Residual Direct Oral Anticoagulant Activity in the Preoperative Setting: Review of the Literature and a Pilot Study Regarding Direct Oral Anticoagulant Preoperative Interruption (Based on Guidelines) and Its Correlation with Patient Characteristics and Blood Product Transfusion

Abstract

Direct oral anticoagulants (DOACs) have been licensed worldwide for several years for various indications. Each year, 10–15% of patients receiving oral anticoagulants will undergo an interventional procedure, and expert groups have issued several guidelines for perioperative management in such situations. According to the PAUSE study, the proposed randomized strategy of stopping DOACs without bridging therapy in patients with atrial fibrillation was associated with low rates of major bleeding and arterial thromboembolism so that its implementation is increasingly safe. The present study was carried out in order to investigate the efficacy and safety of the standardized perioperative DOAC management strategy by measuring the residual activity of oral anticoagulants when stopping them preoperatively in daily practice in a regional hospital. Thirty-two patients were included in the present study. They were patients who suffered from atrial fibrillation or deep vein thrombosis and were receiving an oral anticoagulant, rivaroxaban or apixaban at the indicated dose. These patients underwent an elective surgery or invasive procedure at the Karditsa General Hospital between May 2022 and April 2023. The results showed that in a percentage of >90% of the patients on the day of surgery they had a residual anti-Xa activity below 0.5 U/mL. This rate is considered high and confirms the safety and efficacy of the guideline-recommended protocol for perioperative discontinuation of DOACs.

1. Introduction

Thromboembolic conditions such as atrial fibrillation (AF), deep vein thrombosis (DVT) and pulmonary embolism (PE) are currently a challenge for the clinicians since their incidence of these events is rapidly increasing. Nowadays, direct oral anticoagulants (DOACs) have become the first therapeutic choice in the management of most of these clinical settings [1]. These medications, known as rivaroxaban, apixaban, dabigatran and edoxaban, offer distinct advantages over traditional vitamin K antagonists (VKAs) [2]. These advantages include a fixed dosing regimen, a rapid onset of action and no requirement for routine monitoring [3]. However, despite this fact, a key challenge remains, regarding the management of patients on DOAC therapy in the presence of residual anticoagulant activity, particularly in the preoperative setting.

The proper management of DOACs in the perioperative environment is always a difficult task in daily clinical practice, as it requires a good understanding of the pharmacokinetics of the administered DOAC, its indications, its interactions with other drugs and the changes it may cause in laboratory tests [4]. This information should always be considered to allow clinicians to quickly and easily recognize potential problems, enabling them to resolve them.

Regarding the pharmacokinetics of these drugs and their residual activity, DOACs differ in their pharmacokinetic properties, influencing their half-life and the persistence of anticoagulant effects. For instance, the half-life of rivaroxaban and apixaban, which are known factor Xa inhibitors, is about 5–9 h, while dabigatran, which is a known direct thrombin inhibitor, has a half-life of around 12–17 h [5]. On some occasions, these half-lives may extend, such as in patients with renal impairment, eventually prolonging the drug’s activity [6]. In the preoperative setting, this residual activity can pose a risk of bleeding during surgery if the drug is not appropriately managed [7].

However, challenges are still present, especially in preoperative management, as in this setting, difficulties lie in balancing the need for adequate anticoagulation to prevent thromboembolic events and the desire to minimize bleeding risks during surgery [8]. The timing of discontinuation of DOACs is critical to minimize residual activity. General guidelines recommend stopping most DOACs 24–48 h before surgery, depending on renal function and the type of surgery being performed [4]. For patients with impaired renal function, a longer window may be required to allow the drug to clear the system.

In emergent situations, though, where immediate reversal is necessary, the management of residual DOAC activity becomes more complex. Traditional strategies, such as the use of prothrombin complex concentrates (PCCs) or activated charcoal (in the case of recent ingestion), have been explored [9]. The development of specific reversal agents for DOACs, such as andexanet alfa (for factor Xa inhibitors) and idarucizumab (for dabigatran), has been a significant advancement in managing this residual activity [10]. These agents can rapidly neutralize the anticoagulant effect, thereby reducing the risk of bleeding in the perioperative period [11].

Moreover, in some cases, testing for residual DOAC activity may be considered before surgery, especially if the timing of the last dose is unclear, or if there is concern about the patient’s renal function. Several laboratory tests can help assess the degree of anticoagulation, such as the anti-Xa assay (for factor Xa inhibitors) or diluted thrombin time (for dabigatran) [12]. These tests can provide more precise information regarding the level of residual anticoagulant activity, helping guide clinical decisions.

