Quantitative Benefit-Risk Evaluation of Rivaroxaban in Patients After Peripheral Arterial Revascularization: The VOYAGER PAD Trial.

BACKGROUND: The VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) trial compared rivaroxaban (2.5 mg twice a day) plus aspirin with aspirin alone in patients with symptomatic peripheral artery disease requiring endovascular or surgical limb revascularization, with 50% receiving clopidogrel background therapy. The New Drug Indication application includes benefit-risk assessments using clinical judgment to balance benefits against risks. During its review, the US Food and Drug Administration requested additional quantitative benefit-risk analyses with formal weighting approaches. METHODS AND RESULTS: Benefits and risks were assessed using rate differences between treatment groups (unweighted analysis). To account for clinical importance of the end points, a multi-criteria decision analysis was conducted using health state utility values as weights. Monte Carlo simulations incorporated statistical uncertainties of the event rates and utility weights. Intent-to-treat and on-treatment analyses were conducted. For unweighted intent-to-treat analyses, rivaroxaban plus aspirin would result in 120 (95% CI, -208 to -32) fewer events of the primary composite end point (per 10 000 patient-years) compared with aspirin alone. Rivaroxaban caused an excess of 40 (95% CI, 8-72) Thrombolysis in Myocardial Infarction major bleeding events, which was largely driven by nonfatal, nonintracranial hemorrhage Thrombolysis in Myocardial Infarction major bleeding events. For weighted analyses, rivaroxaban resulted in the utility equivalent of 13.7 (95% CI, -85.3 to 52.6) and 68.1 (95% CI, 7.9-135.7) fewer deaths per 10 000 patient-years (intent-to-treat and on-treatment, respectively), corresponding to probabilities of 64.4% and 98.7%, respectively, that benefits outweigh risks favoring rivaroxaban per Monte Carlo simulation. CONCLUSIONS: These analyses show a favorable benefit-risk profile of rivaroxaban therapy in the VOYAGER PAD trial, with findings generally consistent between the unweighted and weighted approaches.

Safety profile of rivaroxaban in first-time users treated for venous thromboembolism in four European countries.

BACKGROUND: The European rivaroxaban post-authorization safety study evaluated bleeding risk among patients initiated on rivaroxaban or vitamin K antagonists for the treatment and secondary prevention of venous thromboembolism in routine clinical practice. METHODS: Cohorts were created using electronic healthcare databases from the UK, the Netherlands, Germany and Sweden. Patients with a first prescription of rivaroxaban or vitamin K antagonist during the period from December 2011 (in the UK, January 2012) to December 2017 (in Germany, December 2016) for venous thromboembolism indication, with no record of atrial fibrillation or recent cancer history, were observed until the occurrence of each safety outcome (hospitalization for intracranial, gastrointestinal, urogenital or other bleeding), death or study end (December 2018; in Germany, December 2017). Crude incidence rates of each outcome per 100 person-years were computed. RESULTS: Overall, 44 737 rivaroxaban and 45 842 vitamin K antagonist patients were enrolled, mean age, 59.9-63.8 years. Incidence rates were similar between rivaroxaban and vitamin K antagonist users with some exceptions, including higher incidence rates for gastrointestinal bleeding in rivaroxaban users than in vitamin K antagonist users. Among rivaroxaban users, mortality and bleeding risk generally increased with age, renal impairment and diabetes. CONCLUSIONS: This study provides further data from routine clinical practice that broadly support safety profile of rivaroxaban for VTE indication and complement findings from previous randomized clinical trials.

The impact of factor Xa inhibitors on bleeding risk in patients with respiratory diseases.

It is unclear which factor Xa (FXa) inhibitors are associated with higher bleeding risk in patients with respiratory diseases, and there are no studies on the association between prothrombin time-international normalized ratio (PT-INR) and bleeding risk. We conducted a retrospective cohort study comparing 1-year-outcomes and PT-INR between patients with respiratory diseases treated with rivaroxaban (R group, n = 82) or edoxaban (E group, n = 138) for atrial fibrillation or venous thromboembolism from 2013 to 2021. The most frequent event of all bleeding discontinuations was respiratory bleeding in both groups (7.3 and 4.3%, respectively). The cumulative incidence of bleeding discontinuation was significantly higher in the R group (25.6%) than in the E group (14.4%) (hazard ratio [HR], 2.29; 95% confidence interval [CI] 1.13-4.64; P = 0.023). PT-INR after initiation of therapy significantly increased and was higher in the R group than in the E group (median value, 1.4 and 1.2, respectively; P < 0.001). Multivariate analysis using Cox proportional hazards and Fine-Gray models revealed that PT-INR after initiation of therapy was an independent risk factor of bleeding discontinuation events (HR = 4.37, 95% CI 2.57-7.41: P < 0.001). Respiratory bleeding occasionally occurs in patients receiving FXa inhibitors, and monitoring the PT-INR may need to ensure safety.

