Summary

• XARELTO is not indicated for the treatment of portal vein thrombosis (PVT).
• A randomized, controlled study found XARELTO to be effective and safe in hepatitis C virus (HCV)-related, acute, non-neoplastic PVT, with a significantly higher rate of complete PVT resolution and significantly improved short-term survival rate vs warfarin.¹
• In a prospective study evaluating efficacy and safety of XARELTO and apixaban for initial treatment of acute venous thromboembolism of atypical location (VTE-AL), venous thromboembolism (VTE) recurrence and bleeding rates associated with XARELTO and apixaban use in VTE-AL were not different from those observed in patients with venous thromboembolism of typical location (VTE-TL) and patients with VTE-AL treated with enoxaparin.²
• A prospective cohort study evaluating efficacy and safety of direct-acting oral anticoagulants (DOACs) for the treatment of chronic PVT in patients with liver cirrhosis has been published. Recanalization rate and portal vein (PV) flow velocity improvement were higher in the DOACs group (oral XARELTO or dabigatran; 3-month and 6-month complete/partial recanalization rate: 12.8% and 28.2%, respectively) vs the control group (no anticoagulant treatment), while the thromboelastography coagulation index was lower (P<0.05). There was no significant difference between groups in cases of bleeding.³
• A retrospective, single-center study evaluating the efficacy and safety of DOACs, including XARELTO and apixaban, compared with warfarin in the treatment of PVT has been published. A primary failure event (recurrent thromboembolic event) was reported in no patient receiving a DOAC vs 4 patients receiving warfarin (P<0.001), and a primary safety event (bleeding event) was reported in no patient receiving a DOAC vs 1 patient receiving warfarin (P<0.001).⁴
• A retrospective cohort study evaluated the effect of post discharge XARELTO on portomesenteric venous thrombosis (PMVT) following laparoscopic sleeve gastrectomy (SG). The addition of XARELTO 10 mg daily for 30 days post discharge showed a significant reduction in the occurrence of PMVT (P=0.0455). In patients who did not receive XARELTO, 4 PMVT events were reported, compared to none in the XARELTO group. No significant difference in the number of bleeding events was observed between groups.⁵
• A retrospective study compared the efficacy and safety of XARELTO vs dabigatran for treating acute PVT in patients with cirrhosis. Complete and partial recanalization was observed in 75% (39/52) vs 79% (33/42) of patients in the XARELTO vs dabigatran groups, respectively. Persistent occlusion rates were similar in both groups (XARELTO 21% vs dabigatran 19%; log rank P=0.866).⁶
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^7-11
• Case reports describing this off-label use have been summarized below.^12-25

clinical studies

Hanafy et al (2018)¹ conducted a randomized, controlled, interventional, open-label study to evaluate efficacy and safety of XARELTO vs warfarin in the management of acute, nonneoplastic PVT in HCV-related compensated cirrhosis. Of 578 patients with chronic HCV infection, 80 patients with acute PVT who had undergone splenectomy due to hypersplenism and 4 patients with acute PVT due to portal pyemia were selected. Patients were randomized in a 1:1 ratio to receive XARELTO 10 mg/12 hours (study group, n=40) or warfarin (control group, n=40). Both groups received symptomatic therapy for ascites and abdominal pain. PVT was classified into thrombosis confined beyond the confluence of the splenic vein (SV) and superior mesenteric vein (SMV); to the SMV, but with patent other mesenteric vessels; to the whole splanchnic venous system, but with large collaterals; or extensive splanchnic venous thrombosis with only minute collaterals. Both groups were managed with enoxaparin 1 mg/kg every 12 hours subcutaneously (SC) for 3 days; the study group was subsequently treated with XARELTO 10 mg/12 hours to avoid possible liver injury with the full dose of XARELTO, and the control group was subsequently treated with warfarin to maintain their international normalized ratio level at 2-2.5.

The primary efficacy outcome was complete recanalization of the PV or partial recanalization if reopening was >50% of the luminal occlusion, and the secondary efficacy outcome was absence of recurrence following termination of therapy. The primary safety outcome was major bleeding, defined as fatal bleeding and/or symptomatic bleeding in a critical area or organ and/or bleeding that causes a decrease in the hemoglobin level by ≥2 g/dL or leads to the transfusion of ≥2 units of whole blood or red cells.

