Summary

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding during XARELTO therapy. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.¹
• ROCKET AF: Primary safety endpoint (composite of both major bleeding and nonmajor clinically relevant bleeding) occurred in 31% of XARELTO patients that were taking NSAIDs at baseline and in 20% of XARELTO patients that were not taking NSAIDs at baseline.²
• EINSTEIN program: The use of NSAIDs and antiplatelet agents was discouraged.^3,4 Approximately 23% of patients in the safety population took NSAIDs during the EINSTEIN DVT & PE Trials. A subanalysis demonstrated a hazard ratio (HR) of 1.90 for XARELTO and 1.65 for the enoxaparin-vitamin K antagonist (VKA) group for clinically relevant bleeding events in patients with and without concomitant NSAID use. For major bleeding events, the HR was 2.56 for XARELTO and 2.28 for the enoxaparin-VKA group in patients with and without concomitant NSAID use.⁵
• RECORD program: An analysis of the pooled data from the RECORD 1-4 studies demonstrated similar relative rate ratios for any bleeding events, and similar relative rate ratios of major and nonmajor clinically relevant bleeding events in patients taking concomitant NSAIDs over the total at-risk period.⁶
• XAMOS: Concomitant use of NSAIDs and XARELTO was associated with lower incidences of symptomatic thromboembolic events compared with standard-of-care (SOC), without significant increases in major bleeding events.⁷
• XANTUS: An analysis of modifiable and nonmodifiable risk factors associated with major bleeding events demonstrated the use of antiplatelet, NSAID, or paracetamol treatment as an independent factor associated with major bleeding in treatment with XARELTO.⁸
• COMPASS: Approximately 6% of patients were taking NSAIDs at baseline. There was not a pre-specified subgroup analysis evaluating the efficacy and safety of NSAID use and XARELTO in combination with aspirin in patients with stable atherosclerotic vascular disease.⁹
• A systematic review and meta-analysis that evaluated the risk of bleeding associated with concomitant use of oral anticoagulants (OACs) and NSAIDs showed that there was significant increase in risk of bleeding in patients treated with XARELTO and NSAIDs compared with XARELTO alone (odds ratio [OR]=1.61; 95% confidence interval [CI], 1.21-2.14; P=0.001).¹⁰

CLINICAL STUDIES

Stroke Prevention in Nonvalvular Atrial Fibrillation

ROCKET-AF

The ROCKET-AF trial was a phase 3, double-blind, double-dummy, parallel-group, event-driven, noninferiority study designed to evaluate the efficacy and safety of oral XARELTO 20 mg once daily (15 mg for patients with creatinine clearance 30-49 mL/min) and dose-adjusted warfarin (target International Normalized Ratio: 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation at moderate-to-high risk for stroke.¹¹

• The primary safety endpoint was the composite of both major bleeding and nonmajor clinically relevant bleeding. Results stratified by patients on baseline aspirin and/or NSAID are shown in Table: ROCKET-AF: Primary Safety Endpoint While on Treatment (up to Last Dose Plus 2 Days) by Baseline NSAID and/or Aspirin/PAI.¹¹
• A subgroup analysis by specific NSAIDs is not available at this time.

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

EINSTEIN PROGRAM

The EINSTEIN program consisted of three phase 3 event-driven, randomized trials of XARELTO:

1. (EINSTEIN-DVT) - Open-label, noninferiority trial that compared XARELTO alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA (warfarin or acenocoumarol) in patients with confirmed symptomatic DVT without symptomatic PE.³
2. (EINSTEIN-PE) - Open-label, noninferiority study that compared XARELTO (15 mg twice daily for 3 weeks followed by 20 mg once daily) vs subcutaneous (SC) enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT ⁴
3. (EINSTEIN-Extension) - Phase 3, double-blind, event-driven superiority study that compared XARELTO 20 mg once daily to placebo in patients with confirmed symptomatic PE or DVT who have been treated for 6 to 12 months with XARELTO or VKA. ³

• In the EINSTEIN program, the use of NSAID medications was discouraged.^3,4

Davidson et al (2014)⁵ conducted a subanalysis of the EINSTEIN-DVT and EINSTEIN-PE studies to determine the incidence of major and all clinically relevant bleeding for patients treated with XARELTO or enoxaparin-VKA and exposed to NSAIDs or aspirin.

