Exploratory rivaroxaban trial for isolated calf deep vein thrombosis with a risk factor of thrombosis extension: an open-label, multicenter, randomized controlled trial

Background Limited evidence exists regarding the incidence of recurrent venous thromboembolism (VTE) in patients diagnosed with isolated distal deep vein thrombosis (DVT) who are at risk of thrombosis extension whether they receive anticoagulation therapy or not. Objectives The study aimed to investigate the incidence of recurrent VTE and the impact of rivaroxaban in this patient population. Methods This open-label, exploratory, and randomized controlled trial was conducted at 7 centers in Japan between April 2019 and April 2022. Adult patients with isolated distal DVT at risk of thrombosis extension received either rivaroxaban combined with physical therapy or physical therapy alone for 90 days. Whole-leg ultrasound was performed at 14 and 90 days. We assessed a composite outcome of symptomatic or asymptomatic proximal DVT or symptomatic pulmonary embolism as the primary outcome until the end of the treatment period using an intention-to-treat analysis. Major bleeding was evaluated as a key secondary outcome. Results Out of 90 enrolled patients, 3 were excluded due to withdrawal of consent; therefore, we analyzed 87 participants. The rivaroxaban group (n = 42) reported no primary outcomes (0%; 95% CI, 0.0%-8.4%), whereas the physical therapy group (n = 45) had 2 cases of symptomatic proximal DVT (4.4%; 95% CI, 0.5%-15.1%). Major bleeding events occurred in 4 patients in the rivaroxaban group (9.5%; 95% CI, 2.7%-22.6%), whereas no events occurred in the physical therapy group (0%; 95% CI, 0%-7.9%). Conclusion Preliminary data suggest that rivaroxaban may reduce the risk of VTE recurrence among this patient subset, albeit with an increased incidence of bleeding events.


Conclusion:
Preliminary data suggest that rivaroxaban may reduce the risk of VTE recurrence among this patient subset, albeit with an increased incidence of bleeding events.

K E Y W O R D S
anticoagulants, vein thrombosis, randomized controlled trial, recurrence, rivaroxaban

| I N T R O D U C T I O N
Isolated distal deep vein thrombosis (IDDVT) is common, often presenting with a lower recurrence rate of venous thromboembolism (VTE) than of proximal deep vein thrombosis (DVT) especially in asymptomatic cases [1,2].However, symptomatic IDDVT patients with risk factors for thrombosis extension, such as active cancer or severe symptoms, experience a higher frequency of recurrent VTE [3][4][5][6].
Thus, international guidelines suggest anticoagulation therapy for atrisk IDDVT patients [7][8][9].Despite this, evidence from randomized clinical trials (RCTs) is limited, and the necessity of anticoagulation therapy for asymptomatic but at-risk IDDVT patients remains unclear, making the optimal management controversial.
Our exploratory study aimed to investigate the incidence of recurrent VTE in at-risk IDDVT patients irrespective of symptoms.We also evaluated the potential effectiveness and safety of rivaroxaban anticoagulation therapy in this subgroup, contributing to identifying suitable candidates for anticoagulation therapy among IDDVT patients and suggesting future research directions for refining treatment guidelines.

| M E T H O D S 2.1 | Study design and oversight
The ISE CALF DVT study was an open-label, adjudicator-blinded study across 7 institutions in 5 cities within Mie Prefecture, Japan (Supplementary Appendix 1 and 2).Participants were randomized to receive either rivaroxaban plus physical therapy or physical therapy alone.
The trial protocol was approved by the Certified Review Board of Mie University (approval number S2018-001) and the corresponding boards at the participating centers and adhered to the Declaration of Helsinki and the Japanese Clinical Trials Act.Written informed consent was obtained from all participants.The trial was registered in the Japan Registry of Clinical Trials (ID: jRCTs041190009; https://jrct.niph.go.jp/latest-detail/jRCTs041190009).An independent committee, blinded to the treatment assignments, adjudicated all prespecified events.This study follows the Consolidated Standards of Reporting Trials guideline (Supplementary Table S1).

