Summary

• The information contained in this document specifically refers to the use of XARELTO in addition to the concomitant use of dual antiplatelet therapy (DAPT). DAPT is defined as the concurrent use of 2 agents (eg, aspirin [ASA], P2Y₁₂ platelet inhibitors) that reduce both platelet aggregation and thrombus formation.
• In ROCKET AF, ASA use at doses of >100 mg per day was excluded from the study.¹ Treatment with thienopyridine antiplatelet agents was prohibited for 5 days before randomization and throughout the treatment period, except for patients undergoing cardiovascular (CV) interventions who were eligible to receive appropriate DAPT with ASA and a thienopyridine concomitantly with the assigned anticoagulant at the investigator’s discretion.²
• In the EINSTEIN program, patients were allowed to take ASA (up to 100 mg per day), if indicated. Nonsteroidal anti-inflammatory drugs (NSAIDs) and antiplatelet agents were discouraged.^3,4
• An analysis of pooled data from the RECORD 1-4 studies for patients taking platelet function inhibitors (PFIs) or ASA over the total “at-risk” period, demonstrated similar relative rate ratios for any bleeding events (XARELTO: 1.32, 95% confidence interval [CI]: 0.85-2.05; enoxaparin: 1.40, 95% CI: 0.87-2.25), and similar relative rate ratios of major and nonmajor clinically relevant bleeding events (XARELTO: 1.11, 95% CI: 0.55-2.55; enoxaparin: 1.13, 95% CI: 0.47-2.75) between the XARELTO and enoxaparin groups, respectively.⁵
• There are no clinical studies that directly evaluated concomitant use of XARELTO with DAPT (ie, ASA with clopidogrel, ticagrelor, or prasugrel) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).
  • Patients were excluded from the COMPASS study if use of DAPT, other non-ASA antiplatelet therapy, or oral anticoagulant therapy was required.⁶ Additional guidance is provided below.^7,8
• VOYAGER PAD: Use of XARELTO with aspirin versus aspirin alone showed consistent efficacy and safety regardless of concomitant clopidogrel use. The addition of clopidogrel was associated with higher rates of bleeding, especially with longer durations of >30 days.⁹ 
• MAGELLAN was phase 3 trial comparing the efficacy and safety between extended thromboprophylaxis with XARELTO and standard-duration thromboprophylaxis with enoxaparin followed by placebo for the prevention of venous thromboembolism (VTE) in acutely ill medical patients requiring hospitalization.^10,11
  • About 31% of patients in MAGELLAN were taking DAPT at baseline. In a benefit-risk analysis of a MAGELLAN subpopulation, these patients were excluded due to increased risk of major bleeding.¹²
• In the MARINER study, XARELTO did not significantly reduce the risk of symptomatic VTE or death due to VTE compared to placebo in patients who were discharged from the hospital after medical illness. Patients taking concomitant DAPT at baseline were excluded from MARINER.¹³
• In a retrospective cohort study, the concurrent use of XARELTO with dual antiplatelet agents was associated with an increased risk of gastrointestinal bleeding.¹⁴
• In a study of patients on triple antithrombotic therapy, bleeding rates by choice of anticoagulant were 12.2% with warfarin, 14.3% with XARELTO, and 9.9% with apixaban (P=0.7335).¹⁵

CLINICAL STUDIES

Stroke Prevention in Nonvalvular Atrial Fibrillation (NVAF)

The ROCKET AF study was a phase 3, double-blind, double-dummy, parallel-group, multicenter, event-driven, noninferiority study designed to evaluate the efficacy and safety of oral XARELTO 20 mg once daily (QD; 15 mg for patients with creatinine clearance [CrCl] 30-49 ml/min) and dose-adjusted warfarin (target international normalized ratio [INR] of 2.0-3.0) for the prevention of stroke and systemic embolism in patients with NVAF at moderate-to-high risk for stroke.¹

• In ROCKET AF, ASA use at doses of >100 mg/day was excluded from the study.¹
• Treatment with thienopyridine antiplatelet agents was prohibited for 5 days before randomization and throughout the treatment period, except for patients undergoing CV interventions who were eligible to receive appropriate DAPT (ASA and a thienopyridine) concomitantly with the assigned anticoagulant at the investigator’s discretion.²
• The primary safety endpoint was the composite of both major bleeding and nonmajor clinically relevant bleeding. Results for the primary safety endpoint stratified by patients on baseline ASA and/or NSAID are shown in Table: Primary Safety Endpoint (Adjudicated by CEC) While on Treatment (Up to Last Dose Plus 2 Days) by Baseline ASA and/or NSAID.