• In the safety population, there were 4130 and 4116 patients in the XARELTO and enoxaparin-VKA treatment groups, respectively.
• Approximately 23% of the safety population received NSAIDs. The incidence of clinically relevant bleeding and major bleeding are displayed in Table: EINSTEIN DVT and EINSTEIN PE: Incidence of Clinically Relevant Bleeding in Patients with or without Concomitant NSAID Use and Table: EINSTEIN DVT and EINSTEIN PE: Incidence of Major Bleeding in Patients with or without Concomitant NSAID Use.
• A subgroup analysis by specific NSAIDs is not available at this time.

An additional analysis of the EINSTEIN DVT and PE studies by Di Nisio et al (2016)¹² identified risk factors for major bleeding in patients receiving the XARELTO or enoxaparin/VKAs for the treatment of acute venous thromboembolism (VTE). This study confirmed the results of Davidson (2014)⁵ that the concomitant use of antiplatelet or NSAIDs was associated with a higher risk of bleeding. NSAID and/or antiplatelet use doubled the risk of major bleeding during the first weeks of anticoagulation.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

RECORD PROGRAM

RECORD consisted of 4 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 (RECORD1-3) or 30 mg twice daily (RECORD4) for VTE prevention in patients undergoing total hip replacement (RECORD1-2) or total knee replacement (RECORD3-4).^13-16

Eriksson et al (2012)⁶ analyzed the pooled data from the RECORD 1-4 studies to evaluate the safety of concomitant use of NSAIDs and PFIs, including aspirin, 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 postoperative oral study drug intake. Events were followed from the day of surgery until 2 days after the last intake 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.
• The relative rate ratios for any bleeding events over the total at-risk period were similar between the XARELTO and enoxaparin groups (XARELTO 1.22, 95% CI 0.99-1.50; enoxaparin 1.22, 95% CI 0.98-1.51) in patients taking concomitant NSAIDs. Over the total at-risk period, the relative rate ratios of major and nonmajor clinically relevant bleeding events were also similar between the XARELTO and enoxaparin groups (XARELTO 1.28, 95% CI 0.94-1.73; enoxaparin 0.90, 95% CI 0.63-1.28) in patients taking NSAIDs.
• Over the 3 time intervals, both safety endpoints with NSAID concomitant use vs nonuse remained constant between XARELTO and enoxaparin groups.
• A subgroup analysis by specific NSAIDs is not available at this time.

Reduction in the Risk of Major Cardiovascular Events in Patients with Chronic Coronary Artery Disease (CAD) or Peripheral Artery Disease (PAD)

COMPASS Study

COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) was a phase 3, event-driven, double-blind, randomized, study designed to evaluate whether treatment with XARELTO 2.5 mg twice daily and aspirin 100 mg once daily or XARELTO 5 mg twice daily alone is more effective than aspirin 100 mg once daily alone for prevention of myocardial infarction, stroke, or cardiovascular death in 27,395 patients with a history of stable atherosclerotic vascular disease (CAD or PAD).⁹

• Patients were not excluded from enrolling in this study based on NSAID use. Approximately 6% of the study participants were taking NSAIDs at baseline.

OBSERVATIONAL STUDIES

XAMOS STUDY

XAMOS was a noninterventional, open-label cohort study of 17,701 patients that assessed the effectiveness and safety of XARELTO (n=8778) compared with SOC thromboprophylaxis (SOC, n=8635) in routine clinical practice in patients undergoing major orthopedic surgery. For the SOC group, 81.7% received low molecular weight heparin. The dose and duration of treatment were determined by the attending physician prior to enrollment. Thromboembolic events were defined as those occurring within 3 months after surgery, and treatment-emergent bleeding events were defined as starting on or after the day of the first dose and within 48 hours after the last dose of thromboprophylactic drug. Major bleeding events were defined as in the RECORD studies and, according to the European Medicines Agency (EMA) guidelines.⁷

Kreutz et al (2016)⁷ conducted a sub-analysis of the XAMOS trial, focusing on the use of CYP3A4 inhibitors or inducers, P-glycoprotein inhibitors, platelet aggregation inhibitors (PAIs), and NSAIDs.

