Summary

• XARELTO is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery. For patients undergoing hip replacement surgery, XARELTO 10 mg for 35 days is recommended. For patients undergoing knee replacement surgery, XARELTO 10 mg for 12 days is recommended.¹
• XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.¹
• XARELTO is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE-related death during hospitalization and posthospital discharge in adult patients admitted for an acute medical illness and who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding. The dose is XARELTO 10 mg daily in hospital and after hospital discharge for a total recommended duration of 31-39 days.¹
• EINSTEIN-Choice: In 3365 patients with VTE who had completed 6-12 months of anticoagulation therapy and were in equipoise regarding the need for ongoing anticoagulation, XARELTO (at doses of 20 mg and 10 mg daily) significantly lowered the risk of a recurrent event compared to aspirin (100 mg daily), without a significant increase in major bleeding (MB).² An analysis of the EINSTEIN-Choice study found that compared to aspirin, extended anticoagulation with once daily XARELTO reduced recurrent VTE with a favorable benefit-risk profile.³
• In a benefit-risk analysis of the EINSTEIN-Extension study, which compared continued treatment with XARELTO vs placebo in patients with symptomatic DVT or PE who had completed 6-12 months of anticoagulation, continued anticoagulation with XARELTO was associated with a clinically important benefit and favorable benefit-risk profile.⁴
• The phase 3 RECORD clinical study program was composed of 4 randomized, double-blind, double-dummy, multinational studies that compared efficacy and safety of oral XARELTO 10 mg once daily and subcutaneous (SC) enoxaparin 40 mg once daily (RECORD 1-3) or 30 mg twice daily (RECORD 4) for prevention of VTE in patients undergoing elective total hip replacement (THR, RECORD 1-2) or total knee replacement (TKR, RECORD 3-4).^5-8
• MAGELLAN was a phase 3, randomized, double-blind, study comparing efficacy and safety between extended thromboprophylaxis with oral XARELTO 10 mg once daily for 35±4 days and standard-duration thromboprophylaxis with enoxaparin 40 mg for 10±4 days followed by placebo for the prevention of VTE in over 8000 acutely ill medical patients requiring hospitalization.⁹ Patient follow-up continued until day 90±7.¹⁰
  • Five risk factors for bleeding were identified in the MAGELLAN and applied as exclusion criteria to the overall study to form the MAGELLAN subpopulation studied as a retrospective analysis.¹¹
• MARINER was a phase 3, multicenter, prospective, randomized, double-blind, placebo-controlled, event-driven, study that evaluated the efficacy and safety of XARELTO compared with placebo in the prevention of symptomatic VTE and VTE-related death in high-risk, medically ill patients for a period of 45 days posthospital discharge. All patients were contacted for safety follow-up at 75±5 days.^12,13
  • A benefit-risk assessment of the MARINER study resulted in 32.5 fewer symptomatic VTE and VTE-related deaths and 8.2 additional MB events per 10,000 patients treated with XARELTO compared to placebo.¹⁴
  • In a post hoc analysis of the MARINER study, dual antithrombotic therapy with XARELTO plus aspirin was associated with a significant reduction in the primary efficacy outcome of symptomatic VTE and VTE-related death compared with no thromboprophylaxis (0.76% vs 1.28%; P=0.042).¹⁵
• A post hoc analysis of the MAGELLAN and MARINER studies demonstrated that patients with MB events in MAGELLAN (hazard ratio [HR], 8.53; 95% confidence interval [CI], 5.61-12.97; P<0.0001) and MARINER (HR, 3.46; 95% CI, 1.24-9.61; P=0.017) had a significantly higher risk of all-cause mortality compared to patients with no bleeding.¹⁶
• IMPROVE-VTE was a retrospective claims database analysis evaluating the efficacy and safety of prolonged anticoagulation of XARELTO after the initial 3-month treatment period (index date) versus discontinuing anticoagulation following the initial treatment period. Patients were followed up to 12 months postindex date following the initial 3-month treatment period.¹⁷
• Additional citations have been included for your review.^18-28

CLINICAL STUDIES

RECORD

The RECORD clinical development program, a comprehensive program of 4 phase 3 studies with over 12,000 patients, studied XARELTO^® (rivaroxaban tablets) for the prophylaxis of venous thromboembolism in patients undergoing knee (RECORD 3 and 4) or hip (RECORD 1 and 2) replacement surgery. The data from the RECORD program were submitted to the FDA. XARELTO was approved on July 1, 2011 by the FDA for the indication studied in the RECORD program.