Residual DOAC activity in the preoperative setting can increase the risk of bleeding complications during surgery, particularly in procedures that involve high bleeding risks (e.g., neurosurgery, major vascular surgery). Therefore, careful consideration of the patient’s renal function, type of surgery and the specific DOAC used is essential when determining when to hold the medication [1]. Close collaboration between the surgical team, anesthesiologists and hematologists can help ensure optimal patient outcomes.

Managing residual DOAC activity in the preoperative setting remains a complex and evolving challenge. While the benefits of DOACs are undeniable in the prevention of thromboembolic events [13], their anticoagulant effect must be carefully managed to minimize bleeding risks during surgery. Effective strategies include timely discontinuation, the use of reversal agents in certain cases and laboratory testing for residual activity. Ongoing research and the development of better guidelines and tools will likely improve the safety and efficiency of perioperative management in patients on DOAC therapy.

2. Materials and Methods

We therefore conducted a pilot study, in light of the published PAUSE study [14], with the main objective of measuring the residual activity of oral anticoagulants during their discontinuation preoperatively in order to achieve the following:

• Highlight the reliability and safety of the proposed protocol, based on guidelines, regarding the perioperative management of oral anticoagulants in real-time clinical practice at a regional hospital.
• Explore potential associations with patient-related factors such as renal and liver function, as well as hematological parameters.
• Document the blood products that may be required postoperatively and whether they are related to the increased bleeding risk associated with patients receiving DOACs.

Thirty-two patients were included in this study. These patients had atrial fibrillation or deep vein thrombosis and were receiving oral anticoagulants, either rivaroxaban or apixaban, at the appropriate dose. They all underwent scheduled surgery or invasive procedures at the General Hospital of Karditsa from May 2022 to April 2023.

2.1. Inclusion and Exclusion Criteria

2.1.1. Inclusion Criteria

The following inclusion criteria needed to be met for the participation in this study in accordance with the PAUSE study [14]:

• Patient age ≥ 18 years.
• Use of oral anticoagulant either for atrial fibrillation or for deep vein thrombosis:
  Rivaroxaban at a dose of 20 mg or 15 mg daily; or
  Apixaban at a dose of 5 mg × 2 or 2.5 mg × 2 daily.
• Scheduled surgery requiring discontinuation of oral anticoagulants preoperatively.
• Ability to comply with the study protocol.

2.1.2. Exclusion Criteria

Patients were excluded from the study if they had any of the following criteria in accordance with the PAUSE study [14]:

• Creatinine clearance (CrCl), as estimated by the Cockcroft–Gault equation [15]:

  ✓

  CrCl < 30 mL/min for patients receiving Rivaroxaban, or

  ✓

  CrCl < 25 mL/min for patients receiving Apixaban,

  since these DOACs are contraindicated if CrCl is below these thresholds.
• Communication difficulties that hindered the reliable collection of information related to the protocol.
• Inability or unwillingness to provide consent.

2.2. Study Methodology

The protocol implemented for this study is presented in detail in Figure 1. This specific protocol was approved by the Scientific Council of Karditsa Hospital, Thessaly, in June 2022 (Protocol No. 11340/02-06-2022/Decision No. 518). The analysis plan comparing values before and after DOAC discontinuation was defined in advance.

The processing of the samples was strictly for research purposes and anonymous, with no processing or use of the patients’ personal data under any circumstances. All experiments using human specimens were carried out according to the ethical guidelines of the institutional board.

2.3. Patient Characteristics

Thirty-two patients were included in this study, and their characteristics are presented in

Table 1. Patients’ basic characteristics.

Patients’ Characteristics	Patients	Team Rivaroxaban	Team Apixaban
	n = 32	n = 16	n = 16
Age (mean ± SD, %), y	75.9 (13.2)	74.6 (13.4)	77.2 (13)
Sex
male	13	8	5
female	19	8	11
Scheduled surgical procedure #
High hemorrhagic risk	17	7	10
Low hemorrhagic risk	15	9	6

NOTE: The number of patients with available results for each parameter is indicated by n. ^# The classification of high–low hemorrhagic risk was based on the guidelines of the local institutional board on the preoperative determination of bleeding risk.

. There were 19 women (59%) and 12 men (41%), all of whom were receiving oral anticoagulants and were admitted to the General Hospital of Karditsa for scheduled surgery between May 2022 and April 2023.