Mortality after major bleeding in Asian atrial fibrillation patients receiving different direct oral anticoagulants: a nationwide, propensity score study.

In this research, we assessed mortality after major bleeding events in atrial fibrillation (AF) patients taking four direct oral anticoagulants (DOACs). Drawing data from the Taiwan National Health Insurance Research Database between 2016 and 2019, we focused on AF patients on DOACs who had major bleeding episodes. Using propensity score stabilized weighting, we established four comparable pseudo-DOAC groups. Among 2770 patients (460 dabigatran, 1322 rivaroxaban, 548 apixaban, 440 edoxaban), 85.3% were prescribed low-dose regimens. The 7-day mortality rate was 9.0%, surging to 16.0% by the 30th day. Compared with dabigatran, there was a distinct divergence in 7-day mortality of factor Xa inhibitors (p = 0.012), with hazard ratios of 1.83 (95% CI 1.11-3.00, p = 0.017) for rivaroxaban, 2.13 (95% CI 1.23-3.66, p = 0.007) for apixaban, and 2.41 (95% CI 1.39-4.19, p = 0.002) for edoxaban. This pattern remained consistent when analyzing the subgroup that received lower dosages of DOACs. In conclusion, factor Xa inhibitors were associated with a significantly higher risk of 7-day mortality following major bleeding events than dabigatran among AF patients.

Andexanet Alfa: What We Have Learned from Clinical Trials and Real-World Data.

Andexanet alfa is a specific reversal agent for factor Xa inhibitors with immediate reversal of their anticoagulant effect. Andexanet alfa is currently approved for use in patients treated with rivaroxaban and apixaban who have life-threatening or uncontrolled bleeding. New data from both controlled clinical trials and real-world experience are continuously being published, providing greater insight into the clinical characteristics of the drug, such as efficacy and safety. It is worth considering that andexanet alfa could be of benefit in a variety of different clinical scenarios where patients receiving treatment with apixaban and rivaroxaban (and endoxaban) have life-threatening conditions. These different clinical scenarios, which range from pre-treatment of urgent surgery, especially neurosurgical interventions, and concomitant use of andexanet alfa and prothrombin complex concentrate to onset of bleeding more than 6 h prior to admission, should be clarified as well as the issue of "low/high" dose of andexanet alfa and the need for baseline anti-Xa inhibitor levels measured by point-of-care testing. Finally, management of patients at high risk of thrombosis or recent arterial/venous thrombotic events needs to be further explored. In this current opinion, we address these urgent questions in the light of recent literature and clinical trial data.

Identifying the highest risk vascular patients: Insights from the XATOA registry.

BACKGROUND: Patients with coronary and peripheral artery disease (PAD) have a residual risk of major adverse cardiovascular and limb events despite standards of care. Among patients with coronary artery disease (CAD) and/or PAD selected for low dose rivaroxaban (2.5 mg BID) and aspirin, we sought to determine the highest risk vascular patients. METHODS: Xarelto pluc Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA) is a single-arm registry of CAD and/or PAD patients. All participants were initiated on low dose rivaroxaban (2.5 mg BID) and aspirin. We report the incidence risk of major adverse cardiovascular events (MACE) or major adverse limb events (MALE) and major bleeding. A classification and regression tree analysis determined independent subgroups. RESULTS: Between November 2018 and May 2020, 5,808 participants were enrolled in XATOA; 5,532 were included in the full analysis. The median follow-up (interquartile range) was 462 (371-577) days. The incidence risk per 100 patient-years of MACE or MALE was highest among participants with polyvascular disease (2 or more vascular beds affected, n = 2,889). The incidence risk was 9.16 versus 2.48 per 100 patient-years in polyvascular and nonpolyvascular patients respectively. Other subgroups of high-risk patients included participants 75 years or older, with a history of diabetes, heart failure, or chronic renal insufficiency (CRI). Rates of major bleeding were low overall. A classification and regression tree analysis showed that polyvascular disease was the most dominant factor separating higher from lower risk participants, and this was heightened with CRI or diabetes. CONCLUSION: Patients with polyvascular disease represent a substantial subset of patients in clinical practice and should be prioritized to receive maximal medical therapy including low dose rivaroxaban (2.5 mg BID) and aspirin.

