XARELTO - Management of Bleeding and Reversal Agents

Summary

• Andexxa^® (coagulation factor Xa [FXa; recombinant], inactivated-zhzo) is a product of AstraZeneca that has now been withdrawn from U.S. commercial sale.¹ Please refer to the Andexxa Prescribing Information (archived) for complete product details or contact AstraZeneca at 1-800-236-9933.
• An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.²
• Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Partial reversal of laboratory anticoagulation parameters may be achieved with the use of plasma products. A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (prothrombin time [PT], international normalized ratio [INR], or activated partial thromboplastin time [aPTT]) or FXa activity is not recommended.²
• Rivaroxaban has a half-life of 5 to 9 hours in healthy subjects aged 20 to 45 years and 11 to 13 hours in the elderly.²
• Results from 2 randomized studies investigating the use of PCC to serve as a potential antidote or reversal agent for XARELTO in humans demonstrated that PCC reverses the prolongation of PT and the inhibition of endogenous thrombin potential (ETP) in healthy volunteers.^3,4
• In a noninterventional cohort study with prospective follow-up, management of oral factor Xa inhibitor (XARELTO or apixaban)-associated major bleeding using PCC to achieve initial hemostasis was assessed as good in 65% of cases, with 67% for intracranial bleeding and 69% for gastrointestinal (GI) bleeding. Hemostatic effectiveness was rated as moderate and poor/none for 20% and 15% of cases, respectively. There were 5 major thromboembolic events during the 30 days following PCC use.⁵
• A single-center, retrospective study evaluated the efficacy and safety of aPCC in reversing the anticoagulant effect of XARELTO and apixaban in patients with major bleeding (N=217). After administering aPCC, the XARELTO group had 39 (75%) patients who achieved clinical hemostasis and 13 (25%) who did not. In the apixaban group, 131 (79.4%) patients achieved clinical hemostasis, whereas 34 (20.6%) did not.⁶
• The results of a single-blind, prospective, case-control study showed that administration of tranexamic acid was associated with a reduction in postoperative blood loss, improvement of hemoglobinemia at day 5, and reduced transfusion rates during total hip replacement (THR) in patients receiving XARELTO for thromboprophylaxis.⁷
• The results of Annexa-4, a phase 3, randomized, double-blind, placebo-controlled study, demonstrated that andexanet reduced anti-factor Xa activity values in patients with active major bleeding associated with a factor Xa inhibitor.⁸
• The results of a phase 3b/4 single-group cohort study evaluated the efficacy and safety of andexanet alfa in patients with acute major bleeding within 18 hours of factor Xa inhibitor (apixaban, XARELTO, edoxaban, or enoxaparin) administration.⁹
• In XARELTO-treated patients (n=132) the median anti-factor Xa activity decreased from 214.6 ng/mL at baseline to 10.8 ng/mL at nadir (median reduction, 94%; 95% confidence interval [CI], 94-93). Hemostatic efficacy for patients on XARELTO was 81% (95% CI, 73-87).
• The results from an analysis that compared andexanet alfa and PCC are summarized below.¹⁰
• Limited evidence from ex vivo, in vitro, and animal studies suggest the potential use of recombinant factor VIIa (rFVIIa)^11-16, PCC^11,13-17, aPCC^11,13,15, and modified factor Xa antidotes (eg, andexanet alfa)¹⁸ to partially reverse the anticoagulant effects of high-dose XARELTO. In an effort to streamline this response and provide the most relevant and timely information, this data has not been summarized, but is included in Table: Summary of Studies Assessing Reversal Agents for XARELTO.
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^19-41
• There are no specific recommendations on XARELTO reinitiation after a patient has developed a bleeding event. The decision to reinitiate treatment with XARELTO should be based on your clinical judgment.

REVERSAL AGENTS IN HUMAN STUDIES

PCC

Levi et al (2014)³ conducted a randomized, open-label, single center, parallel-group study to investigate the effects of 2 different PCC products, Beriplex^® P/N (a 4-factor PCC) and Profilnine^® SD (a 3-factor PCC) for the reversal of the pharmacodynamic activity of XARELTO in healthy subjects.

