INTRODUCTION

The fact that the elderly population is increasing in the country makes it increasingly frequent to face patients on chronic oral anticoagulant treatment. And much more those who will be operated through oral surgical procedures such as dental extractions³.

Stopping treatment before surgery increases the risk of thromboembolism. On the other hand, not stopping it could mean bleeding episodes that are difficult to control. Therefore, it is necessary to know the perioperative management of the different anticoagulant drugs, in order to reduce the risks and complications associated with the suspension or maintenance of these in the perioperative and postoperative period⁴.

To achieve this objective, the risk of bleeding versus the risk of thromboembolic events must be evaluated and balanced, considering the medical condition of each patient and the type of surgical procedure they will receive⁵.

Today there is a new generation of drugs called Direct Oral Anticoagulants, or DOACs⁶.

These drugs were introduced to the market since 2011. They are synthetic drugs that act specifically by inhibiting thrombin formation. Among the most widely used are dabigatran, rivaroxaban and apixaban⁸.

In general, they have numerous advantages over warfarin, such as its predictable pharmacokinetics, administration in fixed oral doses, shorter half-life, rapid action, few interactions with other drugs, and less probability of generating intracranial hemorrhages⁹.

It is possible that the characteristics and advantages of DOACs make them the most suitable anticoagulants in the future¹⁰.

As they are relatively new medications, the literature regarding them in the area of dentistry is limited. Although to date there are clinical recommendations indicating when to withdraw the drug in the event of surgery, all the guidelines are from the same pharmaceutical companies that generated the drugs and are based on probable clinical estimates, based on pharmacokinetics and standardized values¹¹.

In addition to this, there is no clear consensus on monitoring blood tests, and those that exist for them aren’t validated¹².

The purpose of this review is to deepen the theoretical and practical knowledge that a dental surgeon must have about the mechanism of action of these new drugs, in order to know how to handle DOAC anticoagulated patients who will undergo oral surgery.

 

Material and method

An electronic search was carried out in the databases: PubMed, SCOPUS, EBSCO and BEIC, with no language limit, of articles published between the years 2011 to July 2018. The Mendeley® software was used as a reference manager. The different search strategies were generated by combining the keywords, using the Boolean operators OR and AND.

The same search strategy was generated for the PubMed, EBSCO and BEIC databases. Three different search strategies were used for the Scopus database, one for each anticoagulant studied, as shown in the table below:

I. Selection strategy

Among the articles obtained, all those related to the topic were selected by reading the title and then the abstract, and then all the repeated articles were eliminated. The remaining articles were read in full text and the inclusion and exclusion criteria shown below were applied:

1. Inclusion criteria:

• Studies in adults.
• Studies in subjects under anticoagulant therapy with DOAC.
• Studies in patients undergoing oral surgery
• Studies that include guidelines or recommendations on the management of anticoagulated patients.

2. Exclusion criteria

• Studies in patients under anticoagulant treatment with another medicine that was not exclusively dabigatran, rivaroxaban or apixaban.
• Studies in patients with dual anticoagulant therapy.

II. Level of evidence and degree of recommendation

The analysis of the level of scientific evidence and the degree of recommendation was evaluated according to the parameters of the Center for Evidence Based Medicine¹³.

III. Report quality

The reporting quality of the selected articles was measured with the PRISMA guideline for systematic reviews, iCAHE for clinical guidelines, STROBE for observational studies and CARE for case reports.

IV. Ethical aspects

International ethical guidelines for biomedical research in human beings, carried out by the Council of International Organizations of Medical Sciences (CIOMS) (18) were considered. The existence of the following parameters was evaluated:

• Approval of the study by an ethics committee.
• Declaration of absence of conflict of interest by the authors.
  

V. Descriptrion of results

A descriptive analysis of the different existing protocols for patients under DOAC undergoing oral surgery was carried out, regarding three parameters: Anticoagulant suspension, perioperative management and postoperative management of the patient.

 

Results

From all the databases used, a total of 4781 articles were obtained. These were filtered by title, discarding those that were not related to the research question. From the 207 articles chosen, 98 were repeated. From the remaining 109, the inclusion and exclusion criteria were applied, eliminating 80. Then the full text was read and 19 final recruits were recruited (Figure 1).

 

Figure 1. Outline of results.
Elaborado: Los autores

The analysis of the level of evidence and the degree of recommendation was performed using the Oxford Center for Evidence-Based Medicine (CEBM) guideline (Table I).

Table 1. Level of evidence, degree of recommendation, quality of report and declaration of conflict of interest.