• Of the 80 patients with chronic HCV presenting with acute PVT, 67 were male and 13 were female. Mean age was 43.2±3.8 years.
• Rapid resolution of acute PVT was observed in 85% (n=34) of XARELTO-treated patients within 2.6±0.4 months, while delayed and partial resolution was observed in 15% (n=6) of patients within 6.7±1.2 months. Complete resolution was observed in 45% (n=18) of warfarin-treated patients within 4.3±1.4 months.
• XARELTO-treated patients did not experience major bleeding, abnormal liver function, PVT recurrence, or death.
• The XARELTO group experienced significantly improved short-term survival rate (20.4±2.2 months) compared to the control group (10.6±1.8 months).
• Patients in the control group experienced complications, including severe upper gastrointestinal (GI) tract bleeding (43.3%), hepatic decompensation (22.5%), progression to mesenteric ischemia (12.5%), PVT recurrence (10%), and death (20%; secondary to upper GI bleeding and intestinal infarction).
• The duration until complete thrombus resolution correlated with age, extent of the thrombus, creatinine level, and Model for End-Stage Liver Disease score. The recurrence after complete thrombus resolution correlated with age, extent of the thrombus, thrombogenic gene polymorphism, and use of warfarin.

Janczak et al (2018)² evaluated efficacy and safety of XARELTO vs apixaban in the treatment of VTE-AL (portal, mesenteric, hepatic, splenic, gonadal, renal, and cerebral veins) using prospectively-collected data from the Mayo Thrombophilia Clinic Registry. Patients with acute VTE-AL treated with XARELTO or apixaban were compared with patients with VTE-TL (deep vein thrombosis of extremities and/or pulmonary embolism) receiving XARELTO or apixaban and with patients with VTE-AL treated with enoxaparin.

• Of the 1038 patients that were enrolled in the registry, 623 had acute VTE and received study drug within 14 days of diagnosis; of these, 63 had VTE-AL (36 on DOACs [XARELTO, n=22; apixaban, n=14], 23 on enoxaparin, and 4 on warfarin).
• A total of 560 of 623 patients had VTE-TL (352 on DOACs [XARELTO, n=219; apixaban, n=133]).
• A greater number of patients with VTE-AL treated with a DOAC were female and younger compared with those with VTE-TL and those with VTE-AL treated with enoxaparin.
• VTE-AL treated with DOACs/enoxaparin included: splanchnic (portal-mesenteric-splenic; 26/23), ovarian (8/2), renal (3/5), and cerebral venous sinuses (1/1), respectively.
• The recurrence rate for patients with VTE-AL treated with DOACs (XARELTO, n=2) was 7.3/100 person-years (PY) (95% confidence interval [CI], 0.9-26.3), which was similar to that seen in patients with VTE-TL (2.4/100 PY, 95% CI, 0.9-4.8; P=0.13) and those with VTE-AL treated with enoxaparin (23.7/100 PY, 95% CI, 4.9-69.1; P=0.26).
• The major bleeding rate for patients with VTE-AL treated with DOACs (XARELTO, n=1; apixaban, n=1) was 7.2/100 PY (95% CI, 0.9-26.1), which was similar to that seen in patients with VTE-TL (3.0/100 PY, 95% CI, 1.4-5.7; P=0.26) and those with VTE-AL treated with enoxaparin (22.4/100 PY, 95% CI, 4.6-65.4; P=0.31).
• Mortality rates were higher in patients with VTE-AL treated with a DOAC (21.5/100 PY, 95% CI, 7.9-46.7) than in patients with VTE-TL (8.3/100 PY, 95% CI, 5.4-12.2; P=0.03).
• All patients with VTE-AL with events had cancer.

Ilcewicz et al (2021)⁴ conducted a retrospective, single-center study to evaluate the efficacy and safety of DOACs, including XARELTO and apixaban, compared with warfarin in patients with PVT.

The study evaluated the primary failure outcome, which was the absolute difference in recurrent thromboembolic events 90 days following the initiation of a DOAC vs warfarin for the treatment of PVT. The primary safety outcome was the absolute difference in bleeding events 90 days after the initiation of anticoagulation therapy.