In the RECORD 4 study, patients received either oral XARELTO 10 mg once daily, beginning at least 6-8 h after surgery, or subcutaneous enoxaparin 30 mg every 12 hours, starting 12-24 hours after surgery. Data from RECORD 4 are not included in the approved product labeling for XARELTO.

Since publication of RECORD 4 findings, the sponsor company conducted a verification of the data for all patients in this clinical study. With respect to study findings, additional adverse events (AEs)/serious AEs were identified; however, the distribution of those was balanced between study groups. In the company’s view, verification findings did not appreciably change the conclusions of the study. Thus, the RECORD 4 findings reported in the publication remain consistent with the overall results from the total RECORD program.>

The phase 3 RECORD clinical study program was composed of 4 randomized, double-blind, double-dummy, multinational studies that compared efficacy and safety of oral XARELTO 10 mg once daily and SC enoxaparin 40 mg once daily (RECORD 1-3) or 30 mg twice daily (RECORD 4) for prevention of VTE in patients undergoing elective THR (RECORD 1-2) or TKR (RECORD 3-4).^5-8

• RECORD 1 (THR): Mean duration of prophylaxis was 33.4 days in the XARELTO group and 33.7 days in the enoxaparin group (safety population).
• RECORD 2 (THR): Mean duration of prophylaxis was 33.5 days in the XARELTO group and 12.4 days in the enoxaparin group (safety population).
• RECORD 3 (TKR): Mean duration of prophylaxis was 11.9 days with XARELTO and 12.5 days with enoxaparin.
• RECORD 4 (TKR): Mean duration of prophylaxis was 11.7 days with XARELTO and 11.0 days with enoxaparin.

EINSTEIN-Extension

Wells et al (2016)⁴ conducted a benefit-risk analysis of the EINSTEIN-Extension study, which compared continued treatment with XARELTO vs placebo in 1197 patients with symptomatic DVT or PE who had completed 6-12 months of anticoagulation with acenocoumarol, warfarin, or XARELTO.

• EINSTEIN-Extension was a double-blind, randomized, event-driven, superiority study that compared oral XARELTO alone (20 mg once daily) with placebo for continued anticoagulation (6 or 12 months).
• The primary efficacy outcome was symptomatic, recurrent VTE, defined as the composite of DVT or nonfatal or fatal PE. MB was defined as bleeding that was fatal, occurred in a critical location, was associated with a reduction in hemoglobin ≥2.0 g/dL, or required a transfusion of ≥2 units of whole blood or red cells.
  • The predefined outcome of net clinical benefit was the composite of recurrent VTE and MB.
• One-year Kaplan-Meier rates and rate differences of recurrent VTE and MB were calculated. Benefits and risks were evaluated using these rate differences scaled to a population size of 10,000 patients treated for 1 year.
• Of the 1197 enrolled patients, 602 were assigned to XARELTO and 595 were assigned to placebo.
• During a mean treatment duration of 189.5 days, a total of 8 (3.0%; 3 PE and 5 DVT) XARELTO-treated patients and 42 (9.6%; 13 PE and 29 DVT) placebo-treated patients experienced recurrent VTE.
  • In a population of 10,000 patients treated for 1 year, XARELTO treatment would have resulted in 665 (95% CI, 246-1084) fewer recurrent VTEs compared with placebo (number needed to treat [NNT], 15).
• A total of 4 (0.7%; 3 gastrointestinal and 1 menorrhagia) XARELTO-treated patients and 0 placebo-treated patients experienced MB.
  • In a population of 10,000 patients treated for 1 year, XARELTO treatment would have resulted in 68 (95% CI, 2-134) more MB events compared with placebo (number needed to harm [NNH], 147).
• Net clinical benefit was observed in 12 XARELTO-treated patients (1-year Kaplan-Meier rate of 3.6%) vs 42 placebo-treated patients (1-year Kaplan-Meier rate of 9.6%), with a difference of 6.0% (95% CI, 1.8%-10.2%) favoring XARELTO.
  • In a population of 10,000 patients treated for 1 year, XARELTO treatment would have resulted in 598 (95% CI, 175-1021) fewer net clinical benefit outcomes compared with placebo (NNT, 17).
• Kaplan-Meier analysis demonstrated early reduction in recurrent VTE with XARELTO, which continued to improve throughout the duration of treatment. MB gradually increased, plateauing at ±100 days. Overall, continued treatment with XARELTO was associated with a favorable benefit-risk profile.