Sherwood et al (2014)¹⁷ conducted an analysis of the patients in the ROCKET AF study who underwent a percutaneous coronary intervention (PCI) and received DAPT along with XARELTO or warfarin.

• The 153 patients who underwent a PCI (61 on XARELTO, 92 on warfarin) during the study were mostly male with a history of myocardial infarction (MI), diabetes, and previous use of a vitamin K antagonist (VKA).
• At 30 days post-PCI, 37% of the patients were on DAPT along with an oral anticoagulant while 46% of the patients were only on a single antiplatelet agent. A subgroup analysis of efficacy and safety outcomes in patients taking DAPT concomitantly with XARELTO has not been published.
• Patients who underwent a PCI had an increased risk of stroke, systemic embolism, MI, vascular death, and bleeding (major and nonmajor).
  • Patients in the XARELTO treatment group had a higher rate of major and nonmajor bleeding (57.6 vs 28.2) and major bleeding (15.0 vs 8.1) compared to the warfarin group.
  • Patients in the warfarin treatment group had a higher rate of stroke (4.1 vs 1.6) and vascular death (11.1 vs 3.1) compared to the XARELTO group.

PIONEER AF-PCI

PIONEER AF-PCI (An OPen-label, Randomized, Controlled, Multicenter Study ExplorIng TwOTreatmeNt StratEgiEs of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) is an exploratory study designed to evaluate the safety of 2 XARELTO treatment strategies and 1 VKA strategy in patients with NVAF who have undergone a PCI.^18-20 The primary outcome was percentage of subjects experiencing a TIMI clinically significant bleeding event, (defined as TIMI major bleeding events, TIMI minor bleeding events, and TIMI bleeding events) requiring medical attention, over 12 months.

Study Design

• Patients were randomized to receive 1 of 3 treatment strategies:
  • XARELTO 15 mg daily (10 mg for CrCl = 30-50 ml/min) plus clopidogrel 75 mg daily for 12 months
  • XARELTO 2.5 mg twice daily (BID) plus low-dose ASA (75-100 mg daily) plus clopidogrel 75 mg daily for 1, 6, or 12 months; followed by XARELTO 15 mg daily (10 mg for CrCl = 30-50 ml/min) plus low-dose ASA
  • Dose-adjusted VKA plus low-dose ASA (75-100 mg daily) plus clopidogrel 75 mg daily for 1 or 6 months; followed by dose-adjusted VKA plus low-dose ASA.

Results

• In stented AF patients, XARELTO at both doses reduced the risk of clinically significant bleeding, all-cause mortality or recurrent hospitalization for adverse events as compared with standard of care VKA plus 1, 6, or 12 months of DAPT.
• Secondary endpoints: Major adverse CV events (composite of CV death, MI, or stroke) occurred in 6.5% of the XARELTO 15 mg qd + P2Y12 inhibitor group, 5.6% of the XARELTO 2.5 mg BID + DAPT group, and 6.0% in VKA + DAPT group (P≥0.05 for both comparisons). Stent thrombosis occurred in less than 1% of patients regardless of treatment strategy.

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

The EINSTEIN program consists of 3 randomized studies of XARELTO^3,4:

1. Acute DVT study (EINSTEIN-DVT) - Treatment of acute DVT
2. Acute PE study (EINSTEIN-PE) - Treatment of acute PE
3. Continued treatment study (EINSTEIN-Extension) - Continued treatment in patients who have received treatment for either acute DVT or PE

• In the EINSTEIN program, patients were allowed to take ASA (up to 100 mg daily) if indicated. NSAIDs and antiplatelet agents were discouraged in these studies.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

The phase 3 RECORD clinical study program was composed of 4 double-blind, double-dummy, multinational studies that compared efficacy and safety of oral XARELTO 10 mg QD and subcutaneous (SC) enoxaparin 40 mg QD (RECORD 1-3) or 30 mg BID (RECORD 4) for prevention of VTE in patients undergoing elective total hip replacement (RECORD 1-2) or total knee replacement (RECORD 3-4).^21-24

Eriksson et al (2012)⁵ analyzed the pooled data from the RECORD 1-4 studies to evaluate the safety of concomitant use of NSAIDs and PFI, including ASA, in patients receiving either XARELTO or enoxaparin after total hip or knee arthroplasty.