Elaborado: Los autores

Discussion

On the preoperative, perioperative and postoperative management of patients under DOAC in oral surgery:

Firriolo and colls. (2012) carried out a bibliographic review in which they published a series of recommendations based on experiences and opinions of other experts. Specifically, in the case of dabigatran, they noted that it would not be necessary to suspend the drug before treatment, especially when there are local hemostatic measures such as sutures, gels, or traxenamic acid rinsed for 5 days. However, they recommend that, in case of known hemostasis problems in the patient, consideration should be given to discontinuing the medication at least 24 hours earlier or longer, depending on the risk of probable bleeding, kidney function, and the presence of other medications.

Since the anticoagulant effect stabilizes rapidly, re-incorporation of the next dose should be considered at least 24 to 48 hours after tooth extraction or once the clot is visibly stable⁵⁵.

Weitz and colls. (2012) published a case of a patient taking dabigatran who presented bleeding complications that were difficult to manage postoperatively. Together with the case, they present a systematic review and conclude that 10 hours of waiting after the last dose of the drug gives a safe working range, without the need to suspend it⁵⁶.

Spyropoulos and colls. (2012) published a series of clinical cases of DOAC anticoagulated patients undergoing different types of major surgery. In the article, the authors mention bridging therapy, used in warfarinized patients as an antithromboembolic protocol during major surgery, in which warfarin treatment is replaced by low-molecular-weight heparin prior to the procedure and is resumed during the following days. postoperative period³. To date, there are no case reports of bridge therapy applied in DOAC-treated patients undergoing dental surgery. The authors refer that this protocol should be used only in patients with intermediate or high thromboembolic risk.

Van Dierman and colls. (2013) conducted an extensive systematic review of patients on dabigatran undergoing different types of surgery, which they propose as a clinical guide for general dental surgeons. Patients were selected to undergo simple dental treatments (up to 3 tooth extractions or implants, flaps, alveoloplasties and apicoectomies) and were given the following recommendations: Do not stop taking the medicine or take it for up to 3 hours after the procedure. Pre and postoperative measures were taken, such as minimizing local trauma, sutures, use of hemostats, and local pressure. No subsequent complications were reported⁷.

Cohen et al. (2013) conducted a review and developed a clinical management guide for patients anticoagulated with any of the 3 drugs studied. In it they recommend making a detailed medical history of the patient, asking about previous episodes of excessive bleeding associated with the use of anticoagulants or diseases of some kind. They also suggest that, in these patients, interventions such as simple tooth extractions or localized periodontal surgery should be done at the first visit to assess bleeding, followed by local hemostatic measures such as gelites and sutures. In the case of complex surgeries where increased bleeding is expected, consideration should be given to postponing the medication for 48 hours, after consulting with the attending physician. If the post-operative wound heals properly, he recommends taking the medication the day after surgery.

All these recommendations consider a healthy patient, without kidney or liver disease. If this is the case, the drug should be suspended for up to 5 days, depending on the opinion of the treating physician⁵⁷.

Romond et al. published in 2013 a case report of a 67-year-old patient treated with dabigatran 150 mg in 2 daily doses, who had to undergo 8 tooth extractions and preprosthetic surgery. They asked him to stop the medication 2 hours before surgery. It was performed under sedation and local hemostatic measures were taken such as anesthesia with vasoconstrictor, gelite and immediate positioning of the prosthesis. The patient had minimal bleeding during the following week and the wound healed correctly. The medicine was taken up the next day. The authors highlight not having had the antidote for dabigatran, which they considered sufficient reason to suspend the drug taking into account the magnitude of the surgery. They conclude that tooth extraction under dabigatran or involves an increased risk of bleeding but that there must be a consensus between the dentist and the attending physician⁶.

Breik and colls. (2014) published a recommendation guide based on a case series of 5 anticoagulated dabigatran patients undergoing single or multiple tooth extractions. The authors recommend not removing the drug in procedures with little risk of bleeding, such as periodontal treatment, endodontics, or simple rehabilitation. They also do not mention that the drug should be suspended before a simple uncomplicated tooth extraction, since bleeding can be managed with local hemostatic measures such as suture and Gelite. In cases where several extractions are required, the consultation with the treating physician should be made, suggesting the suspension of the drug 24 hours before or up to 48 hours before if the patient presents abnormal renal function. APTT or TT can be evaluated prior to surgery for monitoring. Dabigatran can be replaced 24 or 48 hours after the procedure¹⁰.

