoperative bleeding [32]. Similarly, a meta-analysis by Ockerman et al. demonstrated that not interrupting antiplatelet therapy prior to minor oral surgery did not elevate the risk of postoperative bleeding [57]. In our study, a subgroup analysis was conducted to evaluate the impact of concomitant antiplatelet therapy. The results indicated that the risk of bleeding in patients on DOACs or VKAs who were also receiving antiplatelet drugs was not significantly increased. Furthermore, the bleeding tendency in patients on DOACs was lower than that of patients on VKAs.

The lower bleeding risk associated with DOACs compared to VKAs may be attributed to the distinct pharmacokinetic profiles of the two drug classes. VKAs exert their anticoagulant effect by inhibiting multiple coagulation factors and have a long half-life, exceeding 55 h, without circadian variation [58]. In contrast, DOACs have a shorter half-life, typically ranging from 7 to 17 h [59]. The interval between the last dose of DOACs and the planned surgery is critical for reducing the bleeding risk in patients. Additionally, the overall safety profile of DOACs appears to be more favorable than that of VKAs. However, given the limited literature on the use of anticoagulants in dentoalveolar surgery, it is crucial to interpret our findings in the context of studies evaluating bleeding risk with DOACs and VKAs in other surgical procedures. A recent meta-analysis of randomized controlled trials found that patients undergoing catheter ablation for atrial fibrillation had a notably lower risk of major bleeding when treated with DOACs compared to those using VKAs [60]. Raschi et al. further highlighted that while DOACs substantially reduced the risk of intracranial bleeding, they may increase the risk of gastrointestinal bleeding [61]. Notably, our subgroup analysis revealed a significantly lower bleeding risk with dabigatran compared to VKAs. In contrast, no statistically significant differences were observed between VKAs and rivaroxaban, apixaban, or edoxaban. Substantial heterogeneity was detected in the edoxaban subgroup, likely attributable to the limited number of included studies and small sample sizes, which reduced statistical power.As the first commercially available direct oral anticoagulant, dabigatran benefits from more mature clinical research, including a larger body of high-quality studies demonstrating consistent outcomes and low heterogeneity. However, due to methodological limitations—particularly the observational design of included studies and limited precision in some estimates—we downgraded the overall evidence quality. Consequently, these findings warrant cautious interpretation and require validation through future rigorously designed studies.

It is important to note that, because routine laboratory monitoring is typically not needed for DOAC therapy, more invasive dental procedures, such as multiple tooth extractions, can often be managed by spreading treatment over several visits [43]. In contrast, for patients on VKAs, it is necessary to check the INR before surgery, enabling the completion of a single, more comprehensive dental procedure, which is generally more convenient and cost-effective than multiple appointments. At the same time, it is also a challenge for the general condition of elderly patients. Compared to VKAs, DOACs offer a quicker onset of action, a more consistent anticoagulant effect, a broader therapeutic window, and fewer drug interactions. The properties of DOACs can greatly simplify perioperative anticoagulation management, allowing for a shorter interruption of anticoagulant therapy and a reduced risk of thromboembolism when compared to VKAs. This makes DOACs a favorable option for patients undergoing oral surgery.

Clinically, many dentists who advocate for the uninterrupted use of oral anticoagulants express greater concern about the risk of embolic events in patients who temporarily discontinue anticoagulation therapy. Douketis et al. conducted a study focusing on patients with atrial fibrillation who selectively interrupted DOACs treatment for short periods [62]. Although the sample size was relatively small, the results indicated that a minority of these patients experienced postoperative arterial and venous thromboembolism. To date, no cases of severe bleeding associated with dental procedures have been reported in anticoagulated patients. In contrast, there have been multiple reports of rebound hypercoagulation and serious embolic events in patients who stopped warfarin therapy for dental procedures [63]. Furthermore, Vene et al. demonstrated a 20-fold increase in the risk of short-term thromboembolic events following the cessation of dabigatran and rivaroxaban [64]. Additionally, a significant accumulation of thromboembolic events has been observed within the first week after discontinuation of DOACs. The risk of thromboembolism associated with the discontinuation of anticoagulation therapy for dental surgery has yet to be quantified, primarily due to the brief duration of treatment interruption and the small sample sizes in most studies. Our review of the literature supports these observations, revealing that postoperative bleeding in patients requiring additional hemostatic measures was effectively managed with favorable outcomes. Sutures, pressure, gelatin sponge, oxidized cellulose, chitosan-based hemostatic agents, and sponges impregnated with tranexamic acid are effective strategies for achieving postoperative hemostasis. This suggests that the bleeding risk associated with uninterrupted anticoagulation therapy is minimal and manageable. In contrast, postoperative thromboembolism represents a far more severe and often unacceptable complication. Although this analysis demonstrated an increased risk of postoperative bleeding in patients receiving DOAC or VKA therapy, clinically consequential bleeding events, such as those requiring hospitalization or causing irreversible harm, were infrequently reported in the included literature. We contend that this risk remains manageable in clinical practice. Therefore, we propose that the uninterrupted use of oral anticoagulants during dentoalveolar surgery remains a viable and relatively safer approach.

