Summary

• In the MAGELLAN study, at day 10, XARELTO was noninferior to enoxaparin in reducing the risk of venous thromboembolism (VTE) in the per-protocol population (P=0.003). At day 35, extended-duration thromboprophylaxis with XARELTO was superior to standard-duration enoxaparin followed by placebo in reducing the risk of VTE in the modified intent-to-treat (mITT) population (P=0.02).¹
  • Clinically relevant bleeding rates were significantly higher in the XARELTO arm than in the enoxaparin/placebo arm during the entire study period (P<0.001 from day 1 to day 10, and from day 1 to day 35).
• Five risk factors for bleeding were identified in the MAGELLAN and applied as exclusion criteria to the overall trial. The MAGELLAN subpopulation was a retrospective analysis. In the MAGELLAN subpopulation, rates of any VTE event were consistent with the MAGELLAN overall population at day 10 and day 35.²
  • Major bleeding rates were similar in the XARELTO arm and the enoxaparin/placebo arm in the MAGELLAN subpopulation.
• The 5 exclusion criteria were also applied prospectively in the MARINER trial. In MARINER, XARELTO did not significantly reduce the risk of symptomatic VTE or death due to VTE compared to placebo post discharge in patients who were hospitalized for acute medical illness.³
  • Major bleeding rates were similar in the XARELTO arm to the placebo arm.
• A benefit-risk assessment of the MARINER study resulted in 32.5 fewer symptomatic VTE and VTE-related deaths and 8.2 additional major bleeding events per 10,000 patients treated with XARELTO compared to placebo.⁴
• An exploratory analysis of the MARINER study evaluated whether XARELTO 10 mg daily could reduce the incidence of fatal and major thromboembolic events (symptomatic VTE, myocardial infarction [MI], nonhemorrhagic stroke, and cardiovascular [CV] death) compared with placebo when given to acutely ill medical patients at the time of discharge for 45 days. Extended-duration XARELTO in hospitalized medically ill patients resulted in a significant 28% reduction in fatal and major thromboembolic events, without a significant increase in major bleeding.⁵
• A post hoc analysis of the MAGELLAN and MARINER trials demonstrated that patients with major bleeding 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.⁶
• An additional relevant citation has been included for your review.⁷

CLINICAL STUDIES

MAGELLAN Study

MAGELLAN was a phase 3, international, randomized, double-blind trial 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 post discharge periods.^1,8

Methods

Patients were included in the study if they were: ≥40 years of age; hospitalized for a specified acute medical illness less than 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.⁸

Inclusion criteria included the following acute medical conditions: chronic New York Heart Association (NYHA) class III/IV heart failure (HF); active cancer; acute ischemic stroke; acute infectious and inflammatory diseases and acute respiratory insufficiency. Patients with acute infectious or inflammatory diseases and those with acute respiratory insufficiency were also required to have at least 1 additional risk factor for VTE. These included: prolonged immobilization, age ≥ 75 years, history of cancer, history of VTE, history of HF, thrombophilia, acute infectious disease contributing to the hospitalization, and BMI ≥35 kg/m².⁸

Patients were excluded if they had conditions that contraindicated the use of enoxaparin or XARELTO, were at an increased risk for bleeding, had certain concomitant conditions, or were taking certain concomitant drugs.⁸

The study randomized 8101 patients to receive either subcutaneous placebo daily for 10±4 days plus XARELTO 10 mg daily for 35±4 days or subcutaneous enoxaparin 40 mg daily for 10±4 days plus oral placebo daily for 35±4 days. All enrolled study participants underwent mandatory bilateral lower limb venous ultrasonography at 2 time points, on day 10±4 and day 35±4.