• The analyses are deemed to evaluate the risk potential in subgroups, and are of an exploratory, descriptive nature; no statistical significance of findings can be derived. ORs are given with 95% CIs in context of the overall results to explore directional trends.
• NSAID use had no influence on thromboembolic events. However, ORs for major bleeding events (EMA definition) were higher in NSAID users compared with nonusers in the XARELTO (OR: 1.50; 95% CI: 1.06-2.13) and SOC (OR: 1.70; 95% CI: 1.16-2.49) groups. See Table: XAMOS: Incidence of Thromboembolic and Treatment-Emergent Bleeding Events in Patients with or without Concomitant Use of NSAIDs.

XANTUS Study

XANTUS was a real-world, international, prospective, observational study designed to assess the safety and effectiveness of rivaroxaban for stroke prevention in routine clinical practice in patients with NVAF newly initiated on rivaroxaban (N = 6784). In this study, patients taking rivaroxaban had low rates of stroke and major bleeding; most patients (96.1%) did not experience a major event (major bleeding, death or stroke/systemic embolism) during the study.⁸

Kirchoff et al (2020)⁸ conducted a sub-analysis of the XANTUS prospective registry data set, focusing on the modifiable and nonmodifiable risk factors associated with major bleeding events. In the analysis, modifiable and nonmodifiable risk factors of major bleeding were identified in an unselected cohort of NVAF patients treated with rivaroxaban, and the potential maximum benefits of reducing modifiable risk factors were modeled.

A total of 128 of the 6784 (1.9%) patients on rivaroxaban experienced a major bleeding event over a mean treatment duration of 329 days (2.1 events per 100 patient-years). The patients with major bleeding events typically were older in age, had heart failure and vascular heart disease, and had concomitant antiplatelets, NSAIDs, or paracetamol.

Multivariate analysis of the modifiable risk factors and subsequent univariate analysis identified corresponding Hazard Ratio (HR) with 95% CI. Concomitant antiplatelet, NSAID, or paracetamol treatment at any time during the study was identified as a modifiable risk factor (HR=1.80; 95% CI 1.24-2.61). Incidence of major bleeding in patients with concomitant antiplatelets, NSAIDS, and paracetamol use are presented in Table: Major Bleeding Events in Patients Taking Rivaroxaban with Concomitant Antiplatelet, NSAID, or Paracetamol Use.

DRESDEN NOVEL ORAL ANTICOAGULANT (NOAC) REGISTRY DATA

Beyer-Westendorf et al (2014)¹⁸ assessed a prospective, noninterventional registry of 2600 NOAC patients to analyze XARELTO persistence. Of the 1204 patients who were taking XARELTO for stroke prevention in atrial fibrillation, 123 (10.2%) had concomitant NSAID use at baseline. In the group of patients who discontinued XARELTO due to bleeding (n=67), concomitant therapy with antiplatelet drugs was present in 5 cases (7.5%), with NSAIDS in 3 cases (4.5%) and a combination of both in 1 case (1.5%).

retrospective studies

A retrospective cohort study of 475 Japanese patients given NOAC therapy identified concomitant NSAID drug therapy as one of the significant risk factors related to overall bleeding and actionable gastrointestinal bleeding.¹⁹

SYSTEMATIC REVIEWS AND META-ANALYSES

Zheng et al (2023)¹⁰ conducted a systematic review and network meta-analysis of 27 studies to evaluate the risk of bleeding in patients receiving OACs, which included both VKAs and direct OACs (DOACs) such as XARELTO, dabigatran, apixaban, and edoxaban, in combination with NSAIDs or alone.

• Subgroup analyses conducted according to the types of DOACs showed that there was a significant increase in the risk of bleeding in patients treated with XARELTO and NSAIDs compared with XARELTO alone (OR=1.61; 95% CI, 1.21-2.14; P=0.001).

ADDITIONAL REFERENCES

The American Society of Regional Anesthesia and Pain Medicine developed guidelines specifically for interventional spine and pain procedures in patients on antiplatelets/anticoagulants, including XARELTO.²⁰

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 13 February 2024.