SUMMARY

• If anticoagulation must be discontinued to reduce the risk of bleeding associated with any surgery or procedure, XARELTO should be stopped at least 24 hours before the procedure. In the case of all emergency-type procedures, the risk of bleeding should be weighed against the need for surgery.¹
• In 1 randomized study of 57 patients, no statistically significant differences were found in bleeding episodes during and after dental implant placements among patients receiving uninterrupted XARELTO therapy and healthy volunteers receiving placebo.²
• In a prospective study, no statistically significant differences were found in the frequencies of post-extraction hemorrhaging in patients on XARELTO compared to warfarin or dabigatran, (P=0.209 vs. P=0.425), respectively.³
  • The frequency of post-extraction hemorrhaging in patients on XARELTO and patients not on any anticoagulant was 5.88% and 0.39%, respectively. The difference between the two groups was significant (P=0.002).
• There are currently no evidence-based, standard national guidelines issued by organizations such as the American Dental Association (ADA) or the American Association of Oral and Maxillofacial Surgeries on the dental management of patients receiving target-specific oral anticoagulants such as XARELTO. The ADA has a consensus statement discussing anticoagulant medication regimens during dental procedures.^4,5
• The use of anticoagulation during a dental procedure is based on the physician’s clinical assessment of the individual patient. Some factors of consideration are the type and complexity of the surgical procedure, the presence and degree of any renal impairment, and the presence of other risks for hemostasis.⁴
• The terminal elimination half-life of XARELTO is 5 to 9 hours in healthy subjects aged 20 to 45 years. The terminal elimination half-life is 11 to 13 hours in the elderly.¹
• Additional retrospective studies were identified during a literature search and are summarized for your review.^6-9

PRODUCT LABELING

Dosage and Administration

Surgery and Intervention

If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, XARELTOshould be stopped at least 24 hours before the procedure to reduce the risk of bleeding. In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention. XARELTO should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. If oral medication cannot be taken after surgical intervention, consider administering a parenteral anticoagulant.¹

Clinical Pharmacology

Pharmacokinetics

XARELTO is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of XARELTO is 5 to 9 hours in healthy subjects aged 20 to 45 years.¹

GUIDELINES

ANTICOAGULATION MANAGEMENT DURING DENTAL PROCEDURES

The ADA does not provide specific guidelines on patients taking target-specific anticoagulant agents. A consensus paper issued by the ADA in 2012 states that the anticoagulation management of dental patients should be based on the type and complexity of the surgical procedure, the presence and degree of any renal impairment, and the presence of other risks for hemostasis (liver impairment, alcoholism, kidney failure, thrombocytopenia, hemophilia/other hematological disorders, cytotoxic medication).⁴

There is no increased risk of bleeding associated with continuation of anticoagulant therapy during minor procedures such as tooth extractions.⁴ For more complicated procedures such as oral/maxillofacial surgeries, administration of an anticoagulant agent should not be restarted until the risk of postoperative bleeding is minimal (eg, after a stable fibrin clot is formed), usually within 24-48 hours following surgery, because the onset of the anticoagulant effect of these drugs is rapid (compared with warfarin).^5,10 Procedures with presumed bleeding risks are presented in Table: Dental Procedures and Associated Bleeding Risk.¹¹

CLINICAL DATA

Gomez-Moreno et al (2016)² conducted a prospective, randomized clinical trial to evaluate the incidence of bleeding complications after dental implant placement in patients taking uninterrupted XARELTO therapy.

Study Design/Methods

• The study included 57 patients, divided into 2 groups: 18 patients (12 men and 6 women ranging from 46 to 73 years) who received XARELTO therapy for over 6 months before the implant surgery and a control group of 39 healthy patients without primary or secondary coagulation disorders.
• Both groups were comparable for age, sex, and extent and site of the surgical implant procedures. Key exclusion criteria included patients who had antecedents of bleeding episodes in previous oral surgical interventions, patients in treatment by other drugs with a coagulant action, hemophilia, metabolic bone disorders, a history of renal failure, poor oral hygiene, periodontal disease, and a bleeding index >20%.
• All patients taking XARELTO received dental implants without interruption or modification of XARELTO dosage.
• All surgical procedures were performed in an outpatient setting. Nonabsorbable sutures were used, and all patients were given gauze with tranexamic acid 5% to bite on for 30-60 minutes.
• The primary endpoint was the number of bleeding complications during the 8-day postoperative follow-up period.

Results

• In all patients, the peri-implant tissue status was good, inflammation signs were not observed, and the healing time was normal.
• One XARELTO patient presented with moderate bleeding (defined as large clots disrupting the surgical area and requiring additional hemostatic measures) the day after surgery, and 2 control patients presented with moderate bleeding the day after and on the second day. Bleeding was managed with gauzes impregnated with tranexamic acid.
• No statistically significant differences (P=0.688) were found in the number of bleeding episodes between groups.

Hiroshi et al (2022)³ conducted a prospective, multicenter study (across 68 hospitals in Japan from November 2008 to December 2015) to evaluate the frequency of bleeding events post tooth extraction in patients receiving continuous DOAC administration compared to continuous warfarin administration, or non-administration of anticoagulants. Additionally, the study aimed to observe the effects of the timing of DOAC (dabigatran or XARELTO) administration, and the timing of tooth extraction on the frequency of hemorrhages post-extraction.