EINSTEIN-Choice

Prandoni et al (2018)³ evaluated data from EINSTEIN-Choice to compare the benefit-risk profiles of extended XARELTO treatment (20 mg or 10 mg once daily) and extended aspirin treatment (100 mg once daily) in patients with VTE who had completed 6-12 months of anticoagulation.

• EINSTEIN-Choice was a phase 3, randomized, double-blind superiority study that compared the efficacy and safety of 2 doses of XARELTO (20 mg and 10 mg, once daily) with aspirin (100 mg once daily) in patients with VTE who had completed 6-12 months of anticoagulation therapy and for whom there was equipoise with respect to the need for ongoing anticoagulation.²
• One-year cumulative incidences of recurrent VTE and MB were estimated, and benefits and risks were calculated by determining between-group differences in a hypothetical population of 10,000 VTE patients treated for 1 year.
• Baseline characteristics were similar among the 3 treatment groups.
• The cumulative incidences of recurrent VTE were 1.9%, 1.6%, and 5.0% in the XARELTO 20 mg, XARELTO 10 mg, and aspirin groups, respectively.
• The cumulative incidences of MB were 0.7%, 0.4%, and 0.5% in the XARELTO 20 mg, XARELTO 10 mg, and aspirin groups, respectively.
• The incidences of the combined outcome of recurrent VTE and MB were 2.8% and 3.4% lower in the XARELTO 20 mg and XARELTO 10 mg groups, respectively, than in the aspirin group.
• For 10,000 patients treated for 1 year, there would be 284 (95% CI, 106-462) and 339 (95% CI, 165-512) fewer events with XARELTO 20 mg and XARELTO 10 mg, respectively, than with aspirin.
  • The NNT to prevent 1 episode of DVT or PE with XARELTO rather than with aspirin was 33 for XARELTO 20 mg and 30 for XARELTO 10 mg.
• The cumulative incidence of recurrent VTE was lower with XARELTO vs aspirin across all subgroups, while the cumulative incidence of MB varied between subgroups. Net clinical benefit and NNT to NNH ratio favored XARELTO across all subgroups, except for comparison of XARELTO 20 mg with aspirin in patients with cardiac disease.

MAGELLAN

MAGELLAN was a phase 3, international, randomized, double-blind study designed to evaluate efficacy and safety of extended thromboprophylaxis with XARELTO compared with standard-duration enoxaparin for the prevention of VTE in hospitalized acutely ill medical patients during the inpatient and postdischarge periods.^9,29

A total of 8101 patients (XARELTO, n=4050; enoxaparin/placebo, n=4051) were randomized. Patients were randomized to receive SC placebo once daily for 10±4 days and XARELTO 10 mg once daily for 35±4 days or SC enoxaparin 40 mg once daily for 10±4 days and oral placebo once daily for 35±4 days.⁹