• Subjects were treated with XARELTO 20 mg twice a day on days 1-4, followed by 1 dose of XARELTO 20 mg on day 5. Four hours after the XARELTO dose on day 5, subjects were randomized to receive a single bolus dose of 1 treatment: Profilnine^® SD 50 IU/kg, Beriplex^® 50 IU/kg, or 100 mL saline.
• PT (using STA Neoplastin^® and Thromborel^® S) and ETP were measured before and after PCC and saline administration.
• Of 35 subjects enrolled, 34 subjects completed the study and 1 subject withdrew consent. All subjects were Caucasian, 51% of subjects were female, the mean age was 42.3 years, and the mean body mass index was 25.7 kg/m².
• After XARELTO administration, the mean maximum PT value was ~21 seconds at steady state. While PT prolongation varied depending on PT reagent used, the effects of PCC were consistent within 30 minutes.
  • 4-factor PCC reduced the mean PT by 2.5-3.5 seconds within the first 30 minutes. Mean PT values continued to decrease until approximately 12 hours after the XARELTO dose (or 8 hours after the PCC dose). After this time, the PT values with PCC were similar to that in the saline group.
  • 3-factor PCC reduced PT by 0.6-1.0 seconds within the first 30 minutes.
• 3-factor PCC more rapidly reversed XARELTO-induced changes in ETP than 4-factor PCC.
  • The ETP, as measured by area under the curve (AUC), decreased over the 4 hours after administration of the last XARELTO dose. Three-factor PCC administration produced an increase in the ETP AUC, which surpassed baseline levels 2-4 hours after PCC administration and continued to increase over the measurement period. Following 3-factor PCC administration, mean AUC values surpassed prestudy levels 6-8 hours after PCC administration.
• After XARELTO administration, maximum thrombin levels were decreased. The administration of 4-factor PCC did not increase maximum thrombin levels. After administration of PCC, maximum thrombin levels returned toward prestudy baseline values slowly at first, with a larger and faster increase in thrombin generation occurring about 4 hours after PCC administration, particularly after 3-factor PCC.
• XARELTO prolonged the lag time by approximately 2-3 minutes. The administration of PCC did not influence the XARELTO-induced prolongation of the lag time.
• The administration of either PCC product did not alter mean antifactor Xa values, and neither PCC product reversed XARELTO-induced prolongation of aPTT.
• Treatment-emergent adverse events occurred in 51.4% of patients with the most common being abdominal discomfort, gingival bleeding, back pain, and headache (8.6% each).
  • There were no clinically evident thromboembolic events after the administration of PCC.

Eerenberg et al (2011)⁴ reported the results of a randomized, double-blind, placebo-controlled, crossover study in 12 healthy male subjects evaluating the effects of PCC on the reversal of anticoagulant effects of XARELTO. All subjects received XARELTO 20 mg twice daily or dabigatran 150 mg twice daily for 2.5 days. The last dose given on the third day was not taken with food. Each subject was then randomized to receive either a single bolus of PCC 50 IU/kg (n=6) or an equivalent volume of saline (n=6) on the third day. A nonactivated PCC (Cofact^®) was used, and blood was collected for up to 24 hours after PCC infusion. Each subject received the other anticoagulant following the same protocol after a wash out period of 11 days.

• XARELTO’s effect on coagulation parameters:
  • Mean PT was prolonged from 12.3±0.7 seconds at baseline to 15.8±1.3 seconds.
  • ETP was 92%±22% at baseline and was inhibited to 51%±22%.
• After PCC administration:
  • PT approximated the baseline value (12.8±1.0 seconds; P<0.001) and was stable over a 24-hour period; saline did not reverse the prolongation of PT that resulted from administration of XARELTO (16.2±0.8 seconds; P=0.4).
  • PCC reversed the inhibition of ETP that was observed after XARELTO administration (114%±26%; P<0.001), but saline did not (41%±6%; P=0.2).

Schulman et al (2018)⁵ conducted a prospective, noninterventional, observational, multicenter cohort study to evaluate use of PCC, at a dose of 2000 units, for the management of factor Xa inhibitor-associated major bleeds. Patients were eligible for inclusion if they had received PCC infusion (2000 units) for major bleeding while on XARELTO or apixaban therapy, and if they had not received other hemostatic agents, including plasma, platelets, aPCC, or rFVIIa prior to administration of PCC. Final follow-up was performed 30±2 days after treatment with PCC.