• The safety endpoints evaluated in this study were the composite of major and nonmajor clinically relevant bleeding occurring after the first dose of postoperative oral study drug was taken. Events were followed from the day of surgery until 2 days after the last dose of study drug, which was considered the “at-risk” period.
• The time relative to surgery was stratified into 3 time periods: day 1-3, day 4-7, and after day 7. Characteristics between the XARELTO and enoxaparin groups were similar. Over 70% of patients in both groups concomitantly used NSAIDs at least once, and 9% concomitantly used PFIs or ASA at least once.
• For patients receiving PFIs or ASA, the ratios for any bleeding events over the total “at-risk” period were similar between groups (XARELTO 1.32, 95% CI: 0.85-2.05; enoxaparin 1.40, 95% CI: 0.87-2.25). The ratios of major and nonmajor clinically relevant bleeding events in patients taking PFIs and ASA were also similar between XARELTO and enoxaparin treated patients (XARELTO 1.11, 95% CI: 0.55-2.55; enoxaparin 1.13, 95% CI: 0.47-2.75) over the total “at-risk” period. Over the 3 time intervals, both safety endpoints with PFI or ASA concomitant use versus nonuse remained constant between the XARELTO and enoxaparin groups.

Reduction of Risk of Major CV Events (CV Death, MI, and Stroke) in Chronic CAD or PAD

COMPASS was a phase 3, event-driven, double-blind, randomized study designed to evaluate whether treatment with XARELTO 2.5 mg twice daily and ASA 100 mg once daily or XARELTO 5 mg twice daily alone is more effective than ASA 100 mg once daily alone for prevention of MI, stroke, or CV death in 27,395 patients with a history of stable atherosclerotic vascular disease (CAD or PAD).⁶

Study Design/Methods

• Primary efficacy outcome: the composite of MI, stroke, or CV death
• Primary safety outcome (based on modified International Society on Thrombosis and Hemostasis criteria): major bleeding, including fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding leading to hospitalization (including presentation to an acute care facility without overnight stay)
• Patients were excluded from COMPASS if use of dual antiplatelet therapy, anticoagulation, or other anti-thrombotic therapy was required.

Need for DAPT During Study Period

• If patients developed the need for DAPT during the study period (ie, in the event of an acute coronary syndrome [ACS] or in patients who underwent PCI with stenting), investigators could make the decision to temporarily discontinue XARELTO until DAPT was no longer clinically required. Alternatively, investigators could also transition patients in need of DAPT to the 2.5mg BID dose of XARELTO (or matching placebo).⁷
• Study XARELTO and XARELTO placebo were to be restarted once DAPT was discontinued (following completion of therapy of an adequate duration).⁸

COMPASS Subanalysis – Patients with CAD

• Among COMPASS study patients that had stable CAD (N=24,842), 1120 developed a need for DAPT.⁷
  • In the XARELTO (2.5 mg twice daily)-plus-ASA arm, 358 (4%) patients required DAPT during the study, of which 344 had XARELTO treatment discontinued and 14 continued XARELTO (2.5 mg twice daily).
  • In the XARELTO (5 mg twice daily)-alone arm, 384 (5%) patients required DAPT during the study, of which 369 had XARELTO treatment discontinued and 15 continued XARELTO (2.5 mg once daily).