| Patients
Detailed definition of patient characteristics and inclusion/exclusion criteria are available in Supplementary Appendix S4.
Adults (aged ≥20 years) newly diagnosed with IDDVT through whole-leg ultrasound (US) within 3 days prior to enrollment were eligible.Eligibility required at least 1 risk factor for thrombus extension as referenced in the American College of Chest Physicians' guidelines [7], including symptoms such as swelling and pain; a large thrombus or a thrombus near the popliteal vein; active cancer; previous proximal DVT or pulmonary embolism (PE); or ≥72 hours of bed rest during hospitalization.As a result, the study included asymptomatic IDDVT patients identified through screening who presented these risk factors.Wholeleg US, assessing all lower extremity veins, was performed by experienced sonographers following standard practice.IDDVT diagnosis relied on detecting incompressibility in the distal veins (peroneal, tibial, soleus, or gastrocnemius veins) under compression.
Exclusion criteria included patients with contraindications to rivaroxaban such as a significant liver or kidney disease or pregnancy.
Additional exclusions were acute PE or proximal DVT, need for anticoagulants for other conditions, severe health issues with life expectancy under 3 months, or inability to use graduated compression stockings (GCSs) or elastic bandages.

| Randomization and study intervention
The patient registration, randomization, and study procedures are detailed in Supplementary Appendix 5.

Essentials
• Rivaroxaban's impact in patients with isolated distal deep vein thrombosis at risk of thrombosis extension has not been well studied.
• An exploratory randomized trial assessed potential effectiveness and safety in such patients.
• Rivaroxaban increased bleeding event rates.Participants were enrolled by investigators through a web-based system administered by the data center and randomly assigned in a 1:1 ratio to receive either rivaroxaban plus physical therapy (rivaroxaban group) or physical therapy alone (physical therapy group).
Randomization used a minimization method with adjustment factors of active cancer, planned surgery, and institution.
The rivaroxaban group was planned to receive 15 mg orally twice daily for the first 21 days, followed by 15 mg once daily up to day 90 (±14 days), as per the Japanese product label [10].However, the protocol allowed for starting with 15 mg once daily from the outset at the investigator's discretion due to concerns such as high bleeding risk.All participants received physical therapy, including wearing knee-length GCSs (ankle pressure of 15-30 mmHg), regular walking, and ankle exercises.
Rivaroxaban administration was suspended due to medical necessity, such as invasive treatment or adverse events, with appropriate measures taken based on clinical practice.After resolving events, the investigator determined whether to resume or discontinue rivaroxaban.Participants were considered adherent if their rivaroxaban administration rate was at least 80%.

| Surveillance and follow-up
This study comprised an intervention period from day 1 to day 90 and a follow-up period up to day 365.During the intervention period, whole-leg US was conducted on day 14 (±3 days) and day 90 (±14 days) to monitor thrombus status.Investigators verbally confirmed treatment adherence at each follow-up visit.Suspected recurrent VTE events, including PE or proximal DVT (encompassing cases where IDDVT extended into proximal veins), were confirmed with additional imaging techniques, such as computed tomography, pulmonary arteriography, lung scintigraphy, or whole-leg US.

| Endpoints
The primary outcome comprised a composite of symptomatic or asymptomatic proximal DVT or symptomatic PE (including fatal cases), assessed during the visit on day 90 (±14 days).Secondary outcomes included symptomatic PE, symptomatic or asymptomatic proximal DVT, recurrent IDDVT, major bleeding, clinically relevant bleeding (encompassing major and clinically relevant nonmajor bleeding), and all-cause mortality.These outcomes adhered to prespecified criteria (Supplementary Appendix S6).Major bleeding was defined according to the International Society on Thrombosis and Haemostasis standards [11].Clinically relevant nonmajor bleeding was defined as events that did not qualify as major bleeding but included those requiring medical intervention, unscheduled visits, telephone inquiries, or the discontinuation of rivaroxaban.This category also included events that caused symptoms such as pain and interfered with activities of daily living [12].In the safety analysis, adverse events, including bleeding and death, were monitored through 2 days after the last intervention.Two patients in the physical therapy group missed their day 90 visit; therefore, their data for this time point were imputed using information from their next available visit, during which no primary events or bleeding events were recorded.