Our review had several limitations. First, not all of the included studies were prospective; approximately one-third were retrospective analyses based on medical records, which may be subject to inherent biases. Conducting methodologically robust randomised controlled trials (RCTs) is often limited by ethical constraints, posing challenges to achieving high-quality evidence in certain clinical contexts. The GRADE assessment showed the level of evidence to be very low, and the results should be interpreted with caution.Additionally, the definition of bleeding varied across studies, potentially leading to either an overestimation or underestimation of bleeding outcomes. We could only evaluate postoperative bleeding events, as data on postoperative bleeding was largely unavailable. Furthermore, the extent of invasiveness associated with dentoalveolar surgery varied across the studies included in the analysis. The degree of procedural invasiveness represented a crucial variable that may influence the frequency and severity of bleeding episodes. The risk of postoperative bleeding varied between extracting teeth that cannot be preserved due to advanced periodontitis and the removal of complex impacted teeth. All of these factors can contribute to heterogeneity. Although these studies had serious biases, they provided valuable data relevant to our research question and represented the best available evidence at the time of our review. These biases may have influenced the study results and may limit the generalizability of the findings. We recommend that future studies address these biases more rigorously to improve the reliability of research findings in this field.

5. Conclusions

Our review compared the bleeding risk of patients on uninterrupted DOACs versus VKAs following dentoalveolar surgery. We found that patients receiving DOACs or VKAs have an increased risk of bleeding during dentoalveolar surgery. However, severe bleeding requiring hospitalization or causing irreversible damage is rare. Patients using DOACs appear to have a lower bleeding risk compared to those on VKAs. This difference is mainly observed with dabigatran etexilate, while it remains unclear for rivaroxaban, apixaban, and edoxaban. The current quality of evidence is very low, and these findings should be interpreted with caution. Future studies with higher quality evidence are required to strengthen the validity of these findings.

Author contributions

DK and SY performed literature searching, data collection and ana lyses, drafted the manuscript. DK and YBY provided help in the literature searching and figure revises. ZZG critically reviewed the manuscript. All authors agree to be accountable for the study.

Ethics approval

Not applicable.

Funding

Not applicable.

CRediT authorship contribution statement

Ke Dou: The data collection, Analysis, Interpretation.

Declaration of Competing Interest

The authors declare that they have no competing financial or personal relationships with other people or organizations that could influence their work.

Footnotes

Scientific field of dental Science: Oral and Maxillofacial Surgery; Dental Pharmacology

^{Appendix A}

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jdsr.2025.08.002.

Contributor Information

Ke Dou, Email: 1574673547@qq.com.

Yue Shi, Email: 1923377428@qq.com.

Baoyi Yang, Email: christineyaang@163.com.

Zhiguo Zhao, Email: zhaozhiguo1980@126.com.

Appendix A. Supplementary material

Supplementary material

mmc1.docx^{(13.6KB, docx)}

Supplementary material

mmc2.docx^{(23.9KB, docx)}

Data availability statement

The data of individual participants behind the results reported in this paper will be shared with researchers who provide reasonable suggestions on methods after identification.

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Supplementary Materials

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Data Availability Statement

The data of individual participants behind the results reported in this paper will be shared with researchers who provide reasonable suggestions on methods after identification.

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PERMALINK

Risk of bleeding with dentoalveolar surgery in patients taking direct oral anticoagulants or vitamin K antagonists: A systematic review and meta-analysis

Ke Dou

Yue Shi

Baoyi Yang

Zhiguo Zhao

Abstract

Objective

Methods

Results

Conclusions

1. Introduction

2. Materials and methods

2.1. Study design and literature search

2.2. Eligibility criteria

2.3. Data extraction

2.4. Quality assessment

2.5. Data analysis

3. Results

3.1. Search results and studies selection

Fig. 1.

3.2. Basic characteristics and quality assessment

Table 1.

Fig. 2.

Fig. 3.

3.3. DOACs vs. VKAs

3.4. DOACs vs. Control

3.5. VKAs vs. Control

4. Discussion

5. Conclusions

Author contributions

Ethics approval

Funding

CRediT authorship contribution statement

Declaration of Competing Interest

Footnotes

Contributor Information

Appendix A. Supplementary material

Data availability statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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