Curtin and colls. published in 2014 a review in which they emphasize the lack of clear clinical guidelines for the management of these patients and recommend the reader to know the existence, brand name and generic name of DOACs, as well as their interactions with other drugs and always consult with the treating physician⁵⁸.

Sivolella and colls. published a review in 2015 summarizing all previous publications on the management of patients taking dabigatran undergoing oral surgery. They concluded that the management of these patients is essentially based on the drug's half-life and kidney function. They also note that there are no clear protocols in this regard50.

Val and colls. performed a systematic review published in 2016 of 8 series of cases on anticoagulated patients with DOAC and other drugs between 2005 and 2015⁵⁹. They conclude that for dental procedures in which a risk of minimal or low bleeding is estimated, no Dabigatran and rivaroxaban must be discontinued in patients with normal renal function, since bleeding can be managed with local hemostatic measures.

Hanken and colls. published in 2016 a retrospective observational study that compared a group of 52 patients treated with rivaroxaban 20 mg daily, who underwent 1 to 6 tooth extraction or implant placement without suspending DOAC, compared to 285 healthy subjects subjected to the same interventions. The authors found an increased risk of bleeding complications in only 6 cases, all of them treatable with local hemostatic measures (local pressure, fibrin sponges, gelites and suture)44. Therefore, they conclude that it is not necessary to suspend the drug.

In the study by Abayon and colls. The same conclusion was reached in 2016. They evaluated a series of cases of 25 patients receiving 20 mg daily of rivaroxaban or apixaban undergoing different dental procedures, including simpe tooth extractions. Three strategies were followed: No interruption, partial interruption or total interruption of the drug. They concluded that whatever protocol was chosen, performing extractions was a safe procedure to do when the basic measures of local hemostasis are applied correctly⁶⁰.

A similar result was reached from the study by Caliskan and colls. (2017). It seems that in the case of simple tooth extractions in anticoagulated patients with DOAC, it is not necessary to alter or suspend the usual dose, since subsequent bleeding (if any) is controllable with local hemostatic measures⁵⁴.

Unlike classical medication, such as warfarin, which is adjusted according to the patient's INR, DOACs are prescribed in fixed doses. Depending on their pharmacokinetics, patients who do not have normal kidney or liver function will always have a high plasma concentration. This should always be taken into account when complex extraction is required or extensive incisions are required.

The multidisciplinary approach is important in this type of scenario. Knowing how to make a correct inter-consultation indicating the procedure, the expectation of bleeding, the time that the intervention will take and the size of the bloody wound are data that the dentist should provide to the patient treating physician so that, added to the patient's systemic condition, it can be decided if the drug suspension is necessary.

It seems that the use of local hemostatic measures is also very important in the postoperative management of anticoagulated patients. It highlights the use of gelitas and sutures. Although the success of both was not quantified in any of the studies included in this review, the authors report that their use was sufficient measures for the control and prevention of postoperative bleeding.

In summary, the final equation that must be put in the balance when deciding whether or not to stop the anticoagulant mainly considers two things:

The risk of thromboembolism (influenced by the time that has passed since anticoagulant treatment and dose were started).
And the risk of perioperative or postoperative bleeding (based on the number of teeth to be extracted, the time the surgery will take and the experience of the operator).

If you decided to suspend the drug, then the surgery should be rescheduled calculating the date based on the patient's kidney function in order to estimate the time it will take for the anticoagulant to clear and thus ensure hemostasis.

All authors agree that local hemostatic measures must always be available, even when anticoagulant treatment has been discontinued. The most named are: The use of gelites, hemostatic sutures, local pressure and traxenamic acid embedded in gauze^44.49–53.

It is also recommended as a general rule to try a procedure as atraumatic as possible and not to extract more than 3 teeth per session^27.35.45.

The summary of the recommendations described by each author are found in Table II.

 

Table. Management protocols according to the author.

Elaborado: Los autores

Conclusions

1. Both DOAC suspension and maintenance during oral surgery appear to be equally safe alternatives.
2. The management of anticoagulated patients in oral surgery should be based on the cost-benefit evaluation of the patient, taking into account the thromboembolic risk and the ability to control an intra or postoperative bleeding event.
3. More comparative studies with larger population samples are required to assess the real impact of performing oral surgery on anticoagulated patients.
4. Knowledge of local hemostatic measures in oral surgery is essential for the management of anticoagulated patients.

 

Conflicts of interest: The author declares that he has no conflict of interest.

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Javiera Mora; https://orcid.org/0000-0002-4636-7946