The primary efficacy outcome was the proportion of patients that had good effectiveness with PCC, while the primary safety outcome was thromboembolic events (symptomatic deep vein thrombosis [DVT] or pulmonary embolism [PE], ischemic stroke, heart valve or cardiac chamber thrombosis, symptomatic peripheral arterial thrombosis, or myocardial infarction [MI]) within 7 days of PCC treatment.

• Of the 71 patients that were screened, 66 were included in the study and analyzed for safety and efficacy.
  • Of these, 56% (n=37) received XARELTO (daily dose, 20 mg; time from last dose to PCC, 18.1 hours) and 44% (n=29) received apixaban.
• Tranexamic acid, at a dose of 1000 mg, was administered to 17 patients either before or at the time of PCC administration for intracranial bleeding (n=11), GI bleeding (n=3), or other types of bleeding (n=3).
• INR and PT were normal in 17 XARELTO-treated patients, but anti-factor Xa testing performed in 2 of these patients indicated the presence of drug (66-76 ng/mL).
• Anticoagulation was restarted within the 30-day study period at a median of 5 days in 62% (n=41) of patients, including 6 XARELTO-treated patients.
• Hemostatic effectiveness of PCC was rated as good for 65% (n=43) of patients (95% CI, 53-77), as moderate for 20% (n=13) of patients (95% CI, 10-30), and as poor/none for 15% (n=10) of patients (95% CI, 6-24), without any significant difference between apixaban- vs XARELTO-treated patients.
  • For the 36 patients with intracranial hemorrhage (ICH), the corresponding ratings were 67% (n=24), 17% (n=6), and 17% (n=6), respectively; for the 16 patients with GI bleeding, the corresponding ratings were 69% (n=11), 12% (n=2), and 19% (n=3), respectively.
• Although effectiveness was rated as good for 26 patients with intracranial/intraspinal hemorrhage, 58% of these patients had residual neurological deficit or cognitive impairment. When comparing patients with normal neurological function vs those with residual deficit, there were no significant differences in median duration from onset of bleeding, from last dose of factor Xa inhibitor, or from emergency department arrival to reversal with PCC.
• There were 9 deaths within 30 days (8 with ICH as index event) and 5 major thromboembolic events (diagnosed 1, 2-, 9-, 12-, and 22-days following PCC).

aPCC

Sheikh-Taha et al (2023)⁶ conducted a single-center, retrospective study that evaluated the efficacy and safety of aPCC in reversing the anticoagulant effect of XARELTO and apixaban in patients with major bleeding from August 2019 through July 2022.

• Of the 217 patients included in the study, 52 and 165 were on anticoagulation therapy with XARELTO and apixaban, respectively. The mean age was 76.2 years, and 113 patients were male.
• The most common indication for anticoagulation was atrial fibrillation (n=173), followed by DVT/PE (n=38) and the most common bleeding sites were ICH (n=100), followed by GI (n=87) and visceral (n=15).
• After administering aPCC, the XARELTO group had 39 (75%) patients who achieved clinical hemostasis and 13 (25%) who did not. In the apixaban group, 131 (79.4%) patients achieved clinical hemostasis, whereas 34 (20.6%) did not.
  • Based on the site of bleeding, the risk of not achieving clinical hemostasis was significantly higher for patients with ICH-related bleeding vs nonICH-related bleeding (2.5; 95% CI, 1.44-4.34; P<0.001).
• One 67-year-old female patient developed a DVT on day 2 after receiving aPCC.
• Overall, 8 patients (all with ICH) who did not achieve clinical hemostasis died during hospitalization. Additionally, 1 patient (with ICH) who achieved clinical hemostasis died due to aspiration pneumonia complicated by septic shock.
  • Mortality was significantly lower with non-ICH-related bleeding vs ICH-related bleeding (0.91; 95% CI, 0.86-0.97; P<0.001).

