Efficacy and Safety of Direct Oral Anticoagulants After Mechanical Thrombectomy in Venous Thromboembolism: A Comparative Study of 55 Patients

Introduction

Inherited thrombophilia predisposes individuals to venous thromboembolism (VTE), although antithrombin (AT), protein C (PC), and protein S (PS) deficiencies are less common in Asian populations [1]. Mechanical thrombectomy has emerged as a promising technique to restore blood flow in patients with VTE. This minimally invasive procedure helps reduce the need for extensive post-procedural critical care and leads to improvements in symptoms and overall health status, making it an attractive option for many patients [2,3]. Direct oral anticoagulants (DOACs) are increasingly preferred over traditional vitamin K antagonists for VTE treatment. This preference is largely due to the better safety profile of DOACs, which are associated with a lower risk of bleeding and do not require regular monitoring of blood coagulation levels [4]. There is anecdotal evidence suggesting benefit from DOAC use in patients with AT, PC, and PS deficiencies, leading to increasing prevalence of DOAC use in these patients [5]. However, the effectiveness of DOACs in treating severe cases of VTE after mechanical thrombectomy, especially in Asian patients with inherited thrombophilia, remains unclear. Previous studies involving various DOACs indicated no significant difference in VTE recurrence or major bleeding in patients with thrombophilia treated with DOACs, compared with those treated with vitamin K antagonists; however, they showed a lower recurrence rate [6–8]. Additionally, case reports suggest that DOACs are effective in patients with severe inherited thrombophilia; however, non-adherence can lead to significant recurrence issues [9]. According to current guidelines, catheter-directed thrombectomy can be considered in selected patients with high-risk (massive) pulmonary embolism (PE) or in those with extensive proximal deep vein thrombosis (DVT), particularly in cases of iliofemoral DVT. This approach is recommended for patients who are at risk of developing severe post-thrombotic syndrome or when rapid clot removal is necessary to prevent life-threatening complications or medical thrombolysis failure [10,11]. For VTE patients with thrombophilia, the choice of OACs depends on patient-specific factors, such as renal function and bleeding risk [11].

There is a lack of studies specifically investigating the efficacy and safety of DOACs in Asian patients with inherited thrombophilia undergoing mechanical thrombectomy. Due to the gap in knowledge, we conducted a retrospective study to compare the efficacy and safety of DOACs for symptomatic VTE in Asian patients with and without inherited thrombophilia undergoing mechanical thrombectomy. Therefore, this study aimed to evaluate the use of DOACs combined with mechanical thrombectomy in 55 patients diagnosed with VTE, including 11 patients with confirmed DVT and PE, 27 patients with DVT alone, and 17 with PE alone, from a single center between January 2016 and December 2023.

Material and Methods

ETHICS STATEMENT:

This retrospective study, approved by the Institutional Review Committee of Chi Mei Medical Center (approval number 11112-007), was conducted in strict accordance with the ethical guidelines of the 1975 Declaration of Helsinki to ensure the protection of human participants in medical research. Given the retrospective design of the study, which involved data analysis, informed consent from the participants was not required. This waiver was granted in accordance with ethical standards and regulatory policies, acknowledging that the study posed minimal risk to participants and did not involve direct interaction with them.

This observational study was conducted according to the STROBE guidelines.

PATIENT POPULATION AND ENROLLMENT:

Between January 2016 and December 2023, a total of 55 patients were diagnosed with VTE and underwent a mechanical thrombectomy. We enrolled all of the patients and compared the patients with and without thrombophilia. Among these, 11 had both DVT and PE, 17 had PE alone, and 27 had DVT alone. We excluded patients who did not undergo clot testing for thrombophilia or did not receive mechanical thrombectomy for symptomatic VTE. All diagnoses of PE were confirmed by computed tomography, and DVT was confirmed by either computed tomography or ultrasonography.

Fourteen patients had a diagnosis of reduced function of the AT (n=4), PC (n=6), or PS (n=4) and were classified as group 1 (with thrombophilia). The remaining 41 patients, who did not have thrombophilia, were classified as group 2 (without thrombophilia). We enrolled the patients with VTE and compared those with thrombophilia (n=14) to those without (n=41). Baseline characteristics, general demographics, comorbidities, use of DOACs, and outcomes, including recurrent VTE and bleeding events, were compared between the 2 groups.

DEFINITIONS:

AT deficiency is diagnosed when AT activity is less than 75% of the normal activity level (reference range: 80–120% of normal activity); PC deficiency is diagnosed when PC activity is less than 70% of the normal activity level (reference range: 70–140% of normal activity); and PS deficiency is diagnosed when the free PS antigen level is less than 55% of the normal antigen level (reference range: 60%–120% of normal antigen level). These values are expressed as a percentage of normal activity or antigen levels. All the assays were performed twice to confirm the diagnosis.

The definition of recurrence of VTE typically refers to the development of a new thrombotic event in the same or different location after an initial episode has been treated or is being treated [12]. Gastrointestinal bleeding refers to any form of hemorrhage that occurs in the gastrointestinal tract and extends from the mouth to the anus [13]. Ecchymosis, defined in our study as discoloration of the skin resulting from bleeding underneath and associated with anemia and the need for blood transfusions, is typically caused by bruising [14]. All-cause mortality was defined as death from any cause, including sepsis or malignancy.