The average age of the patients was 75.9 years (SD 13.2). The patients were taking either rivaroxaban or apixaban, with 16 patients in each group.

The scheduled surgical procedures included the following:

✓

Cystoscopies: 5.

✓

Fractures (femur, tibia, patella, radiocarpal): 15.

✓

Hernias (inguinal hernia, hydrocele): 5.

✓

Hip and knee arthroplasty: 2.

✓

Others: 1 endometrial scraping, 1 pilonidal cyst, 1 carpal tunnel syndrome, 1 cholecystectomy and 1 cellulitis.

The surgical procedures were classified as either low or high bleeding risk, as shown in

Table 2. Classification of surgical procedures depending on hemorrhagic risk.

Type of Surgery Hemorrhagic Risk	Cystoscopy	Fracture	Arthroplasty	Hernia	Other	Total
Low	5	-	-	5	5	15
High	-	15	2	-	-	17

. The classification of high–low hemorrhagic risk was based on the guidelines of the local institutional board on the preoperative determination of bleeding risk. The discontinuation of the oral anticoagulant treatment was scheduled 24 to 48 h before the surgery.

The measurement of the activity of DOACs was performed at two different time points:

The first measurement was taken on the scheduled day of the patient’s admission to the hospital to determine the therapeutic levels of the drug, as the patient had been taking their medication normally up until that point. The second measurement was taken on the day of the surgery, while the patient had discontinued the medication 1 or 2 days prior, depending on the protocol, to determine the residual activity of the drug preoperatively.

On the day of admission to the hospital, an additional check was performed for each patient individually:

Renal function (urea–creatinine);

Liver biochemistry (aspartate aminotransferase–SGOT and alanine aminotransferase–SGPT);

Coagulation test (PT, APTT, fibrinogen, D-dimers);

Hematological test (complete blood count, hemoglobin, platelets);

Height and weight were recorded for each patient, and BMI was calculated individually.

Throughout their hospitalization, the blood product transfusions administered preoperatively, intraoperatively, and postoperatively were recorded.

2.4. Blood Processing Methods and Coagulation Assays Used

The pre-procedure blood sample was collected into a Vacutainer tube (Rongye Technology Co., Ltd., Yangzhou, China) containing sodium citrate (0.109 M, 3.2%). The sample was centrifuged for 10 min at 3500 rpm. Plasma was separated into aliquots and stored at 70 °C at the regional hospital. Plasma samples were shipped to be analyzed at the Hematological and Coagulation Laboratory Department of University Hospital Larissa by laboratory technologists who were blinded to patient characteristics.

The following coagulation function tests and assays were used: prothrombin time (PT; HemosIL, Instrumentation Laboratory Company, Bedford, MA, USA), activated partial thromboplastin time (aPTT; HemosIL, Instrumentation Laboratory Company, USA), fibrinogen (FIB; HemosIL, Instrumentation Laboratory Company, USA), d-dimers (D-D; HemosIL, Instrumentation Laboratory Company, USA) and anti-factor Xa levels (anti-Xa; HemosIL, Instrumentation Laboratory Company, USA). All testing was performed on an ACLTOP 750 CTS analyzer (ANTISEL Company, Thessaloniki, Greece). The reference intervals for these assays are as follows: PT = 10.2–13 s; INR = 0.85–1.15; aPTT = 25.1–36.5 s; FIB = 180–400; D-D = 0–243; anti-factor Xa levels = 0.3–0.7. However, the therapeutic range of ant-Xa levels depend on the clinical setting.

2.5. Statistical Analysis

The statistical evaluation of the obtained data was carried out using SPSS v19.0 software (University of Thessaly) and the application of non-parametric methods. The determination of the mean value of each variable examined in this study was calculated using descriptive statistics. The mean expression value of a variable in the various groups that emerged was compared using the Mann–Whitney U test.

3. Results

A total of thirty-two patients were included in the study, as mentioned earlier, the data of whom, after analysis, are presented in

Table 3. Overall characteristics of the patients under examination.