The 2 coprimary efficacy outcomes included the composite of asymptomatic proximal deep vein thrombosis (DVT) (detected by mandatory compression ultrasonography), symptomatic proximal or distal DVT, symptomatic nonfatal pulmonary embolism (PE), and VTE-related death at day 10±4 (tested for noninferiority) and at day 35±4 (tested for superiority).^1,8

The principal safety outcome was clinically relevant bleeding, defined as the composite of major bleeding and clinically relevant nonmajor (CRNM) bleeding events observed no later than 2 days after the last study drug was administered.¹

Results

Baseline characteristics were similar between the XARELTO and enoxaparin groups.¹

The primary efficacy outcome at day 10 for the per-protocol population and at day 35 for the mITT population is presented in Table: Primary Efficacy Outcome and Components at Day 10 and Day 35 in the MAGELLAN Study.¹

In the MAGELLAN study overall, bleeding rates were low, but significantly higher in the XARELTO arm than in the enoxaparin/placebo arm during the entire study period; see Table: Safety Outcomes in the MAGELLAN Study (Safety Population).¹

Net clinical benefit, defined as the composite of the primary efficacy outcome and the principal safety outcome in the per-protocol population, was 6.6% in the XARELTO group and 4.6% in the enoxaparin group by day 10. Net clinical benefit in the mITT population was 9.4% for the XARELTO arm and 7.8% in the enoxaparin/placebo arm by day 35.¹

MAGELLAN Subpopulation

Spyropoulos et al (2019)² conducted a retrospective, benefit-risk analysis in a subpopulation of the MAGELLAN study.

• Five risk factors for major bleeding 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: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e. undergoing acute, in-hospital treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy.
• 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. In the MAGELLAN subpopulation, rates of any VTE event were consistent with the MAGELLAN overall population at day 10 and day 35. Major bleeding rates were similar in the XARELTO arm and the enoxaparin/placebo arm in the MAGELLAN subpopulation. See Table: Primary Efficacy Outcome and Components at Day 10 and Day 35 in the MAGELLAN Subpopulation.

• The risk of major bleeding associated with XARELTO was reduced in both treatment phases within the MAGELLAN study subpopulation. See Table: Safety Outcomes in the MAGELLAN Subpopulation.

Cohen et al (2014)

Cohen et al (2014)⁹ performed a subanalysis of the MAGELLAN study to analyze the relationship between D-dimer, VTE, and major and CRNM bleeding in the MAGELLAN overall study according to treatment regimen. Based on the MAGELLAN protocol, D-dimer concentrations were obtained at baseline and on day 10 predose and postdose, and at day 35. The overall median baseline D-dimer concentration was 0.94 µg/mL. In this post hoc analysis, patients were grouped per either D-dimer ≤2x ULN (low D-dimer group) or >2x ULN (high D-dimer group). Of the 8101 patients randomized in the MAGELLAN study, 7581 had D-dimer measurements available.

• Overall, 4.0% (106/2662) of patients in the high D-dimer group had a VTE by day 10, compared with 1.2% (35/3037) of patients in the low D-dimer group.
• In both D-dimer groups, XARELTO showed consistent efficacy results at day 10 with the overall MAGELLAN population. However, at day 35, the high D-dimer group had consistent results with the overall MAGELLAN population, but the low D-dimer group showed similar rates of any VTE events in the XARELTO and placebo groups.
• In both D-dimer groups, XARELTO showed consistent safety results at day 10 and day 35 with the overall MAGELLAN population.
• At day 35, overall mortality was higher in the high D-dimer group than the low D-dimer group, and the incidence of all adverse events was also slightly higher in the high D-dimer group.
• The results of the multivariate analysis at day 35 confirmed that high D-dimer concentration was an independent predictor of risk of VTE (odds ratio [OR]: 2.29; 95% confidence interval [CI]: 1.75-2.98) and had a similar association to established risk factors for VTE of cancer and age ≥75 years.

MARINER Study

The MARINER^3,10 (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 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 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 ULN. 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 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 major bleeding.
• XARELTO was associated with less symptomatic VTE or death due to VTE than placebo; however, the difference was not statistically significant. Results were similar when stratified by CrCl (≥30 to <50 mL/min or ≥50 mL/min). Patients with CrCl <30 mL/min were excluded.^3,11
• The prespecified secondary efficacy outcomes were evaluated as exploratory analyses without adjustment for multiplicity since superiority was not shown in the primary efficacy analysis. Results of primary efficacy and safety outcomes are provided in Table: Outcomes from the MARINER Study.
• Major bleeding occurred at a similar rate in the XARELTO and placebo groups. Subgroup analyses of major bleeding showed there were no significant interactions between study regimen and subgroup variables, except for in-hospital receipt of thromboprophylaxis (P=0.03) and duration of index hospitalization (P=0.02).¹¹
• Rates for adverse events were similar among the 2 treatment arms.

