Transition from Warfarin to XARELTO

Clinical Studies

The ROCKET AF trial was a phase 3, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter, event-driven, noninferiority study designed to evaluate the efficacy and safety of XARELTO 20 mg once daily (15 mg for patients with creatinine clearance 30-49 mL/min) and dose-adjusted warfarin (target international normalized ratio [INR]: 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) at moderate to high risk for stroke.^5,6

• The study consisted of a screening period, a double-blind treatment period, and a 30-day posttreatment observation period. At the end of the double-blind treatment visit, patients were transitioned from study drug to an open-label vitamin K antagonist (VKA) or other appropriate regimen.
• In the ROCKET AF study during the screening process, patients who were taking a VKA discontinued this therapy prior to initiation of study medication (XARELTO or warfarin).⁷ INRs were performed every 1 to 2 days based on the initial INR. Randomization to either study arm occurred as soon as the INR reached a level of <3, but before the INR fell below 2.0.
• Of the 14,264 patients who were randomized, 7897 (55.4%) were VKA-experienced (ie, use of VKA for at least 6 weeks at the time of screening) and 6367 were VKA-naïve (44.6%).⁸ At the time of screening, 62.4% of patients were receiving a VKA and 55.4% of patients received a VKA for at least 6 weeks at the time of screening.
• Table: Efficacy Endpoints in the ITT Population shows efficacy endpoints in the ITT population. Primary efficacy results by treatment group were similar to the overall study findings. Compared with VKA-naïve patients, VKA-experienced patients tended to have lower stroke and cardiovascular event rates. For secondary endpoints, there was a borderline significant interaction with myocardial infarction (MI), which suggested a higher rate of MI in warfarin-treated patients who were VKA-experienced.
• Outcomes were similar in the per-protocol and on-treatment populations.
• Regardless of prior VKA status, XARELTO was associated with excess bleeding (major or nonmajor clinically relevant bleeding) during the first 7 days after initiation of therapy. XARELTO was associated with less bleeding than warfarin in VKA-naïve patients and similar bleeding in VKA-experienced patients after 30 days.
• Table: Safety Endpoints in the Safety On-Treatment Population shows safety end points in the safety on-treatment population.
• This balance of bleeding and efficacy data support the transition of patients receiving warfarin to XARELTO once the INR has decreased to <3.

Haymart et al (2022)⁹ compared the outcomes of ischemic stroke and major bleeding before and after switching from warfarin to direct acting oral anticoagulants (DOACs; XARELTO, apixaban, dabigatran, and edoxaban) using the Michigan Anticoagulation Quality Improvement Initiative clinical registry in patients with NVAF, grouped by preswitch time in therapeutic range (TTR) guideline thresholds, between 2010 and 2021.

Results

• Of the 6628 patients on warfarin, 524 (7.9%) eligible patients switched to a DOAC (XARELTO, n=146 [27.9%]).
• The mean age at the time of switch was 73.3 (standard deviation [SD], 10.7) years, 231 (44.1%) were females, and 72 (13.7%) patients had chronic kidney disease (CKD).
• Patients received warfarin for a median of 1.28 years (interquartile range [IQR], 0.35-3.66) and the mean (SD) TTR was 0.59% (0.22) at the time of switch from warfarin to DOAC.
• The incidence of major bleeding in patients before and after switching from warfarin to XARELTO was 1.9 per 100 patient-years (95% confidence interval [CI], 0.6-4.4) and 10.3 per 100 patient-years (95% CI, 7.2-14.3), respectively (P<0.001).

Pharmacokinetic/Pharmacodynamic Studies

Kubitza et al (2014)² evaluated pharmacodynamic (PD) and pharmacokinetic (PK) parameters during the transition from steady-state warfarin to XARELTO in healthy subjects in a multicenter, randomized, placebo-controlled, parallel-group study.

Ninety-six men (18-45 years) were randomized into 1 of 3 treatment groups:

• Group A: Warfarin was administered to achieve a steady state with INR 2.0 to 3.0. XARELTO 20 mg once daily was then administered for 4 days, on days 0 to 3.
• Group B: Same regimen as group A. Placebo was then administered for 4 days, on days 0 to 3.
• Group C: XARELTO 20 mg once daily was administered for 4 days (days 0 to 3) without prior warfarin treatment.