Does amiodarone impact on apixaban levels? The effect of amiodarone on apixaban level among Thai patients with non-valvular Atrial Fibrillation.

BACKGROUND: Apixaban and amiodarone are drugs used for non-valvular atrial fibrillation (NVAF) in routine practice. The evidence about apixaban plasma levels in patients who receive apixaban with amiodarone, including bleeding outcomes, has been limited. This study aimed to compare the apixaban plasma levels and bleeding outcomes between apixaban monotherapy and apixaban with amiodarone groups. METHODS: This study was a prospective, observational, and single-center research which was conducted from January 2021 to January 2022 in NVAF patients who received apixaban at a tertiary care hospital located in the center of Bangkok, Thailand. RESULTS: Thirty-three patients were measured for their median (5th-95th percentile) apixaban plasma levels. The trough of apixaban plasma level (Ctrough) were 108.49 [78.10-171.52] and 162.05 [87.94-292.88] µg/L in the apixaban monotherapy and apixaban with amiodarone groups, respectively (p = 0.028). Additionally, the peaks of apixaban plasma level (Cpeak) were 175.36 [122.94-332.34] and 191 [116.88-488.21] µg/L in the apixaban monotherapy and apixaban with amiodarone groups, respectively (p = 0.375). There was bleeding that occurred in 7 patients (21.21%); 5 patients in the apixaban monotherapy group and 2 patients in the apixaban with amiodarone group, respectively. CONCLUSIONS: Amiodarone may increase the peaks and troughs of apixaban plasma levels. The co-administration of apixaban with amiodarone is generally well tolerated. However, the careful observation of bleeding symptoms in individual cases is necessary to ensure safety.

Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation.

BACKGROUND: Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit. METHODS: We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason). RESULTS: We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group. CONCLUSIONS: Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.).

Adoption of new medicines in primary care: A comparison between the uptake of new oral anticoagulants and diabetes medicines.

AIMS: To gain insight in the uptake and practice variation in the prescription of 2 new medicine groups for common conditions in primary care (direct-acting oral anticoagulants [DOACs] and incretin-based therapies) from introduction, around 2007, to 2019 and the correlation between the adoption of those medicines in primary care. METHODS: Prescription data from general practices in the Dutch Nivel Primary Care Database from 2007 to 2019 were used. The percentage of patients with prescriptions for DOACs of all patients with prescriptions for DOACs and vitamin K antagonists was calculated per practice per year, as was the percentage of patients prescribed incretin-based therapies as a proportion of all patients with diabetes medication. Multilevel models were used to estimate practice variation for DOACs and incretin-based therapies, expressed as intraclass correlation coefficients. Linear regression analysis was used to study the association between the prescription of DOACs and incretin-based therapies. RESULTS: Per year, 46-424 general practices and 179 933-1 654 376 patients were included. In 2019, the mean percentage of patients per practice using DOACs or incretin-based therapies was 54.9 and 9.7%, respectively. The intraclass correlation coefficient decreased from 0.75 to 0.024 for DOACs and from 0.33 to 0.074 for incretin-based medicines during the study period. No clear correlation was found between the prescription of DOACs and incretin-based therapies. CONCLUSION: DOACs and incretin-based therapies have different adoption profiles and practice variation is large, especially in the years before these medicines were introduced in guidelines. Early adopters of both medicine classes differ.

Characterization of an andexanet alfa administration protocol guided by drug-specific quantitative anti-Xa assays.

Following FDA approval in 2018, consensus guidelines recommend andexanet alfa as first-line therapy for the management of life-threatening or uncontrollable bleeding in patients taking oral factor Xa (FXa) inhibitors. Dosing is based on the specific FXa inhibitor and dose, and the time elapsed since the patient's last administration of the medication. Additionally, at our institution, anti-FXa screens and drug-specific assays are obtained to guide subsequent dosing based on institution protocol. The objective of this study was to evaluate andexanet alfa utilization based on anti-Xa and FXa-inhibitor-specific assays and assess associated outcomes. This was a retrospective, single-center study aimed to describe the use of anti-FXa and specific direct oral anticoagulant assays to guide the utilization and administration of andexanet alfa. Secondary endpoints evaluated included thrombotic events during index hospitalization, hospital length of stay, hospital mortality, and discharge disposition. Overall, most patients were prescribed apixaban for atrial fibrillation and received andexanet alfa for reversal of intracranial hemorrhage in the emergency department. In general, DOAC-specific assays were concordant with last known times; however, there appears to be minimal correlation with DOAC-specific assay levels and survival. There were 9 thrombotic events (8.7%) in 8 patients. In this cohort, collection of an anti-FXa assay screen was a practical strategy to guide reversal with andexanet alfa; however, the addition of DOAC-specific assay levels may not enhance clinical utility.