Patients’ Characteristics	Patients	Team Rivaroxaban	Team Apixaban
	n = 32	n = 16	n = 16
Age (mean ± SD, %), y	75.9 (13.2)	74.6 (13.4)	77.2 (13)
Sex
male	13	8	5
female	19	8	11
BMI (mean ± SD, %)	28.5 (4.8)	29.2 (4.1)	27.8 (5.5)
Laboratory parameters(mean ± SD, %)
Hemoglobin, g/L	11.9 (2.4)	12 (2.2)	11.7 (2.7)
Platelets, ×106/L	243 (93)	248 (74)	238 (111)
Creatinine, μmol/L	1 (0.4)	0.97 (0.3)	1.1 (0.5)
Creatine Clearance, mL/min	76.5 (42.6)	83.6 (43.7)	69.4 (41.6)
Medical Instruction
Lower DOAC dose §	11	2	9
Scheduled surgical Procedure #
High Hemorrhagic risk	17	7	10
Low Hemorrhagic Risk	15	9	6

NOTE: The number of patients with available results for each parameter is indicated by n. Abbreviations: BMI, body mass index; DOAC, direct oral anticoagulants. ^# The classification of high–low hemorrhagic risk was based on the guidelines of the local institutional board on the preoperative determination of bleeding risk. ^§ Rivaroxaban, 15 mg; apixaban, 2.5 mg × 2.

.

The patients were divided into two groups based on the anticoagulant they were taking (rivaroxaban or apixaban):

3.1. Rivaroxaban Group

A total of 16 patients participated in this group, 8 of whom were men (50%) and 8 of whom were women (50%). The average age of the patients was 74.6 years (SD 13.4). The average BMI was 29.2 (SD 4.1). This is a group with a relatively elderly population and an increased BMI.

All patients, except for two, received the full dose of the anticoagulant at 20 mg, while the remaining two patients received a dose of 15 mg based on the treating physician’s decision. The first case involved a 91-year-old patient with a GFR of 50, and the second case involved an 84-year-old patient with a GFR of 46.

The dose of rivaroxaban given to the patients was in accordance with the guidelines for renal function and liver biochemistry and was adjusted based on each patient’s results.

3.2. Apixaban Group

A total of 16 patients participated in this group, 5 of whom were men (31%) and 11 of whom were women (69%). The average age of the patients was 77.2 years (SD 13), and they were older than the rivaroxaban group. The average BMI was 27.8 (SD 5.5). Again, this is a group with an elderly population and an increased BMI.

Nine of the sixteen patients received a reduced dose of the anticoagulant at 2.5 × 2 mg, while the remaining seven received the full dose of 5 × 2 mg. According to the drug’s SPC, the recommended dose of apixaban is 2.5 mg, taken orally twice daily for patients who meet at least two of the following criteria:

Age ≥ 80 years;

Body weight ≤ 60 kg;

Serum creatinine ≥ 1.5 mg/dL.

For the nine patients in the Apixaban group who received a reduced dose, all were older than 80 years, but only four had serum creatinine values ≥ 1.5 mg/dL. The dose of anticoagulants given to the patients was in accordance with the guidelines for renal function and liver biochemistry and was adjusted based on each patient’s results.

3.3. Anti-Xa Activity

The cut-point of 50 ng/mL was used to define a clinically acceptable low residual anticoagulant effect and was based on the reference range of the anti-Xa assay as therapeutic ranges of heparin levels are 50 ng/mL [16]. Moreover, it was also mainly decided based on the PAUSE study protocol [14], as there is no widely accepted cut-point that defines a safe level of residual anticoagulation to allow a surgery/procedure to proceed. Alternative cut-points such as 30 ng/mL are also discussed in this study.

DOAC discontinuation for each patient was based on the assessed bleeding risk. Therefore, 15 patients were scheduled for low-bleeding-risk procedures and DOAC discontinuation was performed 24 h before surgery, while 17 patients were scheduled for high-bleeding-risk procedures and DOAC discontinuation was performed 48 h before surgery.

In the total group of patients (n = 32), the preoperative anti-Xa activity of the DOACs was 0.87 U/mL (SD 0.82), with a maximum value of 2.97 U/mL and a minimum of 0 U/mL. On the day of surgery, the anti-Xa activity of the DOACs was 0.24 U/mL (SD 0.36), with a maximum of 1.88 U/mL and a minimum of 0 U/mL. The average GFR was 76.5 (SD 42.6), with a maximum value of 160 and a minimum of 26.

The average residual anti-Xa activity in the total group of patients as well as in the individual subgroups is presented in

Table 4. Mean value of residual anti-Xa activity in various groups (U/mL).