In the Perzborn et al (2014)¹¹ study, nanofiltered aPCC (FEIBA NF^®; 0.2-1.0 U/mL) had the following effects:

• PT prolongation was significantly reversed by 22%-77% at all aPCC concentrations in plasma spiked with XARELTO 200-1000 ng/mL, and a ceiling effect of reversal occurred at 0.7 U/mL aPCC.
• Clotting time (CT) prolongation was partially reversed, and only significantly with XARELTO 1656 ng/mL.
• XARELTO-induced lag time (LT) prolongation was reversed by 33%-47%.
• aPCC 0.4 U/mL significantly reversed ETP inhibition (89%) induced by XARELTO 500 ng/mL.
• Maximum plasma concentration (Cmax) inhibition was reversed by 6%-56% at all aPCC concentrations.

aPCC and PCC

Escolar et al (2015)⁴² evaluated the reversal of XARELTO-induced (20 mg) alterations on hemostasis using PCC (Beriplex^®, 50 IU/kg), aPCC (FEIBA 75 U/kg), and rFVIIa (NovoSeven^®, 270 µg/kg) in 8 healthy volunteers. Thrombin generation (TG) and thromboelastometry (TEM) parameters were measured, and modifications in platelet adhesive, aggregating, and procoagulant activities were evaluated using circulating blood.

• The concentrates (rFVIIa≥aPCC>PCC) improved prolonged clotting times and reduced clot firmness caused by XARELTO on TEM tests.
• Reductions in fibrin formation were partially restored by the concentrates (rFVIIa>aPCC≥PCC).

Crawley et al (2026)⁴³ conducted a retrospective cohort study that evaluated the effectiveness and safety of aPCC vs 4-factor prothrombin complex concentrate (4F-PCC) for reversal of apixaban- and XARELTO-associated major bleeding in adult patients at a tertiary care center between June 2016 and July 2022.

• Of the 293 patients included in the study, 252 received aPCC and 41 received 4F-PCC. The mean (standard deviation) age was comparable in the aPCC vs 4F-PCC group (76.2 [12.1] years vs 75.0 [12.7] years, respectively; P=0.552).
• Overall, 185 patients (73.4%) in the aPCC group received apixaban, while 67 (26.6%) received XARELTO. In the 4F PCC group, 19 patients (46.3%) received apixaban and 22 (53.7%) received XARELTO.
• Clinical hemostasis was observed in 194 patients (77.0%) in the aPCC group vs 29 patients (70.7%) in the 4F-PCC group, with no statistically significant difference between the groups (P=0.376).
• Among the aPCC-treated patients with ICH, 25 (21.2%) received 25 U/kg and 93 (78.8%) received 50 U/kg, resulting in a hemostasis rate of 85% and 71.2%, respectively (P=0.12).
• Thromboembolic events were rare, occurring in 4 patients (1.6%) in the aPCC group (3 DVT and 1 MI) and in 2 patients (4.9%) in the 4F-PCC group (1 DVT and 1 ischemic stroke).

Andexanet alfa (PRT064445)

Andexxa^® (coagulation FXa; recombinant], inactivated-zhzo) is a product of AstraZeneca that has now been withdrawn from U.S. commercial sale.¹ Please refer to the Andexxa Prescribing Information (archived) for complete product details or contact AstraZeneca at 1-800-236-9933.

ANNEXA-R⁴⁴ was a phase 3, randomized, double-blind, placebo-controlled study in older healthy subjects to evaluate the safety and efficacy of andexanet to reverse the anticoagulant effects of XARELTO. Subjects were randomized in a 2:1 ratio either to placebo or andexanet. The study was performed in 2 consecutive parts: part 1 evaluated andexanet IV bolus alone and part 2 evaluated an IV bolus followed by a continuous 120-minute infusion. In ANNEXA-R, subjects received XARELTO 20 mg orally once daily for 4 days. On day 4, 4 hours after the last dose of XARELTO (at or near C_max), andexanet was administered as an 800 mg IV bolus (30 mg/min) (part 1) or as an 800 mg IV bolus followed by an 8 mg/min continuous infusion over 120 minutes (960 mg) (part 2).

• Primary endpoint: The percent change of anti-factor Xa activity, measured using a validated chromogenic assay of factor Xa enzymatic activity, from baseline (pre-andexanet/placebo) to nadir (post-andexanet/placebo). Nadir was defined as the smaller value for anti-factor Xa activity at 2 and 5 minutes following the end of the bolus for part 1, and the smallest value between 10 minutes before and 5 minutes after the end of the continuous infusion for part 2.