Efficacy and safety of factor Xa inhibitors in low body weight patients.

STUDY OBJECTIVE: The purpose of this study is to provide evidence for the safety and efficacy of factor Xa inhibitors in patients with a weight ≤60 kg or BMI < 18.5 kg/m2 . DESIGN: Multicenter, retrospective, cohort study. SETTING: Twenty-two Ascension Health hospitals. PATIENTS: Low-body-weight adult patients (weight ≤ 60 kg or BMI < 18.5 kg/m2 ) receiving treatment for atrial fibrillation or venous thromboembolism. INTERVENTION: Factor Xa inhibitors (apixaban or rivaroxaban) or warfarin. MEASUREMENTS AND MAIN RESULTS: This study included 2538 patients between the factor Xa inhibitors (n = 1695) and warfarin (n = 843) groups with a mean weight of 53.5 ± 5.5 kg and BMI of 20.7 ± 3.1 kg/m2 . No significant difference in time to major bleeding was noted after controlling for potential confounders (HR 1.03, 95% CI 0.70-1.53, p = 0.87); similar results were seen following propensity score matching. Thromboembolism (5.3% vs. 6.2%, p = 0.38), composite major + clinically relevant nonmajor bleeding (9.8% vs. 11.5%, p = 0.18), and all-cause mortality (10.7% vs. 12.8%, p = 0.12) were similar between patients receiving factor Xa inhibitors versus warfarin. CONCLUSION: No differences in safety or effectiveness were noted between factor Xa inhibitors versus warfarin. These findings provide encouraging evidence to support the use of factor Xa inhibitors in low-body-weight patients.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity: Prespecified Subgroup Analysis of the ANNEXA-4 Study in Japan.

AIMS: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan. METHODS: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment. RESULTS: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events. CONCLUSION: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

Low-molecular-weight heparin is associated with lower venous thromboembolism events than factor Xa inhibitors in patients with severe blunt trauma: a cohort study from the Trauma Quality Improvement Program.

BACKGROUND: Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a common complication of major trauma. Pharmacological VTE prophylactics are widely used, and low-molecular-weight heparin (LMWH) is recommended. Factor Xa inhibitors are increasingly being used for VTE prophylaxis in both medical and surgical patients. Evidence comparing LMWH and factor Xa inhibitors as VTE prophylactics for severe blunt trauma is lacking. This study aims to compare the efficacy and safety of factor Xa inhibitors and LMHW in VTE prophylaxis. MATERIALS AND METHODS: Patients with severe blunt trauma who received LMWH or a factor Xa inhibitor for VTE prophylaxis in the Trauma Quality Improvement Program between 2017 and 2019 were included. The comparison was performed after using propensity score matching. The outcomes included mortality and incidence of DVT, PE, post-prophylactics haemorrhage control procedures and length of stay. RESULTS: After 2:1 propensity score matching, 1128 patients ( n =752, LMHW group; n =376, factor Xa inhibitor group) were included in the analysis. Patients in the LMWH group had fewer VTE events than those in the factor Xa inhibitor group (DVT, 3.7% vs. 7.2%, P =0.013; PE, 0.4% vs. 3.2%, P <0.001). VTE risk was higher in the factor Xa group (DVT: odds ratio, 1.97; 95% CI, 1.12-3.44; P =0.018 and PE: odds ratio, 9.65; 95% CI, 2.91-44.12; P =0.001). The mortality rate was higher in the LMWH group; however, there was no significant difference (4.0% vs. 1.9%; P =0.075). The difference in the risk of undergoing haemorrhage control surgery after VTE prophylaxis between both groups was insignificant (0.3% vs. 0.0%; P =0.333). CONCLUSIONS: LMWH was associated with a lower risk of VTE than factor Xa inhibitors in patients with severe blunt trauma. The mortality rate was higher in the LMWH group; however, there was no statistically significant difference observed.

Management of venous thromboembolic disease in patients with malignant brain tumours.