	Group	Group Rivaroxaban n = 16	Group Apixaban n = 16	Total n = 32
Surgery
Overall results		0.12	0.35	0.24
Low Hemorrhagic Risk		0.08 n = 9	0.27 n = 6	0.18 n = 15
High Hemorrhagic Risk		0.16 n = 7	0.37 n = 10	0.27 n = 17

.

Overall, among the 32 patients under investigation, 29 (91%) showed residual anti-Xa activity levels below 0.5, and 26 patients (81%) had activity levels below 0.3.

3.3.1. Anti-Xa Activity in the Rivaroxaban Group

Regarding anti-Xa activity:

Preoperatively, in this group, the average value was 0.45 U/mL (SD 0.4), with a maximum value of 1.35 U/mL and a minimum value of 0 U/mL.

Two patients out of sixteen had zero anti-Xa levels preoperatively.

On the scheduled day of surgery, the residual anti-Xa activity had an average value of 0.12 U/mL (SD 0.2), with a maximum value of 0.5 and a minimum value of 0.

On the day of surgery, 7 out of 16 patients (44%) had zero residual activity levels, including the 2 patients who had zero drug levels preoperatively.

Additionally, 15 out of 16 patients (94%) showed residual activity below 0.3 on the day of surgery, and all patients (100%) had residual activity ≤ 0.5 on the day of surgery.

In this group, seven surgeries had a high hemorrhagic risk, and nine had a low hemorrhagic risk. Blood and blood product transfusion were required by 6 (38%) out of 16 patients, specifically as follows:

Four patients received one unit of red blood cells (RBCs) postoperatively, related to high-hemorrhagic-risk surgeries.

Two patients received intensive transfusions both preoperatively and perioperatively:

The first patient received nine RBC units and two platelet concentrates, with a preoperative hemoglobin value of 9 g/L and platelets at 190,000. This patient underwent a high-hemorrhagic-risk surgery (femoral fracture) and had renal dysfunction with creatinine levels of 1.49 and a GFR of 36. Additionally, the patient had prolonged PT-INR and aPTT times. However, they had low anti-Xa activity levels below 0.3 both preoperatively and on the day of surgery.

The second patient received three RBC units and one fresh frozen plasma (FFP), and they underwent a high-hemorrhagic-risk surgery (shin fracture) with normal renal function. This patient also had low anti-Xa activity levels below 0.3 U/mL both preoperatively and on the day of surgery. Hemoglobin and platelet counts were 11.7 g/L and 187,000, respectively. The patient had prolonged PT-INR and aPTT times.

3.3.2. Anti-Xa Activity in the Apixaban Group

Regarding anti-Xa activity:

Preoperatively, in this group, the average value was 1.28 U/mL (SD 0.9), with a maximum value of 2.97 and a minimum value of 0.

One patient out of sixteen had zero anti-Xa levels preoperatively.

On the scheduled day of surgery, the residual anti-Xa activity had an average value of 0.35 U/mL (SD 0.5), with a maximum value of 1.88 and a minimum value of 0.

However, among the 16 patients, 11 (69%) had residual activity below 0.3 on the day of surgery, and 14 (88%) had residual activity ≤ 0.5 on the day of surgery.

Two patients showed zero residual activity levels, including the one patient who had zero drug levels preoperatively.

In this group, 10 surgeries were of high hemorrhagic risk, and 6 were of low hemorrhagic risk. Blood and blood product transfusion were required by 8 (50%) out of 16 patients, specifically as follows:

Seven patients received one to two RBC units postoperatively, related to high-hemorrhagic-risk surgeries. One patient received intensive transfusions both preoperatively and postoperatively, as their preoperative hemoglobin was 5 g/L and platelets were at 150,000. The patient received six RBC units and two FFPs and underwent a high-hemorrhagic-risk surgery (femoral fracture) but had low anti-Xa activity levels below 0.3 on the day of surgery. This patient also received a reduced dose of medication, had normal renal function and showed prolonged PT-INR and aPTT times.

In general, postoperative transfusion needs were not significant, except for three patients who underwent surgeries with increased hemorrhagic risk, particularly femoral fractures. An interesting finding is that the rivaroxaban group had lower anti-Xa activity levels compared to the apixaban group, and more patients in the rivaroxaban group had levels ≤ 0.3 U/mL compared to the apixaban group

Statistical analysis of the data did not reveal statistically significant correlations between various parameters in the groups under investigation (total patients, rivaroxaban group, apixaban group). All p values were > 0.05.