Results

• A total of 80 subjects were randomized in ANNEXA-R: 53 to the andexanet arm and 27 to the placebo arm. The mean age was 57.9 years and 39% of the subjects were women. The treatment groups were balanced with respect to baseline characteristics.
• Part 1: A bolus of andexanet rapidly (within 2-5 minutes) reduced anti-factor Xa activity to a greater extent than placebo in subjects receiving XARELTO (92%±11% vs 18%±15%; P<0.001. After completion of the andexanet bolus, reversal of antifactor Xa activity persisted for 2 hours.
• Part 2: When administered as a bolus plus a 2-hour infusion, andexanet reduced anti-factor Xa activity to a greater extent than placebo (97%±2% vs 45±12%; P<0.001). In the placebo group, anti-factor Xa activity decreased over time at the expected rate for clearance of the anticoagulant. Reversal of anti-factor Xa activity with andexanet persisted for 1-2 hours after completion of the infusion. All andexanet-treated subjects had at least 80% reversal of anti-factor Xa activity, with the exception of 1 subject who did not receive the full dose of andexanet due to a malfunction with the IV administration, compared to none of the placebo-treated subjects (P<0.001).
• There were no serious or severe adverse events, and no thrombotic events reported. The most common side effects were urticaria and administration site conditions. No subjects developed antibodies to factor X or Xa (measured through day 43).
• The publication does not present data on the efficacy and safety of andexanet in patients requiring urgent reversal of factor Xa inhibitor activity for bleeding or emergency surgery. For additional information on this study, please consult the full publication (http://www.nejm.org/doi/pdf/10.1056/NEJMoa1510991).

ANNEXA-4⁸ is a multicenter, prospective, open-label, single-group study which assessed the efficacy and safety of andexanet in 352 patients with acute major bleeding within 18 hours after administration of a factor Xa inhibitor.

Study Design/Methods

All patients received a bolus of andexanet, followed by a 2-hour infusion. Dosing:

• Patients that had taken XARELTO or apixaban more than 7 hours before andexanet administration:
  • Bolus Dose: Andexanet 400 mg over 15 min; Infusion Dose: Andexanet 480 mg
• Patients that have taken enoxaparin, edoxaban, or XARELTO 7 hours or less before andexanet administration, or at an unknown time:
  • Bolus Dose: Andexanet 800 mg over 30 min; Infusion Dose: Andexanet 960 mg
• Key inclusion criteria: ≥18 years of age; acute major bleeding; and received within 18 hours one of the following: apixaban, XARELTO, or edoxaban at any dose or enoxaparin ≥ 1 mg/kg per day.
  • Acute major bleeding was defined as bleeding having ≥1 of the following features: life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g/dL (or a hemoglobin level of ≤8 g/dL if no baseline hemoglobin level was available); or bleeding in a critical area or organ.
• Key exclusion criteria: Planned surgery <12 hours after andexanet treatment; ICH in a patient with a score of <7 on the Glasgow Coma Scale or an estimated hematoma volume of >60 mL; expected survival of <1 month; the occurrence of a thrombotic event within 2 weeks before enrollment; or use of any of the following agents within the previous 7 days: vitamin K antagonist (VKA), dabigatran, PCC, rFVIIa, whole blood, or plasma
• The efficacy population (n=254) included those who met the criteria for bleeding severity and with baseline anti-factor Xa activity of ≥75 ng/mL, or ≥0.25 IU/mL for those receiving enoxaparin. The safety population (n=352) included all patients who received andexanet.

Results:

• Patients had a mean age of 77 years. In the safety population, 64% (n=227) were diagnosed with intracranial bleeding and 26% (n=90) were diagnosed with gastrointestinal bleeding.

Primary efficacy outcome: Percent change in the anti-factor Xa activity (efficacy population) at end of bolus administration:

• XARELTO patients (n=100)
  • The median value for anti-factor Xa activity was reduced from 211.8 ng/mL at baseline to 14.2 ng/mL, a 92% reduction (95% CI, 88-94). At 4, 8, and 12 hours after andexanet infusion, the median value for anti-factor Xa activity was reduced from baseline by 42%, 48%, and 62%, respectively.
• Apixaban patients (n=134)
  • The median value for anti-factor Xa activity was reduced from 149.7 ng/mL at baseline to 11.1 ng/mL, a 92% reduction (95% CI, 91-93). At 4, 8, and 12 hours after andexanet infusion, the median value for anti-factor Xa activity was reduced from baseline by 32%, 34%, and 38%, respectively.
• Enoxaparin patients (n=16)
  • The median value for anti-factor Xa activity decreased from 0.48 IU/mL at baseline to 0.15 IU/mL, a 75% reduction (95% CI, 66-79).
• Efficacy analysis is not shown for the four patients that received edoxaban.