• Patients were included in the study if they were: ≥40 years of age; hospitalized for a specified acute medical illness <72 hours before randomization; anticipated to be immobilized (complete immobilization for ≥1 day during hospitalization followed by decreased mobility for ≥4 days after randomization, and additional anticipated ongoing decreased mobility thereafter) due to hospitalization for a set list of conditions; and given an anticipated survival time of >6 months.²⁹
• The 2 coprimary efficacy outcomes included the composite of asymptomatic proximal DVT detected by mandatory compression ultrasonography, symptomatic proximal or distal DVT, symptomatic nonfatal PE, and VTE-related death from day 10±4 (tested for noninferiority) and then from day 35±4 (tested for superiority).^9,29
  • At the day 10 evaluation, XARELTO demonstrated noninferiority to enoxaparin in reducing the risk of VTE in the per-protocol population (2.7% vs 2.7%, respectively; P=0.003).
  • At the day 35 evaluation, extended-duration XARELTO was superior to standard-duration enoxaparin followed by placebo in reducing the risk of VTE in the modified intention-to-treat population (4.4% vs 5.7%, respectively; P=0.02).⁹
• The principal safety outcome was clinically relevant bleeding, defined as the composite of MB and clinically relevant nonmajor (CRNM) bleeding events observed no later than 2 days after the last study drug was administered.⁹
  • Overall, bleeding rates were low, but significantly higher in the XARELTO arm than in the enoxaparin/placebo arm during the entire study period.⁹

MAGELLAN Subpopulation

Spyropoulos et al (2018)¹¹ conducted a retrospective analysis in a subpopulation of the MAGELLAN study.

• Five risk factors for MB were identified and applied as exclusion criteria to the MAGELLAN study to identify a subpopulation (~80% of the overall population) with potentially improved benefit-risk balance. The exclusion criteria were: active cancer, dual antiplatelet therapy at baseline, any bleeding within 3 months prior or during hospitalization, active gastroduodenal ulcer within 3 months or currently symptomatic, and bronchiectasis or pulmonary cavitation.
• Except for history of cancer, baseline characteristics in the subpopulation were similar to those observed in the original population and were similar between treatment groups.
• The efficacy observed in the overall MAGELLAN population was maintained in the MAGELLAN subpopulation; XARELTO was noninferior to enoxaparin at day 10 (2.4% vs 3.0%, respectively; HR, 0.820; 95% CI, 0.583-1.154), and significantly more effective than enoxaparin/placebo at day 35 (3.9% vs 5.7%, respectively; HR, 0.680; 95% CI, 0.527-0.877).
• The risk of MB associated with XARELTO was reduced in both treatment phases within the MAGELLAN study subpopulation. Rates of MB in the subpopulation were similar between the XARELTO and enoxaparin/placebo groups.

MARINER

The MARINER^12,13 (Medically Ill Patient Assessment of Rivaroxaban versus Placebo In Reducing Post-Discharge VeNous Thrombo-Embolism Risk) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven study that evaluated the efficacy and safety of XARELTO 10 mg once daily (7.5 mg once daily if creatinine clearance [CrCl] ≥30 to <50 mL/min) vs placebo in the prevention of symptomatic VTE and VTE-related death in high-risk, medically ill patients for a period of 45 days posthospital discharge.

• Patients were ≥40 years of age hospitalized 3-10 days for acute medical conditions such as heart failure (HF), acute respiratory insufficiency or exacerbation of chronic obstructive pulmonary disease, acute ischemic stroke, acute infectious diseases, or inflammatory diseases, including rheumatic diseases. Patients also had to have had an increased VTE risk, as demonstrated by a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) risk score ≥4 or a risk score of 2-3 with a plasma D-dimer >2 times upper limit of normal. The IMPROVE score ranges from 0 to 10, with increased scores signifying a higher risk of VTE. Patients must also have received low-molecular-weight heparin (LMWH) or unfractionated heparin during their hospitalization for thromboprophylaxis.
• The primary efficacy outcome was the composite of all symptomatic VTE or death due to VTE. Symptomatic VTE included lower-extremity DVT or nonfatal PE. The principal safety outcome was MB.
  • XARELTO was associated with fewer symptomatic VTE events or deaths due to VTE than placebo; however, the difference was not statistically significant (0.83% vs 1.10%, respectively; HR, 0.76; 95% CI, 0.52-1.09). Results were similar when stratified by CrCl. Patients with CrCl <30 mL/min were excluded.^13,30
  • MB occurred at a similar rate in the XARELTO and placebo groups (0.28% vs 0.15%, respectively; HR, 1.88; 95% CI, 0.84-4.23).