Study Design/Methods

• Simple extractions, defined as extraction procedures that did not involve detachment or eversion of the mucoperiosteal flap and shaving of the alveolar bone, were performed on the cases evaluated.
• The inclusion criteria consisted of the following: age ≥20 years old, treatment by surgeon with ≥3 years of experience, tooth extraction time ≤15 min, a platelet count of ≥100,000 for 7 days post-extraction, and a prothrombin time-international normalized ratio (PT-INR) of <3.0 for 7 days post-extraction in patients on warfarin who did not discontinue or require a dose reduction of warfarin to undergo the tooth extraction.
• Hemorrhage post-extraction was defined as:
  • Observation of oozing hemorrhage on or the day after the procedure, and with hemostasis achieved using simple compression.
  • Hemorrhage requiring treatment other than wound compression.

Results

• Overall, of the 51 patients (35.2%) continuously administered XARELTO, the average age was 70.6±10.2 years, 29 patients (56.9%) were men, and 22 patients (43.1%) were women.
• Patients in the XARELTO group (average age: 70.1 ± 9.51 years) had a total of 88 teeth extracted, of which 62 (70.5%) and 26 (29.5%) were extracted from males and females, respectively.
• According to the analysis by each patient, the frequency of post-extraction hemorrhaging in the XARELTO group was 5.88% vs 2.77%, 3.19%, and 0.39% in the warfarin (P=0.209), dabigatran (P=0.425), and the group that received no anticoagulants (P=0.002), respectively. See table: Incidences of clinically significant post-extraction bleeding and their difference
• According to the analysis by each tooth, the frequency of post-extraction hemorrhaging in the XARELTO group was 3.41% vs 3.63%, 1.65%, and 0.39% in the warfarin (P=1.000), dabigatran (P=0.395), and the group that received no anticoagulants (P=0.008), respectively. See table: Incidences of clinically significant post-extraction bleeding and their difference
• Hemorrhaging after extraction in patients on XARELTO occurred in 3 patients who were treated between 9 AM and 12 PM. See table: Incidence of clinically significant post-extraction bleeding according to the timings of direct oral anticoagulant administration and tooth extraction
• According to a multivariant analysis, the extraction technique (odds ratio [OR]: 25.808; P=0.039) and the use of nerve block injections to the inferior alveolus (OR: 31.606; P=0.044) were identified as risk factors for hemorrhage after extraction in the XARELTO group.

Real-World EVIDENCE

Ono et al (2022)⁶ conducted a retrospective study that compared the risk of post-extraction bleeding in patients on warfarin (n=1557) or DOACs (n=3696) from the DeSC database (large-scale administrative claims database in Japan) between April 2015 to November 2020. The post-extraction bleeding was assessed 7 days after the extraction. In the weighted population (n=517.7 for both groups), the incidence of post-extraction bleeding was 1.9% vs 2.2% (OR: 0.86; 95% confidence interval [CI]: 0.47-1.57) or revisit was 1.3% vs 1.5% (OR: 0.91; 95% CI: 0.43-1.95) and there was no difference between XARELTO and warfarin, respectively.

Lababidi et al (2018)⁷ conducted a retrospective, controlled, cohort study to evaluate a noncessation protocol for patients taking (DOACs; XARELTO, n=26; apixaban, n=14; and dabigatran, n=3) compared to warfarin during dental extractions. Patients on DOAC therapy (n=43 underwent 53 dentoalveolar procedures) were compared to patients on uninterrupted warfarin therapy (n=50 underwent 59 dentoalveolar procedures). Under physician advice, 15 of the 53 dentoalveolar procedures were performed following perioperative cessation of a DOAC. Minor bleeding events were recorded in the warfarin (n=9) and noncessation DOAC group (n=4), 15.3% and 10.5%, respectively, showing no statistically significant difference (odds ratio: 0.65; P=0.56). Patients in the DOAC session group recorded no bleeding events.

Cocero et al (2019)⁸ conducted a retrospective cohort study of patients (N=100) undergoing tooth extractions while continuing DOACs (dabigatran, n=39; apixaban, n=37; XARELTO, n=24). Incidence of excessive bleeding occurring from a few hours up to 7 days following extractions was the primary endpoint. There was no bleeding in the patient population without comorbidities (0%; 95% CI: 0-8%). In patients with comorbidities, 4 bleeding cases were identified (6.25%; 95% CI: 2.5-15%; P=0.29); 3 cases were mild (2 with apixaban and 1 with XARELTO) and 1 was moderate (XARELTO). Extractions of couples and triples of multirooted teeth (P=0.004) significantly triggered bleeding in patients with comorbidities.

Miller et al (2018)⁹ conducted a retrospective cohort study of 12 patients on DOACs (XARELTO, n=7; apixaban, n=2; dabigatran, n=2; and edoxaban, n=1) undergoing 17 oral surgical procedures. In 52.9% of the cases (n=9), the DOAC was discontinued, vs 5.8% (n=1) and 41.2% (n=7) of cases in which the DOAC was continued or not recorded, respectively. There were no reports of bleeding complications for any of the patients.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 07 June 2023.