Primary efficacy outcome: Hemostatic efficacy 12 hours after the andexanet infusion (efficacy population):

• Of 249 patients who could be evaluated for hemostatic efficacy, 82% (n=204) had excellent (n=171) or good (n=33) hemostatic efficacy at 12 hours (95% CI, 77-87). For gastrointestinal bleeding, 85% (95% CI, 76-94) had excellent or good efficacy. For intracranial bleeding, 80% (95% CI, 74-86) had excellent or good efficacy.

Primary safety outcomes:

• In the safety population, death occurred in 14% (n=49) of patients and a thrombotic event occurred in 10% (n=34) of patients during the 30-day follow-up period.
• There were 11 thrombotic events within five days after andexanet therapy, 11 thrombotic events between six and fourteen days, and 12 thrombotic events between fifteen and thirty days.
• Antibodies to factor X or Xa did not develop in any patients after andexanet treatment, and no neutralizing antibodies to andexanet developed.

Anticoagulant therapy was immediately discontinued at time of enrollment. During the 30 days after andexanet treatment, 62% (n=220) received at least one dose of parenteral or oral anticoagulant therapy, in which 2% (n=8) experienced a thrombotic event. Twenty eight percent were restarted on oral anticoagulant therapy during follow-up, in which no thrombotic events occurred.

There was no significant relationship between reduction in anti-factor Xa activity and hemostatic efficacy overall, but it was modestly predictive in patients with ICH.

Final Study Report

Milling et al (2023)⁹ conducted a multicenter, prospective, open-label, single-cohort study that evaluated andexanet alfa (low- or high- dose) in 479 patients, >18 years of age, that presented with acute major bleeding and had received one of the following within 18 hours: apixaban, XARELTO, edoxaban, or enoxaparin. Efficacy was assessed by the percent change from baseline in anti-factor Xa activity and by the percent of patients with excellent or good hemostatic efficacy (at 12 hours) after andexanet alfa infusion. The primary safety endpoints were thrombotic events, the development of antibodies to andexanet alfa or to native factor X and FXa to ≥30 days, and death.

• Patients treated with XARELTO and a baseline anti-FXa activity of ≥75 ng/mL, with confirmed major bleeding at presentation, were included in the efficacy population (n=176 [36.7%]). Patients on low-dose FXa inhibitors for the management of coronary or peripheral vascular disease were excluded. All patients given any amount of andexanet alfa were included in the safety population (XARELTO n=132 [37.7%]).
• Acute major bleeding was defined as ≥1 of the following:
  • Potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise
  • Bleeding associated with a drop in hemoglobin of ≥2 g/dL (or a hemoglobin level of ≤8 g/dL if baseline hemoglobin was unavailable)
  • Bleeding in a critical area or organ
• Two possible andexanet alfa dosing regimens (low- or high- dose) were evaluated based on the factor Xa inhibitor the patient received, the dose, and the time since the patient’s last dose (<8 hours, ≥8 hours or unknown) as follows:
  • Low-dose regimen: andexanet alfa 400 mg IV bolus over 15 minutes and a follow-up 480 mg 2-hour infusion
  • High-dose regimen: andexanet alfa 800 mg IV bolus over 30 minutes and a follow-up 960 mg 2-hour infusion
• In XARELTO-treated patients (n=132) the median anti-factor Xa activity decreased from 214.6 ng/mL at baseline to 10.8 ng/mL at nadir (median reduction, 94%; 95% CI, 94-93). Hemostatic efficacy for patients on XARELTO was 81% (95% CI, 73-87).
• For all 4 inhibitors evaluated, within 2 minutes post-andexanet alfa bolus completion, there was a decrease in anti-FXa activity, which was sustained until the end of the continuous infusion.
• A significant difference in anti-factor Xa activity across subgroups by race was not observed.
  • There was a significant correlation between hemostatic efficacy and lower mortality in all patients (P<0.001)
  • Hemostatic efficacy was good or excellent in 80% (95% CI, 75-84) of patients overall