Raskob et al (2022)¹⁴ evaluated data from the MARINER study to assess the benefit-risk profile of XARELTO 10 mg once daily (n=4909) compared to placebo (n=4913) for thromboprophylaxis for 45 days after hospitalization in the intention-to-treat population.

The benefit and risk were assessed as rate differences with 95% CI per 10,000 patients, defined as the difference in proportions between the 2 treatments scaled to a hypothetical population of 10,000 patients to reflect benefits and risks on a population level. The rate differences are interpreted as the number of patients who would experience a particular event when treated with XARELTO minus patients treated with placebo.

See Table: Risk Difference per 10,000 Patients and NNT, NNH for Pairs of Benefit-Risk Outcomes for breakdown of pairings of key efficacy and safety endpoints.

Spyropoulos et al (2022)¹⁵ conducted a post hoc analysis of the MARINER study to evaluate if treatment with dual antithrombotic therapy (XARELTO plus low-dose aspirin) would be superior to no thromboprophylaxis in preventing major thromboembolic outcomes and death.

• Treatment with XARELTO plus aspirin vs no thromboprophylaxis was associated with a significant reduction in the primary efficacy outcome of symptomatic VTE and VTE-related death (0.76% vs 1.28%; P=0.042); see Table: Primary Effectiveness and Safety Endpoints by Treatment Groups.
• MB was low in all groups but was numerically higher in the XARELTO plus aspirin group (0.29%) compared with the no thromboprophylaxis group (0.10%); see Table: Primary Effectiveness and Safety Endpoints by Treatment Groups.

Spyropoulos et al (2020)³¹ conducted an exploratory analysis of the MARINER study to evaluate the effect of XARELTO 10 mg daily (n=4909) or placebo (n=4913) in preventing the prespecified composite endpoint of symptomatic VTE, myocardial infarction, nonhemorrhagic stroke, and cardiovascular death in acutely ill medical patients with CrCl ≥50 at the time of discharge for 45 days. Patients had a baseline CrCl of ≥80 mL/min (52.0%) or 50 to <80 mL/min (47.9%). The composite endpoint occurred in 1.28% and 1.77% in the XARELTO group and placebo group, respectively (HR, 0.72; 95% CI, 0.52-1.00). Safety results reported MB in 0.27% and 0.18% of patients taking XARELTO or placebo, respectively (HR, 1.44; 95% CI, 0.62-3.37).

Analyses From MAGELLAN and MARINER

Raskob et al (2021)³² conducted a post hoc pooled analysis of the MAGELLAN and MARINER studies to assess the benefit and risk of thromboprophylaxis with XARELTO 10 mg once daily extended for 25-45 days after hospitalization for reducing fatal and major thromboembolic outcomes without substantially increasing critical site or fatal bleeding.

• The data from the MARINER study were pooled with the data from the MAGELLAN study in patients who were free of thrombotic or bleeding events up to the last dose of enoxaparin/placebo and who continued in the outpatient phase of thromboprophylaxis.
• A total of 16,496 patients (XARELTO group, n=8222; placebo group, n=8274) were included in the pooled analysis. Baseline demographics and clinical characteristics of the patients were similar in both treatment groups.
• The incidence of the composite of all symptomatic thromboembolic events (symptomatic DVT, nonfatal PE, myocardial infarction, and nonhemorrhagic stroke) and all-cause mortality was 1.80% (148/8222) in the XARELTO group and 2.31% (191/8274) in the placebo group (HR, 0.78; 95% CI, 0.63-0.97).
• Fatal and critical site bleeding occurred in 0.09% (7/8222) of patients in the XARELTO group and 0.04% (3/8274) of patients in the placebo group (HR, 2.36; 95% CI, 0.61-9.11).

Spyropoulos et al (2022)¹⁶ conducted a post hoc analysis of the MAGELLAN and MARINER studies to evaluate the risk of all-cause mortality in patients with MB or CRNM bleeding. Patients were followed for all-cause mortality through day 90 in MAGELLAN and day 75 in MARINER. All bleeding events in patients taking at least 1 dose of study drug from randomization until 2 days after the last dose were evaluated. Patients were grouped into 1 of 4 categories (patients with no bleeding event, patients whose first event was a CRNM bleed, major bleed, or trivial bleed).

