Summary

• For adult and pediatric patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken.¹
• For adult and pediatric patients currently receiving an anticoagulant other than warfarin, start XARELTO 0 to 2 hours prior to the next scheduled administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin (UFH) being administered by continuous infusion, stop the infusion and start XARELTO at the same time.¹
• A subgroup analysis of the EINSTEIN program evaluated the effect of prestudy heparin on the safety and efficacy of XARELTO compared to enoxaparin and vitamin K antagonists (VKAs). There were no significant differences found in the incidences of recurrent venous thromboembolism (VTE) or major and nonmajor clinically relevant bleeding amongst the treatment groups, regardless of prestudy heparin use.²
• A phase 3, open-label, single-arm, nonrandomized, multicenter study evaluated the pharmacodynamics associated with transitioning from enoxaparin 30 mg twice daily (BID) or 40 mg once daily to XARELTO 10 mg once daily for thromboprophylaxis in patients who had undergone elective total hip replacement (THR) or total knee replacement (TKR).³
  • Levels of antifactor Xa activity and prothrombin time (PT) were similar on day 1 and day 3 after transition from enoxaparin to XARELTO initiated 12 to 18 hours after the last BID dose of enoxaparin and 22 to 28 hours after the last once-daily dose of enoxaparin.

CLINICAL STUDIES

EINSTEIN: Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE

EINSTEIN-DVT

The EINSTEIN-DVT study was a phase 3, randomized, open-label, event-driven, noninferiority study that compared oral XARELTO alone (15 mg BID for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin (1.0 mg/kg BID) followed by doseadjusted oral VKA (warfarin or acenocoumarol) in patients with confirmed symptomatic DVT without symptomatic PE.⁴

EINSTEIN-PE

The EINSTEIN-PE study was a phase 3, randomized, open-label, event-driven, noninferiority study evaluating the efficacy and safety of oral XARELTO (15 mg BID for 3 weeks followed by 20 mg once daily) vs subcutaneous enoxaparin (1.0 mg/kg BID) followed by doseadjusted oral VKA in patients with acute symptomatic PE with or without DVT.⁵

Prandoni et al (2015)² performed a retrospective, post hoc, subgroup analysis of patients in the EINSTEIN program. This analysis evaluated the effect of prestudy heparin on the safety and efficacy of XARELTO compared with enoxaparin in combination with and followed by VKA. Study medication was initiated immediately after randomization, but for XARELTO patients who received parenteral anticoagulation before randomization, the initial dose of XARELTO was given 4, 12, and 24 hours after the discontinuation of intravenous UFH, lowmolecular-weight heparin (LMWH) with a BID regimen, and fondapariunux or LMWH with a once-daily regimen, respectively.

• The primary efficacy outcome was acute, symptomatic VTE, which was defined as a composite of DVT and nonfatal or fatal PE.
• The principal safety outcome was clinically relevant bleeding, which was a composite of major and nonmajor clinically relevant bleeding.
• A total of 6937 (83.8%) of the 8281 randomized patients received prestudy heparin and 1344 (16.2%) patients did not.
  • The median duration of prestudy heparin treatment was 1.04 ± 0.74 days and 1.03±0.42 days in the XARELTO and standard treatment groups, respectively.
• The patient demographics were similar between treatment groups, with the exception of mean body mass index, which was significantly lower in patients who did not receive prestudy heparin.
• The 3-month incidences of recurrent VTE were similar in the XARELTO and enoxaparin/VKA groups who did not receive prestudy heparin and who did receive prestudy heparin. Table: Incidence of Recurrent VTE up to 3 Months in Relation to Duration of Prestudy Heparin Use provides the incidence of recurrent VTE up to 3 months in relation to duration of prestudy heparin use.
  • The incidence of recurrent VTE was not related to the duration of prestudy heparin treatment (p_trend=0.77).

• The 14-day incidences of major or nonmajor clinically relevant bleeding were similar among the XARELTO and enoxaparin/VKA groups in patients who did not receive prestudy heparin and in those who did receive prestudy heparin. Table: Incidence of Bleeding Outcomes up to 14 Days in Relation to Prestudy Heparin Use provides the incidence of bleeding outcomes up to 14 days in relation to prestudy heparin use.
• Incidences of major bleeding were found to be numerically lower, but not significantly lower, in the XARELTO group, regardless of prestudy heparin use.

PHARMACODYNAMIC STUDIES

Transition from Enoxaparin to XARELTO

Mills et al (2011)³ conducted a phase 3, open-label, single-arm, nonrandomized, multicenter study designed to evaluate the pharmacodynamics associated with transitioning from enoxaparin 30 mg BID or 40 mg once daily to XARELTO 10 mg once daily for thromboprophylaxis in patients who had undergone elective THR or TKR. Other assessments included evaluation of the effects of age and renal function on XARELTO pharmacodynamics and evaluation of the tolerability associated with transitioning from enoxaparin to XARELTO.

• All patients started treatment with XARELTO 10 mg daily within 2 days of entering the subacute care facility. Patients treated with enoxaparin 30 mg BID started XARELTO within 12 to 18 hours of their last doses of enoxaparin; patients treated with enoxaparin 40 mg daily started XARELTO within 22 to 28 hours of their last doses of enoxaparin.
  • Once patients were discharged, at the discretion of the investigator, they were provided with XARELTO to complete a full prophylaxis regimen (maximum combined prophylaxis of 35 days for THR and 14 days for TKR).
• Fifty-six patients were enrolled in the study; 53 were included in the safety analysis and 52 in the intent-to-treat analysis. Twenty-seven patients (51%) had undergone TKR, with 11% receiving enoxaparin once daily and 89% receiving enoxaparin BID.  Twentysix patients (49%) had undergone THR, with 77% receiving enoxaparin once daily and 23% receiving enoxaparin BID. The median age was 73 years (range, 3289 years) and the median body mass index was 28.7 kg/m². The median estimated glomerular filtration rate (eGFR) was 88.1 mL/min, and a majority of patients (89%) had an eGFR of ≥60 mL/min.
• Between days 1 and 3, there was a significant difference in the area under the concentration-time curves (AUCs) for PT (P<0.0001) following XARELTO administration (see Table: Difference in Mean Maximum Values and AUCs for Coagulation Tests).

• As age increased, renal function declined, which was evidenced by a negative correlation (r=-0.48) between age and eGFR. Patients ≥73 years of age (study median) had greater increases in antifactor Xa activity and PT than patients <73 years of age.
• Antifactor Xa activity and PT were similar in patients with an eGFR below the median (88.1 mL/min) compared to patients with an eGFR of ≥88.1 mL/min.
• Study findings showed that the pharmacodynamics of XARELTO were predictable when given after a final dose of enoxaparin and did not differ in any clinically relevant way between the responses on day 1 and those after repeated dosing (day 3).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) conducted on 19 July 2024 did not identify any relevant citations pertaining to this topic.