• Overall, 33 patients with PVT were included in the analysis, of whom 13 (39.4%) received a DOAC (XARELTO 20 mg/day [n=5], XARELTO 15 mg/day [n=1], apixaban 2.5 mg twice daily [BID; n=3], and apixaban 5 mg BID [n=4]) and 20 (60.6%) received warfarin.
  • None of the patients receiving a DOAC underwent a primary failure event compared with 4 patients receiving warfarin who experienced recurring thromboembolic events (P<0.001). The median time to thrombosis was 36.5 (range, 12-62) days.
  • None of the patients receiving a DOAC experienced a primary safety event compared with 1 patient receiving warfarin who experienced upper GI bleeding (P<0.001). The time to experience a primary safety event was 36 days.
• Of the 10 patients previously diagnosed with cirrhosis, 5 received a DOAC and the remaining 5 were on warfarin.
  • None of the patients experienced a primary failure event or primary safety event within 90 days of commencing anticoagulation therapy.
  • The median Child-Pugh score for patients with cirrhosis receiving DOACs was 6 (range, 511) and that for patients receiving warfarin was 8 (range, 6-9).

Swartz et al (2023)⁵ conducted a retrospective cohort study to evaluate the effect of post discharge XARELTO on the incidence of PMVT following laparoscopic SG. Patients who underwent laparoscopic SG were either given XARELTO 10 mg daily for 30 days after the surgery (XARELTO group) or did not receive XARELTO (control group). The primary outcome was the occurrence of PMVT, and the secondary outcomes were occurrence of VTEs and bleeding events.

• Overall, 292 (XARLETO group, n=146; control group, n=146) patients underwent laparoscopic SG.
• The mean age was 42.7 vs 42.6 years and 80.5% vs 77.5% of patients were females in the XARELTO vs control group, respectively.
• Patients received an average of 3 postoperative doses of chemoprophylaxis prior to discharge, after which patients in the XARELTO group (n=143) received XARELTO 10 mg daily for 30 days. The average length of stay for all patients was 1.4±0.9 days.
• Of the 34 (11.8%) complications observed to 90 days, a total of 4 PMVT events were reported in the control group. All 4 PMVT events occurred in patients who were discharged 1 day following surgery and had received both preoperative and postoperative chemoprophylaxis.
• Patients who received XARELTO after laparoscopic SG showed significant reduction in the occurrence of PMVT (P=0.0455).
• Bleeding complications occurred in 4 and 7 patients in the XARELTO and control group, respectively.

Zhou et al (2023)⁶ conducted a retrospective study to compare the efficacy and safety of XARELTO vs dabigatran in treating acute PVT in patients with cirrhosis. All patients received low molecular weight heparin (4000 anti-XA IU/0.4 mL) within 1-2 days of hospital admission as a bridging treatment. The XARELTO dose was 15 mg twice daily on Days 1-20 followed by 20mg once daily and the dabigatran dose was either 150 or 110 mg twice daily. The primary outcome was recanalization.

• Ninety-four (XARELTO group, n=52; dabigatran group, n=42) patients were enrolled.
• Mean age in both groups was 55 years; 38 (73%) and 23 (55%) patients were male in the XARELTO and dabigatran groups, respectively.
• Median duration of treatment in the XARELTO group was 15 months (range:6-24 months) compared to 18 months (range: 8-24 months) in the dabigatran group (P=0.643). Median follow-up duration in both groups was 36 months (P=0.686).
• Complete recanalization was seen in 24 (46%) patients in the XARELTO group vs 17 (40%) patients in the dabigatran group (log-rank P=0.581); partial recanalization was seen in 15 (29%) in the XARELTO group vs 16 (38%) in the dabigatran group (log rank P=0.359).
• Persistent occlusion rates were similar in both groups (XARELTO 21% vs dabigatran 19%; log rank P=0.866).
• Nine (17%) patients in the XARELTO group and 6 (14%) patients in the dabigatran group reported a bleeding event (P=0.692). Major bleeding was reported in 3 (6%) patients in the XARELTO group and 1 (2%) patient in the dabigatran group (P=0.646).

CASE REPORTS

Several case reports discussed the use of XARELTO in PVT. See Table: Case Reports Describing the Use of XARELTO in PVT

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 27 May 2024.