STRATEGY AND DOSING OF DOACS:

After mechanical thrombectomy and heparinization to maintain an APTT ratio of 2.0 to 2.5, DOACs were introduced once the patient’s hemodynamic condition stabilized, and most of the thrombus had resolved. Dabigatran was administered at 150 mg twice daily following 5 to 10 days of initial parenteral anticoagulation. Rivaroxaban was used at 15 mg twice daily for the first 21 days, followed by 20 mg once daily for long-term treatment. Apixaban was started at 10 mg twice daily for 7 days, followed by 5 mg twice daily for maintenance. Edoxaban was administered at a standard dose of 60 mg once daily after 5 to 10 days of parenteral anticoagulation, with a reduced dose of 30 mg once daily for patients with a body weight of ≤60 kg or with moderate renal impairment. The choice of DOACs was determined by the physician.

STUDY ENDPOINTS:

The primary endpoints of the study were carefully selected to provide a comprehensive assessment of patients’ health outcomes over the follow-up period. These endpoints included VTE recurrence, which is critical for evaluating the efficacy of the treatment protocols used. Additionally, we monitored various bleeding events, including gastrointestinal bleeding, hematuria, and ecchymosis. Furthermore, all-cause mortality was monitored throughout the follow-up period, with DOAC treatment maintained for at least 3 to 6 months, if no adverse effects, and extended based on the physician’s judgment. Patients were followed up at the outpatient department until death.

STATISTICAL ANALYSES:

The data used in this study are presented in several formats to ensure clarity and comprehensiveness. Continuous variables are expressed as the mean±standard deviation (SD). Categorical variables are presented as numbers and percentages to facilitate comparison. For continuous variables, an independent sample t test was used to determine whether there were any statistically significant differences between the means of the 2 groups. For categorical variables, the chi-square test was used to assess the association between groups. Statistical significance was set at a P value of less than 0.05, indicating that results with P values below this threshold were considered statistically significant. All statistical analyses were conducted using SPSS software for Windows, Version 22, which provides a robust platform for data analysis and ensured the accuracy and reliability of the results.

Results

COMPARISON OF BASELINE CHARACTERISTICS AND DEMOGRAPHICS:

In the comparison of baseline characteristics between group 1 (n=14) and group 2 (n=41), as shown in Table 1, there was no statistically significant difference in the presentation of PE between the groups (group 1: 42.9% vs group 2: 53.7%; P=0.547). There was no statistically significant difference in the mean age between the groups (group 1: 55±19.9 years vs group 2: 59±18.8 years; P=0.457). There were no significant differences in the OAC treatment period, comorbidities, or baseline renal function between the groups. There was no statistically significant difference between the groups in the percentage of patients who switched to different OAC therapies (group 1: 7.1% vs group 2: 19.5%; P=0.283). Overall, the data suggested no substantial differences between the 2 groups across the various baseline characteristics measured.

COMPARISON OF CLINICAL OUTCOMES OF RECURRENT VTE AND ALL-CAUSE MORTALITY:

In the comparison of clinical outcomes between the 2 groups (Table 2), there was no statistically significant difference in VTE recurrence (group 1: 7.1% [1/14] vs group 2: 17.1% [7/41]; P=0.664). There was no significant difference in the incidence of bleeding events between the 2 groups (group 1: 35.7% [5/14] vs group 2: 17.1% [7/41]; P=0.259). There was also no significant difference in the incidence of gastrointestinal bleeding between the 2 groups (group 1: 14.3% [2/14] vs group 2: 9.8% [4/41]; P=0.645). Hematuria was noted only in group 2 (2.4% [1/41]), and the incidence of ecchymosis between the 2 groups approached statistical significance (group 1: 21.4% [3/14] vs group 2: 4.9% [(2/41]; P=0.066). There was no significant difference in the incidence of all-cause mortality between the 2 groups (group 1: 7.1% [1/14] vs group 2: 6.7% [2/41]; P=0.903). One patient in group 1 died, and the cause of death was pneumonia, while 2 patients in group 2 later died of malignancy and sepsis.

CLINICAL PRESENTATION AND MEDICATION USE IN PATIENTS WITH THROMBOPHILIA:

The clinical presentation and medication use in patients with thrombophilia are detailed in Table 3, which shows a diverse range of characteristics and treatments. The table includes 14 patients of varying ages, from 23 to 83 years, and body mass index (BMI) ranging from 15.6 to 31.8 kg/m2. Creatinine levels ranged from 0.58 to 1.5 mg/dL. The identified types of thrombophilia included AT, PC, and PS deficiencies. The index events predominantly involved iliofemoral vein thrombosis and bilateral pulmonary trunk embolisms. The medications used for OAC included rivaroxaban, apixaban, dabigatran, and edoxaban, with treatment durations varying from 1 to 23 months. Notably, 1 patient switched from edoxaban to dabigatran, highlighting an adaptation the treatment strategy. This table underscores the heterogeneity in the clinical presentation and therapeutic approaches in patients with thrombophilia.

Discussion

STUDY LIMITATIONS:

This study has several limitations. First, it was a retrospective, nonrandomized study with a limited sample size, which may have introduced selection bias, and existing records may not capture all clinical details. The small sample size limits the generalizability of the findings and reduces the power to detect subtle differences. All the patients in our study underwent mechanical thrombectomy for symptomatic VTE. Second, the timing of mechanical thrombectomy and the choice of DOAC were based on the physician’s judgment. Third, not all patients underwent follow-up imaging to confirm thrombus resolution. Despite these limitations, our study provides important information on the use of DOACs in patients with severe VTE and inherited thrombophilia.

Conclusions

We found no difference in the efficacy and safety of DOACs between VTE patients with and without inherited thrombophilia undergoing mechanical thrombectomy.