This article addresses the management of venous thromboembolism in patients with malignant brain tumours, including both primary and secondary (metastatic) tumours. The available data on patients on venous thromboembolism recurrence and bleeding risks in patients with brain tumours is limited, since these patients have been excluded from most randomised, interventional, head-to-head, clinical trials comparing low molecular weight heparins to vitamin K antagonists or to direct oral Factor Xa inhibitors. More information is available from retrospective observational studies, which however were generally small, and carried a high risk of confounding. Their findings suggest that direct Factor Xa inhibitor use is associated with lower rates of intracranial haemorrhage compared with low molecular weight heparins. Overall, the safety profile of direct oral Factor Xa inhibitors when used to prevent venous thromboembolism recurrence in patients with either primary or secondary brain tumours appears to be favourable. The available data are in favour of using an anticoagulant at a full therapeutic dose in patients with primary and secondary brain tumours experiencing a venous thromboembolism, although they are not yet sufficiently robust to permit recommending a direct Factor Xa inhibitor over low-molecular weight heparin.

Management of cancer-associated thromboembolism in vulnerable population.

Although all patients with cancer-associated thrombosis (CAT) have a high morbidity and mortality risk, certain groups of patients are particularly vulnerable. This may expose the patient to an increased risk of thrombotic recurrence or bleeding (or both), as the benefit-risk ratio of anticoagulant treatment may be modified. Treatment thus needs to be chosen with care. Such vulnerable groups include older patients, patients with renal impairment or thrombocytopenia, and underweight and obese patients. However, these patient groups are poorly represented in clinical trials, limiting the available data, on which treatment decisions can be based. Meta-analysis of data from randomised clinical trials suggests that the relative treatment effect of direct oral factor Xa inhibitors (DXIs) and low molecular weight heparin (LMWH) with respect to major bleeding could be affected by advanced age. No evidence was obtained for a change in the relative risk-benefit profile of DXIs compared to LMWH in patients with renal impairment or of low body weight. The available, albeit limited, data do not support restricting the use of DXIs in patients with CAT on the basis of renal impairment or low body weight. In older patients, age is not itself a critical factor for choice of treatment, but frailty is such a factor. Patients over 70 years of age with CAT should undergo a systematic frailty evaluation before choosing treatment and modifiable bleeding risk factors should be addressed. In patients with renal impairment, creatine clearance should be assessed and monitored regularly thereafter. In patients with an eGFR<30mL/min/1.72m2, the anticoagulant treatment may need to be adapted. Similarly, platelet count should be assessed prior to treatment and monitored regularly. In patients with grade 3-4, thrombocytopenia (<50,000 platelets/µL) treatment with a LMWH at a reduced dose should be considered. For patients with CAT and low body weight, standard anticoagulant treatment recommendations are appropriate, whereas in obese patients, apixaban may be preferred.

Comparative Efficacy and Safety of Measures for the Treatment of Adults with Isolated Calf Muscular Vein Thrombosis: A Systematic Review and Network Meta-analysis.

BACKGROUND: Isolated calf muscular vein thrombosis (ICMVT) can result in pulmonary embolism, but the treatment of ICMVT remains controversial. Therefore, the purpose of the present study was to investigate the optimal treatment for the ICMVT by comparing the efficacy and safety of different treatments. METHODS: A network meta-analysis was conducted to search for studies published from database inception to April 30, 2022, that compared the outcomes of 2 or more treatments for ICMVT. The primary outcomes were efficacy (resolution rate) and safety (adverse reactions). Data were extracted following predefined hierarchy and the Cochrane Collaboration risk of bias tool was used to evaluate the methodological quality of the included studies. We estimated summary odds ratios with 95% credibility intervals using Bayesian network meta-analysis with random effects. RESULTS: A total of 16 studies were enrolled in the study. In terms of efficacy and safety, urokinase thrombolysis combined with low-molecular-weight heparin (LMWH) was most effective but had the lowest safety, while physical therapy was safest but had the lowest efficacy. More important, direct oral factor Xa inhibitors were most likely to be second most effective and safe compared with other treatments. For the duration of treatment, anticoagulant therapy for at least 3 months could effectively increase the resolution rate of ICMVT. CONCLUSIONS: Considering both efficacy and safety, taking direct oral factor Xa inhibitors for at least 3 months was the optimal treatment compared to LMWH, urokinase thrombolysis combined LMWH, physical therapy and warfarin for patients with ICMVT.