Phase 2 Study

A phase 2 study in healthy subjects confirmed a dose dependent decrease in anti-factor Xa activity and a return of anti-factor Xa activity to placebo levels approximately 2 hours after treatment. Adverse events in >10% of patients were infusion-related reaction and postural dizziness. No thrombotic events, serious, or severe adverse events were reported.⁴⁵

Comparative Analysis of Andexanet alfa and PCC

Rayatdoost et al (2024)¹⁰ conducted a study that compared the effectiveness of andexanet alfa (specific therapy) vs PCC (nonspecific therapy, including 4-factor PCCs [Cofact^®, Beriplex^®, Octaplex^®, and Prothromplex] and aPCC [FEIBA]) in XARELTO-anticoagulated blood from 10 healthy donors.

Results

The mean age and weight of the subjects were 35 years and 75 kg, respectively. The blood cell counts were within normal adult ranges and the XARELTO plasma concentration was comparable in all spiked samples of each study group (the 6 direct oral anticoagulant [DOAC] reversal agents).

Coagulation Measurements

PT

• 4-factor PCC concentrations equivalent to 25 and 50 IU kg^-1 shortened the PT for all XARELTO concentrations (37.5, 75, 150, and 300 ng mL^-1). However, 4-factor PCC only normalized PT when XARELTO concentration was <37.5 ng mL^-1.
• aPCC (at concentrations equivalent to 25 and 50 IU kg^-1) reversed PT prolongation by 40-45% (P<0.0001 for both concentrations), and at a concentration equivalent to 50 IU kg^-1 (~0.7 IU mL^-1), aPCC reduced PT from 30 seconds to a minimum of 13.5 seconds for XARELTO concentration of 300 ng mL^-1 (P<0.0001).
• Andexanet alfa (~4.0 µM), reduced PT prolongation by 13-56% for all XARELTO concentrations (P<0.0001).

aPTT

• 4-factor PCCs did not significantly affect aPTT for any XARELTO concentrations, whereas aPCC reduced aPTT prolongation by 20-30% for all XARELTO concentrations (P<0.0001).
• Andexanet alfa reversed aPTT prolongation by 6-27% for all XARELTO concentrations. Additionally, at XARELTO concentration of 300 ng mL^-1, the reversal effect was comparable for andexanet alfa (P=0.9996) and aPCC (P=0.8833; at a concentration equivalent to 50 IU kg^-1).

Thrombin Generation

• At lower XARELTO concentrations, 4-factor PCCs (both concentrations) partially reversed the anticoagulant effects, whereas that was not the case at higher XARELTO concentrations.
• At XARELTO concentrations of >75 ng mL^-1, a shortened lag time was observed for andexanet alfa and aPCC vs 4-factor PCCs (P<0.0001). At XARELTO concentrations of >150 ng mL^-1, significant effects on increasing ETP were observed for andexanet alfa vs 4-factor PCCs and aPCC (P<0.05).

Flow chamber experiments showed that 4-factor PCCs concentration-dependently increased thrombus formation. At a concentration equivalent to 50 IU kg^-1, 4F-PCCs completed clot formation in 6 minutes.

Activated Charcoal

In a case report documented by Mehta et al (2012)⁴⁶, 1g/kg of activated charcoal decreased the INR of a 21-month-old female who ingested two 10-mg tablets of XARELTO. The charcoal was given approximately 2 hours after ingestion. The patient's INR peaked to 3.5 approximately 12 hours after ingestion, and subsequently fell to 1.7 at 20 hours after ingestion of the tablets.

Tranexamic Acid

Clave et al (2012)⁷ assessed the efficacy of tranexamic acid in reducing blood loss during primary cementless THR in patients using XARELTO alone for thromboprophylaxis in a single-blind, prospective, case-control study. A total of 70 patients of a single surgeon who underwent primary THR for osteoarthritis of the hip were included between September 2009 and September 2010. Thirty-seven patients received antifibrinolytic treatment with 1 g IV tranexamic acid administered preoperatively (at incision) and 1 g IV postoperatively at hours 3, 7, and 12. Thirty-three patients did not receive tranexamic acid.