A total of 20,125 patients overall were randomized in both studies. The safety population in MAGELLAN and MARINER included 7,998 and 11,962 patients respectively. Patients in the MB group across both studies (MAGELLAN, n=56; MARINER, n=26) included a higher percentage of males and a history of anemia. CRNM bleeding (MAGELLAN, n=158; MARINER, n=132) and trivial bleeding (MAGELLAN, n=567; MARINER, n=85) were also reported in both studies.

In MAGELLAN, hemoglobin levels, acute respiratory insufficiency, history of VTE, history of anemia, bleeding 3 months before randomization, treatment duration, age, body mass index, CrCl, acute infectious disease, history of cancer, bronchiectasis, and DAPT use at baseline were significantly different across bleeding groups. In MARINER, history of cancer, history of anemia, treatment duration, age, hemoglobin, and HF at baseline were significantly different across bleeding groups.

Patients with MB events in MAGELLAN (HR, 8.53; 95% CI, 5.61-12.97; P<0.0001) and MARINER (HR, 3.46; 95% CI, 1.24-9.61; P=0.017) had a significantly higher risk of all-cause mortality compared to patients with no bleeding. In MAGELLAN, patients with CRNM bleeding had a significantly higher risk of all-cause mortality compared to those with no bleeding (HR, 1.74; 95% CI, 1.09-2.77; P=0.021). In MARINER, patients with CRNM bleeding did not have an increased risk of all-cause mortality compared to those without bleeding (HR, 0.43; 95% CI, 0.10-1.74; P=0.235). An increased risk of all-cause mortality was not observed with trivial bleeding in either study. The most common MB site in both studies was gastrointestinal (55.4% and 65.4% in MAGELLAN and MARINER respectively).

Real-World Evidence

IMPROVE-VTE

IMPROVE-VTE¹⁷ (IMpact of Prolonged anticoagulation with Rivaroxaban On proVokEd Venous ThromboEmbolism) was a retrospective claims database analysis using US Truven MarketScan data (commercial and a Medicare supplemental databases) from January 1, 2012 through March 31, 2017. The analysis evaluated the efficacy and safety of prolonged anticoagulation of XARELTO after the initial 3-month treatment period (index date) versus discontinuing anticoagulation (no anticoagulation or nonaspirin antiplatelet agents but may have received aspirin).

• Patients were included in this study if they had: >1 primary discharge diagnosis code for DVT or PE for a claim associated with a stay at a hospital or emergency department at least 3 months of continuous XARELTO treatment after the qualifying VTE, >12 months of continuous medical and prescription insurance benefits prior to their VTE, and a provoking risk factor such as cancer, inflammatory bowel disease, immobilization, hormonal therapy, and major surgery or trauma. Patients with a VTE or atrial fibrillation disease claim or a prescription claim for any anticoagulant during the baseline period were excluded from this study. Patients were followed until occurrence of an endpoint, insurance disenrollment, or up to 12 months postindex date (intention-to-treat analysis).
• The primary endpoints for this analysis were recurrent VTE (defined as a subsequent hospitalization with a primary International Classification of Diseases, Ninth Revision [ICD-9] or International Classification of Diseases, Tenth Revision [ICD-10] discharge diagnosis for DVT or PE) and MB (defined as subsequent hospitalization for a bleeding event).
• A total of 4990 patients were included in this analysis, 3806 with a provoked VTE receiving prolonged XARELTO treatment beyond the first 3 months (median duration of additional XARELTO use of 3 [range, 2-5] months) and 1184 discontinuing XARELTO at 3 months. Based on propensity-score, baseline characteristics were well balanced.
  • Among patients with a provoked VTE and treated with XARELTO beyond the first 3 months of treatment, there was a lower relative risk of recurrent thromboembolism (HR, 0.56; 95% CI, 0.34-0.91) compared to anticoagulation discontinuation.
  • There was no significant increase in MB among patients receiving prolonged XARELTO treatment compared to those discontinuing treatment at 3 months for the entire cohort (HR, 0.87; 95% CI, 0.51-1.49).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 20 July 2024.