Miao et al (2019)¹² used US outcomes data from 2014 to identify potential candidates for extended thromboprophylaxis by using clinical criteria from the MARINER study.

Raskob et al (2022)

Raskob et al (2022)⁴ 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 Number Needed to Treat (NNT), Number Needed to Harm (NNH) for Pairs of Benefit-Risk Outcomes for breakdown of pairings of key efficacy and safety endpoints.

Spyropoulos et al (2020)

Spyropoulos et al (2020)⁵ conducted an exploratory subgroup analysis of the MARINER study to evaluate whether extended-duration XARELTO reduces the risk of venous and arterial fatal and major thromboembolic events without significantly increasing major bleeding in acutely ill medical patients after discharge.

• As described above, in the MARINER study, medically ill patients with a baseline CrCl of ≥50 mL/min were randomized to XARELTO 10 mg or placebo once daily at hospital discharge for 45 days. This exploratory analysis was performed with the intent-to-treat (ITT) population, including all data through day 45.
• The analysis evaluated the composite efficacy outcome of symptomatic VTE, MI, nonhemorrhagic stroke, and CV death, which was a prespecified secondary outcome of the MARINER study. The principal safety outcome of major bleeding was based on the International Society on Thrombosis and Hemostasis bleeding criteria and included fatal bleeding, bleeding into a critical organ, or bleeding that led to a drop of ≥2 g/dL of hemoglobin or a transfusion of ≥2 units of blood.
• A total of 4909 and 4913 patients were randomized to XARELTO and placebo, respectively, and were included in the ITT population.
  • Baseline characteristics were similar between groups. Mean age was 67.8 years, 55.5% of patients were male, mean baseline CrCl was 87.8 mL/min, and mean duration of hospitalization was 6.7 days.
• The prespecified composite efficacy outcome of symptomatic VTE, MI, nonhemorrhagic stroke, and CV death occurred in 1.28% and 1.77% of patients in the XARELTO and placebo groups, respectively (hazard ratio [HR]: 0.72; 95% CI: 0.52-1.00; P=0.049). Incidence of the components of the composite outcome, with the exception of MI, numerically tended to favor XARELTO. See Table: Time to First Occurrence of Composite Outcome and Components (ITT).
• Major bleeding occurred in 0.27% and 0.18% of patients in the XARELTO and placebo groups, respectively (HR: 1.44; 95% CI: 0.62-3.37; P=0.398). See Table: Time to First Occurrence of Major Bleeding Event, On-Treatment (Safety Analysis Set).

Pooled Analysis from MAGELLAN AND MARINER

Spyropoulos et al (2022)⁶ conducted a post hoc analysis of the MAGELLAN and MARINER trials to evaluate the risk of all-cause mortality in patients with major bleeding or nonmajor clinically relevant 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 one 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 nonmajor clinically relevant bleed, major bleed, or trivial bleed).  

A total of 20,125 patients overall were randomized in both trials. The safety population in MAGELLAN and MARINER included 7,998 and 11,962 patients respectively. Patients in the major bleeding group across both studies (MAGELLAN: n=56; MARINER: n=26) included a higher percentage of males and a history of anemia. Nonmajor clinically relevant 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, BMI, creatinine clearance, 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 heart failure at baseline were significantly different across bleeding groups.

Patients with major bleeding 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 non major clinically relevant 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 nonmajor clinically relevant 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 trial.  The most common major bleeding site in both trials was gastrointestinal (55.4% and 65.4% in MAGELLAN and MARINER respectively).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) conducted on 09 July 2024 did not identify any relevant citations pertaining to this topic.