| Statistical analysis
Due to the unique characteristics of our study population-predominantly asymptomatic yet at risk for VTE extension-no statistical tests were planned for group comparisons in this exploratory study.The target of enrolling 150 patients over a 1.5-year period was determined based on historical data from the participating facilities, reflecting the study's practical feasibility.
Categorical variables were presented as numbers and percentages; continuous variables were presented as mean and SD or median and IQR.The incidence of primary and secondary outcomes was calculated as the proportion of patients experiencing at least 1 event, relative to the total number of patients in the intention-to-treat analysis set.The 2-sided 95% CI for the rate of occurrence was calculated using the Clopper-Pearson method.All statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc).

| R E S U L T S A N D D I S C U S S I O N
Between April 10, 2019, and April 30, 2022, 90 patients were enrolled.Despite an extended enrollment period, the number of participants remained below expectations, largely due to the COVID-19 pandemic's impact.Due to financial constraints, extending the enrollment period was not feasible.Three patients withdrew after randomization; therefore, 87 patients remained in the intention-totreat set.The patients were divided into 42 in the rivaroxaban group and 45 in the physical therapy group (Figure).The study population predominantly consisted of patients with active cancer (67.8%), advanced age (≥75 years; 58.6%), inpatient status (47.1%), anemia (57.5%), and positive D-dimer results (94.3%), with infrequent IDDVT-related symptoms (10.3%;Table 1).Primary reasons for performing USs were elevated VTE risk (81.6%) and perioperative screening (37.9%;Supplementary Table S2).
None of the participants received the initial 15 mg twice daily dosing.All started 15 mg once daily, based on high bleeding risk or when thrombosis extension risk was not considered particularly high (Supplementary Table S3).Two patients in the physical therapy group required anticoagulation: one for a left subclavian venous thrombosis after randomization and another due to newly detected paroxysmal atrial fibrillation (Figure).Over 90% of participants in both groups adhered to wearing GCS for 3 or more days weekly (Table 1).Followup ultrasonography at day 14 did not alter the initial treatment plans, and protocol adherence was maintained despite temporary suspensions of rivaroxaban due to bleeding events (Supplementary Table S4).
We prospectively collected clinical data during the follow-up period up to day 365.Detailed results from this extended follow-up period are provided in Supplementary Table S5.
Main findings in this study are as follows: the incidence of the composite outcome (proximal DVT or symptomatic PE) in IDDVT patients at risk of thrombus extension upon comparing the outcomes of rivaroxaban treatment with those of physical therapy alone for 3 months was 0% vs 4.4%, respectively, but with a high incidence of bleeding events in the rivaroxaban group.
Prior studies involving symptomatic IDDVT patients identified VTE recurrence rates of 3.8% to 11.4% without anticoagulation [5,13,14], contrasting with a 1.6% recurrence rate in asymptomatic IDDVT patients not receiving anticoagulation [15].In our study, the 4.4% incidence of primary outcomes in the physical therapy group appears higher than the 1.6% in the previous study of asymptomatic patients.This discrepancy can be attributed to the fact that, although approximately 90% of our study population was asymptomatic, all participants had at least 1 risk factor for thrombus extension.Furthermore, the 2 patients who experienced primary outcomes, despite lacking IDDVT-related symptoms, had active cancer, indicating an elevated risk of recurrent VTE.Based on these findings and using the 0.7% incidence reported in a previous study [16], we projected that a sample size of 302 participants would be necessary for a definitive trial to accurately assess rivaroxaban's efficacy, assuming a 2-sided alpha of 0.05 and a statistical power of 80%.
Previous studies reported that active cancer significantly increases the risk of anticoagulation-related bleeding [17][18][19][20].Recent RCTs and meta-analyses have provided comprehensive insights into the bleeding risks associated with direct oral anticoagulants in VTE patients with active cancer [21][22][23][24][25].Despite the high bleeding risk status, direct oral anticoagulants have demonstrated safety comparable with that of standard therapy with low-molecular-weight heparin.Two RCTs involving rivaroxaban reported a 3 to 6-month cumulative major bleeding incidence of 1.4% to 6% [23].However, the rate of major bleeding in our rivaroxaban cohort was higher (9.5%), likely due to the high proportion of participants with active cancer and other risk factors such as advanced age and anemia.Specifically, 3 of the 4 patients with major bleeding had active cancer and additional known risk factors, including advanced age, brain metastasis, anemia, thrombocytopenia, and prior major bleeding [18,19,[26][27][28][29].Given these findings, it may be challenging to further stratify patients with lower bleeding risk within our study population.
Considering that the rivaroxaban group had no primary endpoint events despite using 15 mg once daily, exploring a lower dose such as 10 mg daily could be a reasonable approach for future studies.
Additionally, newer anticoagulants like factor XIa inhibitors may offer a reduced risk of bleeding [30].Therefore, future studies could consider evaluating these alternatives to optimize the risk-to-benefit ratio for patients with IDDVT.In the rivaroxaban group, participants adhered to the prescribed treatment protocol without significant deviations.On the other hand, in the physical therapy group, 2 participants required a switch to anticoagulation therapy due to changes in their medical conditions.
The study had several limitations, including its exploratory design, small sample size, and the specific characteristics of our study population.Most participants were asymptomatic, with a high proportion having active cancer, advanced age, inpatient status, anemia, or recent or upcoming surgery.Furthermore, the guidelines do not recommend routine DVT screening for asymptomatic patients, even with thrombosis extension risk [7][8][9], which were included in our study.This may limit the applicability of our findings to the general population.
Therefore, the results should be regarded as preliminary and interpreted with caution.