4. Limitations

This study has limitations. The limited sample size of 32 patients significantly restricts the statistical power of this study and therefore further analysis is needed with the incorporation of more patients. Additionally, the 50 ng/mL cut-off point used in this study to define a clinically important residual preoperative DOAC level was not established. Further studies are needed to better assess the correlation between preoperative DOAC treatment and bleeding risk among patients.

5. Discussion

The proper management of DOACs in the perioperative setting is always a challenging task in everyday clinical practice, as it requires a good understanding of the pharmacokinetics of the administered DOAC, its safety profile [17,18], its indications, interactions with other drugs and the changes it may cause in laboratory tests. This information must always be considered so that clinicians can more quickly and easily identify potential problems and resolve them.

Every year, 1 in 6 patients with atrial fibrillation, or approximately 6 million patients worldwide, require perioperative management of oral anticoagulants [13]. Common questions raised in this clinical context concern the correct timing for perioperative discontinuation and re-initiation of DOAC therapy, whether bridging with heparin is needed and whether preoperative coagulation testing is necessary.

The uncertainty regarding the perioperative management of DOACs stems from the fact that a prolonged discontinuation of DOAC therapy may increase the risk of thromboembolism, while a very short discontinuation period may increase the risk of bleeding, which in turn delays the re-initiation of anticoagulation and leads to a vicious cycle.

Preoperatively, coagulation testing has been suggested to identify patients with unacceptable residual levels of anticoagulants, which would affect the timing of surgery. However, this suggestion is not a standard practice, as conventional coagulation tests in patients on oral anticoagulants are not entirely reliable or capable of making such decisions.

Most clinical studies published on the perioperative management of DOACs have not provided significant recommendations so far. Although monitoring residual activity of DOACs is not routinely recommended for patients on such medications, in specific cases, it can aid in decision-making.

The PAUSE study was the first to demonstrate high percentages of patients (>90%) with atrial fibrillation receiving oral anticoagulants, who exhibited residual drug activity below 50 ng/mL, and proposed the safe application of a specific protocol in this clinical context. Specifically, perioperative discontinuation of DOACs 24 or 48 h before surgery (depending on the type of surgery, with low or high bleeding risk, respectively) was associated with low rates of major bleeding and arterial thromboembolism, so the application of such a strategy is becoming increasingly safe.

This specific protocol was applied in the current study at a regional hospital, providing us with the opportunity to assess its application in everyday clinical practice and highlight its strengths as well as potential weaknesses in its implementation.

In the present study, which involved a statistical sample of 32 patients who were receiving oral anticoagulants (rivaroxaban or apixaban) and were admitted to Karditsa Hospital for scheduled surgery, it was found that more than 90% of patients on the day of surgery showed residual anti-Xa activity below 0.5 U/mL. This high percentage confirms the safety and effectiveness of the proposed protocol based on guidelines for perioperative discontinuation of DOACs. Notably, nine patients had zero anti-Xa activity levels on the day of surgery, further supporting the above finding. The results of our study in all groups, both in the total patient sample and in the individual subgroups, align with the findings of the PAUSE study.

In this study, no statistical correlations were found between the parameters under investigation, which is due to the small sample size (32 patients). Additionally, some patients (6/32) had zero drug levels on the day of their hospital admission, which could suggest patient non-compliance with the prescribed treatment or early drug discontinuation by the attending physician ahead of surgery to reduce the bleeding risk during the operation.

The optimal management of these patients remains an ongoing goal for clinicians and laboratory physicians, and further research is required so that the implementation of a simple and safe protocol can be adapted to any potential clinical and therapeutic context.

6. Conclusions

The present study confirmed the reliability and safety of the proposed protocol, based on guidelines, regarding the perioperative management of oral anticoagulants in clinical practice at a regional hospital. However, this study has limitations. The limited sample size of 32 patients significantly restricts the statistical power of this study and therefore further analysis is needed with the incorporation of more patients.

This specific protocol was implemented in a regional hospital and it appeared that its application is easy and feasible. The patients had no difficulties in understanding it and cooperated to complete it. More than 90% of patients exhibited residual anti-Xa activity below 0.5 U/mL on surgery day. This percentage is high and allows for a safe surgical process with the application of a simple and easy protocol with reduced hemorrhagic risk. It is also noteworthy that, in the rivaroxaban group, 94% of patients showed residual activity below 0.3 U/mL on the day of surgery, which is the optimal concentration at which a patient should be taken to surgery according to the PAUSE study. However, in the apixaban group, the corresponding percentage was only 56%.