Results

• During the transition period from warfarin to XARELTO, the PD profiles varied and depended on the type of test used.
• There was an additive effect on the prolongation of prothrombin time (PT)/INR during the initial transition period.
  • For PT, the mean maximum prolongation of PT (seconds) was 4.39-fold of the baseline in group A, 1.88-fold for group B, and 1.57-fold for group C. See Figure: PT (a) and INR (b) After Administration of Warfarin Followed by XARELTO; Warfarin Followed by Placebo; and XARELTO Alone.
  • For INR, the mean maximum INR was prolonged to 6.65-fold of the baseline in group A, 2.25-fold in group B, and 1.79-fold in group C. See Figure: PT (a) and INR (b) After Administration of Warfarin Followed by XARELTO; Warfarin Followed by Placebo; and XARELTO Alone.
• XARELTO had minimal effect on PT/INR at trough concentrations (ie, 24 hours after XARELTO dosing).
• During the transition from warfarin to XARELTO, inhibition of factor Xa activity and all parameters of endogenous thrombin potential and prolongation of activated partial thromboplastin time were enhanced, but to a lesser extent than PT. The effects of XARELTO on anti-factor Xa activity, HepTest, and prothrombinase-induced clotting time were not affected by warfarin pretreatment.

Burghaus et al (2014)¹⁰ used a computational coagulation model to evaluate changes in the combined effect of discontinued warfarin and various XARELTO concentrations on blood coagulation when transitioning from warfarin to XARELTO. Various simulations showed that there was a strong synergistic effect in the initial 2 to 3 days after discontinuation of warfarin at an INR of 2.5 which decreased over time and became negligible. Findings from this study justified the dosing schedule found in the Prescribing Information for switching from warfarin to XARELTO.

Transition from XARELTO to Warfarin

Clinical Studies

As part of the ROCKET AF study, patients were transitioned from study medication to open-label VKA after completion of the double-blind treatment period.⁷ Patients were then observed for 30 days. The study protocol stated that VKA therapy could be initiated at its anticipated maintenance dose. To maintain blinding, INR values were not obtained for at least 3 days after initiation of open-label VKA therapy.

PK/PD Studies

Moore et al (2014)³ conducted an open-label, sequential, 2-treatment-period study to assess the PD changes during the transition from XARELTO 20 mg once daily to warfarin (INR of 2.0 to 3.0) in healthy adults.

The study consisted of a screening phase followed by 2 treatment periods, separated by a 14-day washout period:

• First treatment period: Subjects received XARELTO 20 mg once daily for 5 days followed by coadministration with warfarin 5 or 10 mg once daily for 2 to 4 days. When trough levels were ≥2.0, subjects were transitioned to warfarin monotherapy (up to 15 mg once daily) for 4 days to achieve an INR of 2.0 to 3.0.
  • After the first treatment period was completed, subjects received vitamin K, 1 mg, as a single oral dose, and there was a washout period of 14 days.
• Second treatment period: Subjects received the identical warfarin regimen as the first treatment period.
  • After the second treatment period was completed, subjects received vitamin K, 5 mg, as a single oral dose to return coagulation parameters to normal prior to their release from the study.

Results

• Of the 46 subjects enrolled, 31 (67.4%) completed the study.
• When coadministered, peak INR values of XARELTO and warfarin were higher than when either agent was administered alone.
• Changes in mean absolute PT followed a similar trend as observed with INR.
• The effect of XARELTO on PT and INR at trough levels was minimal, indicating that the optimal time to assess a patient's INR is ~24 hours after the last XARELTO dose when coadministered.
• Both drugs were well tolerated, and no meaningful bleeding events were observed.

Siegmund et al (2014)⁴ used a cascade modeling approach to predict the combined effect of XARELTO and warfarin on blood coagulation when transitioning from XARELTO to warfarin. This computer model of blood coagulation simulated the combined effects of XARELTO 20 mg once daily and warfarin (INR of 2.0 to 3.0) on the INR during coadministration. The results of the simulation studies suggest that warfarin INR during the transition period should be measured at the XARELTO trough concentrations (ie, 24 hours after the last XARELTO dose). At this point, the effect of XARELTO on INR is minimal.

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.