Effectiveness and Safety of Direct Oral Anticoagulants in the Treatment of Visceral Vein Thrombosis

Foreword The “Hepatology Digest – Liver Vascular Diseases” column is a scholarly column co-initiated by Dr. Xingshun Qi from the Department of Gastroenterology at the General Hospital of Northern Theater Command, at the invitation of the editorial board of Hepatology Digest. This column regularly collects and summarizes research progress in the field of liver vascular diseases, selecting and discussing one significant paper every two weeks (Wednesday). The aim is to help readers understand the reasoning behind the findings, inspire clinical research thinking, and apply what they have learned in practice.

Article Summary Visceral vein thrombosis (VVT) is a rare type of venous thromboembolism (VTE), including portal vein thrombosis (PVT), mesenteric vein thrombosis, splenic vein thrombosis, and Budd-Chiari syndrome (BCS) (Di Nisio M, et al. Journal of Thrombosis and Haemostasis. 2020; 18: 1562-8). The treatment goal for VVT is to delay thrombus progression, promote vascular recanalization, and prevent VTE recurrence. Effective management strategies for VVT remain controversial. The American College of Chest Physicians (ACCP) guidelines recommend anticoagulation therapy for symptomatic VVT patients (grade 1B), and no anticoagulation for incidentally discovered VVT patients (grade 2C) (Kearon C, et al. Chest. 2012; 142(6): 1698-1704). For anticoagulation, it is recommended to start with low molecular weight heparin (LMWH) or unfractionated heparin (UFH) and transition to vitamin K antagonists (VKAs). The latest guidelines from the International Society on Thrombosis and Haemostasis (ISTH) suggest using full treatment doses of direct oral anticoagulants (DOACs) for acute symptomatic VVT in non-cirrhotic patients without active bleeding, although clinical evidence is limited (Di Nisio M, et al. Journal of Thrombosis and Haemostasis. 2020; 18: 1562-8).

In February 2024, Journal of Thrombosis and Haemostasis published a paper titled “Efficacy and safety of direct oral anticoagulants in splanchnic vein thrombosis: a pooled analysis of literature studies”, aiming to evaluate the effectiveness and safety of DOACs in treating VVT.

Calcaterra et al. systematically searched PubMed, Web of Science, and Scopus databases for articles on DOACs in the treatment of VVT, with the last search on July 11, 2023. Results were reported using weighted mean prevalence (WMP) and 95% confidence intervals (CI). A total of 1218 articles were identified, with 13 retrospective studies, 2 prospective studies, and 1 randomized controlled trial ultimately included, comprising 648 patients. Results showed partial recanalization, complete recanalization, VTE recurrence, mortality, and major bleeding rates of 60.3%, 51.7%, 2.8%, 3.4%, and 5.8%, respectively, following DOAC treatment. Subgroup analysis indicated consistent outcome rates across prospective, retrospective, cirrhotic, and PVT patient studies. Meta-regression analysis revealed that older age and cancer were associated with lower recanalization rates, while cirrhosis was associated with higher major bleeding and mortality rates.

In summary, DOACs exhibit good effectiveness and safety in treating VVT, but current conclusions are primarily based on observational studies, necessitating high-quality randomized controlled trials to confirm these findings.

Analysis of Key Research Findings and Their Clinical Significance

1. Study Selection Process A total of 1218 relevant articles were identified; after removing duplicates, 475 articles were screened, and 16 studies (648 patients) were included.
2. Quality Assessment of Included Studies Of the 16 included studies, 2 were high-quality, 1 was medium-quality, and 13 were low-quality.
3. Characteristics of Included Studies and Patients The 16 included studies involved 648 VVT patients treated with DOACs, with patient numbers ranging from 10 to 100, an average age of 52 years (38-65 years), and 58% male (20%-80%). The median duration of anticoagulation was 7.6 months (3.0-28.1 months).
4. Recanalization Eight studies reported partial recanalization in 321 patients treated with DOACs. The partial recanalization rate was 60.3% (95% CI: 41.8%-76.3%), with significant heterogeneity (I2=84.9%; P<0.001) and no significant publication bias (Egger’s P=0.866). Subgroup analysis showed partial recanalization rates of 74.4%, 55.8%, 83.9%, and 64.1% in prospective, retrospective, cirrhotic, and PVT patient studies, respectively, with no significant differences.

Ten studies reported complete recanalization in 445 patients treated with DOACs. The complete recanalization rate was 51.7% (95% CI: 36.0%-67.0%), with significant heterogeneity (I2=87.4%; P<0.001) and no significant publication bias (Egger’s P=0.800). Subgroup analysis showed complete recanalization rates of 44.3%, 54.4%, 54.2%, and 61.6% in prospective, retrospective, cirrhotic, and PVT patient studies, respectively, with higher rates in PVT patient studies.