• Twelve patients on antiplatelet therapy (6 in group A and 6 in group B) had therapy interrupted 5 days prior to surgery and resumed 1 day after surgery.
• Both group A and group B were given XARELTO, started 6-8 hours after surgery for 30 days.
• To assess tranexamic acid action, pre- and postoperative blood effusion volume; real blood loss; need for packed red blood cell (PRBC) transfusion; hemoglobinemia at day 0 (preoperative), day 1 and day 5; and complications were systematically collected.
• Blood loss and mean hemoglobinemia between groups are provided in Table: Blood Loss and Mean Hemoglobinemia.

• In group A, no PRBC transfusions were needed; in group B, there were 4 transfusions. No thromboembolic complications were observed at discharge or at 3-months follow-up.

MANAGEMENT OF BLEEDING

ROCKET AF - Nonvalvular Atrial Fibrillation

Piccini et al (2014)⁴⁷ conducted an analysis of the safety population (those who received at least 1 dose of study drug) within the ROCKET AF trial to determine whether management of bleeding and subsequent outcomes differed between those treated with XARELTO vs those treated with warfarin.

• Among the 14,143 randomized patients, 779 (5.5%) experienced major bleeding (XARELTO, n=395; warfarin, n=384).
• The most common products administered for transfusions within 5 days of the major bleed were PRBCs (XARELTO: n=176, warfarin: n=143) and fresh frozen plasma (FFP; XARELTO: n=45, warfarin: n=81). Whole blood cells, platelets, and cryoprecipitate were also transfused.
• The most common agents used for pharmacologic management post-major bleed at 0-24 hours included vitamin K (XARELTO: 32 [7.4%], warfarin: 54 [13.2%]), PCCs (XARELTO: 4 [0.9%], warfarin: 9 [2.2%]), epsilon-aminocaproic acid (XARELTO: 2 [0.5%], warfarin: 3 [0.7%]), and tranexamic acid (XARELTO: 2 [0.5%], warfarin: 11 [2.7%]).
• Outcomes following International Society on Thrombosis and Haemostasis (ISTH) major bleeding were as follows: stroke or systemic embolism (XARELTO: 20 [4.7%], warfarin: 22 [5.4%]); composite of all stroke, non-central nervous system embolism, MI/unstable angina (UA), and all-cause death (XARELTO: 104 [24.8%], warfarin: 120 [29.9%]); all-cause death (XARELTO: 86 [20.4%], warfarin: 105 [26.1%]); and MI/UA (XARELTO: 11 [2.6%], warfarin: 7 [1.7%]).

EINSTEIN - Treatment of DVT and PE

Eerenberg et al (2015)⁴⁸ conducted a post-hoc analysis to compare the severity of clinical presentation and clinical course for major bleeding with XARELTO vs low-molecular weight heparin (LMWH)/VKA in patients involved in the EINSTEIN studies. Of 8246 patients studied, there were 40 major bleeding episodes in patients being treated with XARELTO and 68 episodes with LMWH/VKA. In the analysis, vitamin K was given 28 times, but only once to a patient being treated with XARELTO. In the XARELTO treatment arm, FFP was given 3 times, PCC was given twice, and rFVIIa was given once. In the LMWH/VKA treatment arm, FFP was given 9 times and PCC was given 8 times. Additionally, erythrocytes were transfused in 35% of the bleeds in patients on XARELTO and 65% of the LMWH/VKA group.

Registry Data

Beyer-Westendorf et al (2015)⁴⁹ analyzed rates, management, and outcome of XARELTO-related bleeding using data from a prospective, noninterventional oral anticoagulation registry.

• Between October 1, 2011 and December 31, 2013, 1776 patients were enrolled in the registry and 42.9% (n=762) of patients reported 1082 bleeding events during/within 3 days after last intake of XARELTO.
• 6.1% of the events were classified as major and PCC (n=3), FFP (n=3), and PCC/FFP were used in 9 of these cases.
• Of the 6 patients who received PCC, only 1 case showed significant improvement (corrected INR from 4.0 to 1.4, PT ratio 17% to 62%, aPTT 65.8 to 37.8 seconds). Slight changes were observed in 3 patients, but in 2 of these patients the last intake of XARELTO was >24 hours before admission. One patient died as a result of pneumonia and septic shock on day 16.

SUMMARY TABLE

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 31 March 2026.