Summary

• In a randomized study assessing efficacy and safety of XARELTO in the treatment of leg superficial-vein thrombosis (SVT), there were no identifiable differences in efficacy or safety between XARELTO and placebo in patients with symptomatic SVT; however, comparisons were undermined by a significantly smaller-than-planned sample size.¹
• In a phase 3b, randomized, noninferiority study, XARELTO was found to be noninferior to fondaparinux for the treatment of SVT in terms of symptomatic deep-vein thrombosis (DVT) or pulmonary embolism (PE), progression or recurrence of superficial vein-thrombosis, and all-cause mortality. Compared to fondaparinux, XARELTO was not associated with more major bleeding.²
• An additional citation identified during a literature search is included in the REFERENCES section for your review.³

CLINICAL STUDIES

Kearon et al (2020)¹ conducted a randomized study to assess the effectiveness and safety of low-dose XARELTO compared with placebo in patients with symptomatic SVT of a severity that did not require immediate treatment with fondaparinux or intermediate-dose low-molecular-weight heparin.

• Patients ≥18 years with symptomatic leg SVT ≥5 cm in length were eligible for inclusion. Key exclusion criteria included: symptoms present for >42 days; receiving or needing to receive an anticoagulant for another indication; SVT already treated with >3 days of anticoagulant therapy; SVT requiring a course of anticoagulant therapy or surgical management; proximal DVT or PE within the past 12 months; creatinine clearance <30 mL/min; or on a medication expected to interact significantly with XARELTO.
• Patients were randomized to either XARELTO 10 mg or matching placebo, taken orally once daily for 45 days, and were followed for a total of 90 days.
• The primary efficacy outcome was treatment failure during the 90 days, which was the composite of required treatment with nonstudy anticoagulant therapy for the initial SVT (subdivided as failure to improve or deterioration), recurrent SVT or isolated distal DVT (including asymptomatic), occurrence of proximal DVT or PE, or required surgery for SVT. Secondary efficacy outcomes included leg pain severity, and venous disease-specific and general health-related quality of life over 90 days. The primary safety outcome was major bleeding at 90 days.
• Poor enrollment led to early study termination after 85 of the planned 600 patients were randomized to XARELTO (n=43) or placebo (n=42). Mean age was 59 years, 49% of patients were female, and 98% had a unilateral SVT. Baseline characteristics were similar between groups.  
• Treatment failure within 90 days was reported in 1 (2.3%) XARELTO-treated patient (failure of original SVT to improve) and in 5 (11.9%) placebo-treated patients (failure of original SVT to improve, worsening of original SVT, and development of new SVT) (absolute risk reduction: 9.0%; 95% confidence interval [CI]: -22 to 5.9%).  
• Leg pain improvement did not differ at 7 (P=0.16) or 45 days (P=0.89) but was greater with XARELTO at 90 days (P=0.011). No difference in venous disease-specific (P=0.99) or general health-related (P=0.37) quality of life was observed over 45 days.
• Within 90 days of randomization, there were no major bleeding events or deaths in either group.

SURPRISE Study

SURPRISE² compared efficacy outcomes in patients with SVT and additional risk factors given either XARELTO or fondaparinux to assess whether XARELTO is noninferior to fondaparinux in the prevention of thromboembolic complications.

• In this phase 3b, open-label, masked endpoint, randomized, noninferiority study, patients ≥18 years with symptomatic SVT were recruited from 27 sites in Germany.
• Patients were eligible for inclusion if they had symptomatic thrombosis (≥5 cm in a supragenual superficial-vein segment) and ≥1 additional risk factor (>65 years, male sex, prior venous thromboembolism, cancer, autoimmune disease, or thrombosis of nonvaricose veins). Key exclusion criteria included: symptoms for >3 weeks, thrombus within 3 cm of the sapheno-femoral junction, indication for full-dose anticoagulation therapy, or substantial hepatic or renal impairment.  
• Patients were randomized 1:1 to receive oral XARELTO 10 mg or subcutaneous fondaparinux 2.5 mg once daily for 45 days.
• The primary efficacy outcome was the incidence of the adjudicated composite of death from any cause, symptomatic DVT or PE, symptomatic proximal extension of the SVT toward the sapheno-femoral junction, or symptomatic recurrent SVT within 45 days of treatment initiation. The primary safety outcome was adjudicated major bleeding within 45 days of treatment initiation, censored 2 days following the last dose of study drug.
• Of the 485 patients enrolled in the study, 472 were randomly assigned to XARELTO (n=236) or fondaparinux (n=236). Baseline characteristics were similar between groups. The median duration of follow-up was 91 days and was similar between groups.
• In the 435 patients included in the per-protocol analysis set, the primary efficacy outcome occurred in 7 (3%) of 211 patients (95% CI: 1.6-6.7) in the XARELTO group and in 4 (2%) of 224 patients (95% CI: 0.7-4.5) in the fondaparinux group (hazard ratio: 1.9; 95% CI: 0.6-6.4; P=0.0025 for noninferiority) at day 45.
• There were no major bleeding events in either group. One death (not treatment-related) was reported in the XARELTO group due to cardiogenic shock on day 50 following type A aortic dissection.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 21 November 2024.