1. VTE Recurrence Six studies reported VTE recurrence in 297 patients treated with DOACs. The VTE recurrence rate was 2.8% (95% CI: 1.4%-5.9%), with no significant heterogeneity (I2=0.0%; P=0.787) and no significant publication bias (Egger’s P=0.249). Subgroup analysis showed VTE recurrence rates of 1.8%, 3.7%, 2.1%, and 2.1% in prospective, retrospective, cirrhotic, and PVT patient studies, respectively, with no significant differences.
2. Mortality Nine studies reported mortality in 395 patients treated with DOACs. The mortality rate was 3.4% (95% CI: 1.6%-7.3%), with no significant heterogeneity (I2=13.2%; P=0.318) and significant publication bias (Egger’s P=0.0012). After Trim-and-Fill adjustment, the WMP estimate for mortality was 6.3% (95% CI: 3.0%-12.6%). Subgroup analysis showed mortality rates of 1.1%, 4.6%, 4.2%, and 4.5% in prospective, retrospective, cirrhotic, and PVT patient studies, respectively, with lower mortality in prospective studies.
3. Major Bleeding Sixteen studies reported major bleeding in 648 patients treated with DOACs. The major bleeding rate was 5.8% (95% CI: 3.7%-8.9%), with no significant heterogeneity (I2=29.2%; P=0.125) and significant publication bias (Egger’s P=0.010). After Trim-and-Fill adjustment, the WMP estimate for major bleeding was 8.9% (95% CI: 5.6%-13.9%). Subgroup analysis showed major bleeding rates of 3.5%, 6.5%, 7.6%, and 6.2% in prospective, retrospective, cirrhotic, and PVT patient studies, respectively, with higher rates in cirrhotic and PVT patient studies.
4. Meta-Regression Analysis Meta-regression analysis indicated that older age was associated with lower partial (Z=-2.631; P=0.009) and complete (Z=-4.268; P<0.001) recanalization rates, cancer was associated with lower complete recanalization rates (Z=-2.195; P=0.028), and cirrhosis and myeloproliferative diseases were associated with higher major bleeding rates (Z=2.388; P=0.017; Z=3.073; P=0.002) and higher mortality rates (Z=2.420; P=0.0155). However, anticoagulation duration had no significant effect on partial recanalization (Z=-0.792; P=0.428), complete recanalization (Z=-0.074; P=0.941), or major bleeding rates (Z=0.587; P=0.557).

Conclusion and Outlook This study confirms the good effectiveness and safety of DOACs in treating VVT, improving patient quality of life and adherence while ensuring treatment outcomes. For PVT patients, clinicians should comprehensively evaluate whether to use DOACs based on liver disease staging, thrombosis recurrence or progression risk, and bleeding risk. While this study recommends DOACs for VVT treatment, high-quality randomized controlled trials are needed in the future to compare the effects of traditional anticoagulants and DOACs on VVT patient outcomes.

Translator Xiaomin Wang, Department of Gastroenterology, General Hospital of Northern Theater Command, Dalian Medical University Graduate School.

Initiator and Reviewer of the Hepatology Digest – Liver Vascular Diseases Column Xingshun Qi, Director of the Department of Gastroenterology, General Hospital of Northern Theater Command, Adjunct Master’s Supervisor at China Medical University, Shenyang Pharmaceutical University, Dalian Medical University, and Jinzhou Medical University, Adjunct Doctoral Supervisor at Northeastern University and China Medical University, Postdoctoral Research Supervisor at the General Hospital of the Northern Theater Command, Representative of the Chinese Association for Science and Technology, Vice Chairman of the Integrative Cancer Predisease Committee of the Chinese Anti-Cancer Association, Youth Member of the 11th Committee of the Chinese Medical Association Gastroenterology Branch, Member of the Hepatobiliary Disease Group, Member of the Minimally Invasive Interventional Collaboration Group, Member of the Hepatology-Related Gastrointestinal Disease Collaboration Group of the Chinese Medical Association Hepatology Branch, Standing Member of the 11th Committee of the Liaoning Medical Association Gastroenterology Branch. Currently serves as Senior Editorial Board Member of BMC Gastroenterology, Editorial Board Member of Therapeutic Advances in Gastroenterology, and Academic Editor of the Canadian Journal of Gastroenterology and Hepatology. Recipient of the Outstanding Doctoral Dissertation Award of the Army in 2016. Included in the 2019 list of the Top Ten Young Talents of the 12th Liaoning Youth Science and Technology Award, Elsevier’s 2021, 2022, and 2023 lists of Highly Cited Chinese Researchers, Central Theater Command’s Key Talent in Science and Technology Innovation in 2022, Military Youth Science and Technology Talent of the Year 2022, and Youth Top Talent of the Xingliao Talent Plan in 2022. According to Scopus, his H-index is 48, with a total of 8060 citations.