Symptomatic Peripheral Artery Disease After Lower Extremity Revascularization

VOYAGER PAD was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international, endpoint-driven trial designed to evaluate whether the combination of XARELTO 2.5 mg BID plus aspirin 100 mg once daily is more effective than aspirin 100 mg once daily alone for reduction in the risk of major atherothrombotic vascular outcomes, consisting of both CV and limb events in patients with symptomatic peripheral artery disease undergoing lower extremity revascularization.²⁵

A prespecified subgroup analysis was conducted to assess the effect of concomitant therapy with clopidogrel on the primary efficacy and safety outcomes.⁹ Of 6564 randomized patients (XARELTO-plus-aspirin group, n=3286; aspirin-alone group, n=3278), 3313 received concomitant clopidogrel.^9,25 The median duration of follow-up was 28 months.²⁵

• The median age was 67 years in patients with and without concomitant clopidogrel use at baseline.
  • Baseline characteristics showed that compared with patients without concomitant clopidogrel use, the proportion of those with concomitant clopidogrel use was higher in female patients (differed by region and race) and in those with hypertension, type 2 diabetes mellitus, hyperlipidemia, and/or a higher prevalence of CV risk factors and concomitant CAD.⁹
• In both the XARELTO-plus-aspirin group and aspirin-alone group, concomitant clopidogrel use at randomization was observed in 51% of patients. The median duration of clopidogrel was 29.0 days in both groups.⁹
• The primary efficacy endpoint of composite of acute limb ischemia (ALI), major amputation for vascular etiology, MI, ischemic stroke, or CV death at 3 years for XARELTO was consistent, regardless of concomitant clopidogrel use. In patients with vs without concomitant clopidogrel use, the absolute risk reduction (ARR) for the primary endpoint was 2.3% (hazard ratio [HR]: 0.85; 95% CI: 0.71-1.01) vs 2.8% (HR: 0.86; 95% CI: 0.73-1.01; P=0.92), respectively. See Table: Efficacy of XARELTO With and Without Concomitant Clopidogrel.⁹
  • In patients with vs without concomitant clopidogrel use, the ARR for ALI within 30 days of treatment was 0.30% (HR: 0.45; 95% CI: 0.141.46) vs 0.81% (HR: 0.48; 95% CI: 0.22-1.01; P=0.93); correspondingly, the ARR for ALI within 180 days of treatment was 1.48% (HR: 0.47; 95% CI: 0.28-0.81) vs 1.44% (HR: 0.60; 95% CI: 0.39-0.92; P=0.49).⁹

• The principal safety outcome of TIMI major bleeding, at 3 years, for XARELTO was consistent, regardless of concomitant clopidogrel use (P=0.71). See table: Safety of XARELTO With and Without Concomitant Clopidogrel.⁹

• The 1-year incidence of International Society on Thrombosis and Haemostasis (ISTH) major bleeding in the XARELTO-plus-aspirin group vs placebo-plus-aspirin group with clopidogrel use for >30 days was 3.74% vs 1.18% (absolute risk increase [ARI], 2.79%; HR: 3.20; 95% CI: 1.44-7.13) and with clopidogrel use for ≤30 days was 2.24% vs 1.73% (ARI, 0.46%; HR: 1.30; 95% CI: 0.68-2.47; P=0.07).⁹

Acute Coronary Syndrome

ATLAS ACS TIMI-51 was a phase 3, multicenter, event-driven study designed to determine whether XARELTO (2.5 mg BID or 5 mg BID) was safe and reduced the risk of the composite of CV death, MI, or stroke in patients with a recent ACS, as compared with placebo. All patients were to receive standard medical therapy, including low-dose ASA and 93% of patients received a thienopyridine as background therapy.²⁶

• The primary safety endpoint was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding events not associated with coronary artery bypass graft (CABG) surgery. The rate of TIMI major bleeding not related to CABG was significantly increased with XARELTO compared with placebo (2.1% vs 0.6%, P<0.001). This was observed with both the 2.5 mg dose (P<0.001)²⁷ and the 5 mg dose (P<0.001).

GEMINI-ACS-1 is a phase 2, randomized, double-blind, double-dummy, active-controlled, multicenter study assessing the safety and feasibility of XARELTO plus clopidogrel or ticagrelor and ASA plus clopidogrel or ticagrelor in patients within 10 days of an ACS event in approximately 3000 patients.^28,29 The primary outcome was TIMI clinically significant bleeding (major, minor, or requiring medical attention).