Characteristic
Categorical variables are presented as numbers and percentages.Regarding the primary and secondary endpoints, the rate of the occurrence of events is reported as the number of patients developing at least 1 event divided by the total number of patients in the intention-to-treat analysis set.Absolute risk reduction is calculated as the event rate in the physical therapy group minus the event rate in the rivaroxaban group.Clinically relevant bleeding comprises major bleeding and clinically relevant nonmajor bleeding.
DVT, deep vein thrombosis; IDDVT, isolated distal deep vein thrombosis; PE, pulmonary embolism. a The 95% CI of the rate of occurrence was calculated using the Clopper-Pearson method.
The 95% CI for the risk difference is based on the score statistic.
T A B L E 3 Summary of primary outcomes or major bleeding events.A 75-year-old female, enrolled 8 months after surgery for cholangiocellular carcinoma, initially presented with a large thrombus in her left soleus vein (measuring 6 cm).However, during the intervention period, she experienced a complication of recurrent cancer followed by proximal DVT.
Assessed for eligibility and randomized (N=90) Allocated to the rivaroxaban group (N=45) Allocated to the physical therapy group (N=45) 42 were included in the intention-to-treat analysis 45 were included in the intention-to-treat analysis 3 withdrew consent Lost to follow-up (N=0) Completed follow-up (N=42) Receiving allocated intervention (N=42) Significant deviation (N=0) Lost to follow-up (N=0) Completed follow-up (N=45) Receiving allocated intervention (N=43) Switch to anticoagulation therapy (N=2) Day 90 analysis F I G U R E Study flowchart.Participant progression through the study. a Efficacy and safety clinical outcomes at day 90 (±14 days).
a Chronic lung disease was defined as persistent lung disorders such as asthma, chronic obstructive pulmonary disease, and restrictive lung diseases.b History of major bleeding was diagnosed if the patient had a history of major bleeding according to International Society on Thrombosis and Haemostasis criteria.c Anemia was defined as hemoglobin level <13 g/dL for men and <12 g/ dL for women.d Thrombocytopenia was defined as platelet count <100 × 10 9 /L.e Creatinine clearance level was calculated using the Cockroft-Gault formula.OGIHARA ET AL.T A B L E 2