Study Design

• Patients will be randomized to receive 1 of 4 treatments:
  • XARELTO 2.5 mg BID plus clopidogrel 75 mg QD for 12 months
  • XARELTO 2.5 mg BID plus ticagrelor 90 mg BID for 12 months
  • ASA 100 mg QD plus clopidogrel 75 mg QD for 12 months
  • ASA 100 mg QD plus ticagrelor 90 mg BID for 12 months

Results

• The primary endpoint of TIMI non-CABG clinically significant bleeding was observed in 154 patients. The frequency of the primary endpoint was 5.0% for XARELTO and 5.0% for ASA (HR: 1.09; 95% CI: 0.80-1.50; P=0.5840).
• The most common type of bleed in both groups is TIMI bleeding requiring medical attention; TIMI major bleeding was 1% for both groups, and intracranial hemorrhage was <1% for XARELTO and 0% for ASA.

MAGELLAN

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 postdischarge periods.^10,30

• About 31% of patients were taking concomitant DAPT at baseline.¹²

Spyropoulos et al (2019)¹² conducted a retrospective, benefit-risk analysis in a subpopulation of the MAGELLAN study.

• DAPT at baseline was one of five risk factors for major bleeding that 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. Other risk factors were active cancer, 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.
• Like that observed in the overall MAGELLAN study population, within the MAGELLAN subpopulation, at day 10, XARELTO was noninferior to enoxaparin, and at day 35, XARELTO was significantly better than enoxaparin/placebo for total VTE.
• The risk of major bleeding associated with XARELTO was reduced in both treatment phases within the MAGELLAN study subpopulation.

MARINER

The MARINER^13,31 (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) compared with placebo in the prevention of symptomatic VTE and VTE-related death after hospital discharge in high-risk, medically ill patients for a period of 45 days posthospital discharge.

• Patients taking DAPT at baseline were excluded from MARINER.¹³

Retrospective Studies

Chilbert et al (2022)¹⁵ was a multi-site, retrospective cohort study that compared the safety of patients taking triple therapy, oral anticoagulants (warfarin, apixaban, or XARELTO), ASA, and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel). Adult patients admitted for hospitalization or elective procedure who were discharged on triple therapy were included in the study. If a patient was on triple therapy prior to admission, they were excluded.  

Comparison of bleeding rates within 90 days of triple therapy start between the oral  anticoagulant groups and the comparison of bleeding rates between the P2Y12 inhibitor groups were the primary and secondary outcomes, respectively. ISTH criteria for major or clinically relevant nonmajor bleeding was used to analyze bleeding.

A total of 372 patients were included in the study with a majority prescribed warfarin (n=238), followed by apixaban (n=71), and XARELTO (n=63). The most frequent dosing for Apixaban was 5 mg BID in 81.7% of patients and for XARELTO it was 20 mg daily in 70.0% of patients.

Please see Tables: Patient Product Characteristics and Patient Safety Outcome for P2Y12 inhibitor choice, ASA strength, and bleeding rates on triple therapy.

Bleeding rates in patients treated with a P2Y12 inhibitor was 11.2%, 12.8%, and 33.3% for the clopidogrel group, ticagrelor group, and prasugrel group, respectively. Risk factors associated with bleeding in this study included the use of prasugrel vs clopidogrel (odds ratio [OR]: 4.35, 95% CI: 1.20-15.72; P=0.025) and hemoglobin less than 12 mg/dL at admission (OR: 2.54, 95% CI: 1.28-5.04; P=0.008).

Sherid et al (2014)¹⁴ conducted a retrospective cohort study to compare the risk of gastrointestinal bleeding between XARELTO and dabigatran. The medical records from 2 hospitals were reviewed for patients on either XARELTO (n=147) or dabigatran (n=227) from October 2010 to April 2013. The concomitant use of DAPT agents (ASA and a thienopyridine consisting of clopidogrel, ticlopidine, or prasugrel) was present in 5.44% of patients in the XARELTO group compared to 8.37% of patients in the dabigatran group (P=0.1934). The concomitant use of DAPT agents was not associated with an increased risk of gastrointestinal bleeding in the dabigatran group; however, the concurrent use of XARELTO with DAPT agents was associated with an increased risk of gastrointestinal bleeding (OR: 7.4; P=0.0378).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 10 April 2024.