Summary

• XARELTO is not approved for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS).
• The primary endpoint of the phase 2 GEMINI 1 ACS study was thrombolysis in myocardial infarction (TIMI) noncoronary artery bypass graft (non-CABG) clinically significant bleeding, which was observed in 154 patients. The frequency of the primary endpoint was 5.0% for XARELTO and 5.0% for aspirin (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.80-1.50; P=0.5840).^1,2
• The ATLAS ACS 2-TIMI 51 study found that XARELTO (2.5 mg twice daily [BID] or 5 mg BID), when compared to placebo, significantly reduced the risk of the composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke in patients with a recent ACS (P=0.008).³
• Several subgroup analyses of the ATLAS ACS 2-TIMI 51 study were conducted.
  • Fatal or irreversible bleeding and ischemic events: In a subanalysis that compared fatal or irreversible bleeding and ischemic events to assess net clinical outcomes of therapy, XARELTO 2.5 mg BID, when added to aspirin and clopidogrel/ticlopidine, was associated with a net reduction in fatal or irreversible events compared to placebo.⁴
  • Neurological outcomes: Among patients with ACS who experienced a stroke, the addition of XARELTO 2.5 mg BID to standard-of-care (SOC) antiplatelet therapy was associated with improved neurological outcomes.⁵
  • ST-segment elevation myocardial infarction (STEMI): XARELTO reduced the primary efficacy endpoint by 15%, and significantly increased non-CABG TIMI major bleeding rates (2.2% vs 0.6%).⁶
  • Stent thrombosis: The rate of definite/probable stent thrombosis was significantly lower with XARELTO (P=0.017).⁷
  • Cardiac biomarker elevations: XARELTO 2.5 mg BID significantly reduced CV death by 45% and all-cause death by 42%, compared to placebo, in patients with cardiac biomarker elevation. XARELTO was associated with a higher incidence of non-CABG TIMI major bleeding (P<0.001).⁸
• The selection of the 2.5 mg and 5 mg doses for XARELTO in the ATLAS ACS 2-TIMI 51 study were determined by the results of the ATLAS ACS-TIMI 46 study.⁹
• In a pooled analysis of patients receiving background aspirin monotherapy in the ATLAS ACS-TIMI 46 and ATLAS ACS 2-TIMI 51 studies, the addition of XARELTO to aspirin was associated with a significant reduction in CV death, MI, and stroke compared with aspirin alone (combined XARELTO doses vs placebo, 11.4% vs 16.3%; P=0.016). The combined XARELTO dose groups were associated with higher rates of non-CABG TIMI major bleeding (primarily driven by the 5 mg BID dose); however, the 2.5 mg dose group was not, and the overall number of patients experiencing a non-CABG TIMI major bleeding event was low (1.5%).¹⁰
• Additional studies pertaining to the use of XARELTO in ACS has been included in the REFERENCES section for your review.^11-15

PRODUCT LABELING

Please refer to the following sections of the enclosed full Prescribing Information that are relevant to your inquiry: WARNINGS AND PRECAUTIONS, USE IN SPECIFIC POPULATIONS, and PATIENT COUNSELING INFORMATION.¹⁶

CLINICAL STUDIES

GEMINI 1 ACS

GEMINI 1 ACS was a phase 2, multicenter, randomized, double-blind, parallel-group study that compared low-dose XARELTO plus a P2Y12 inhibitor to aspirin plus a P2Y12 inhibitor in patients with unstable angina, nonST-segment elevation myocardial infarction (NSTEMI), or STEMI, with treatment starting within 10 days after presentation and continuing for 6 to 12 months.^1,2

Methods

• Inclusion criteria: History of diabetes or prior MI for patients <55 years of age; for patients with unstable angina, at least 1 of the following: ischemic electrocardiographic changes, revascularization for the index ACS event, or a TIMI risk score of ≥4
• Major exclusion criteria: History of active bleeding, intracranial hemorrhage, or clinically significant gastrointestinal bleeding within 12 months; creatinine clearance <20 mL/min; use of omeprazole for patients in the clopidogrel strata
• Primary endpoint: TIMI clinically significant bleeding not related to CABG (non-CABG major, minor, or requiring medical attention)
• Exploratory ischemic endpoints: Composite of death, CV death, MI, stroke, or definite stent thrombosis; all-cause death; and individual component ischemic endpoints measured throughout the entire study period (intention-to-treat population)
• Patients were randomized to 1 of the following dosing interventions:
  • Aspirin (ASA) 100 mg once daily plus clopidogrel 75 mg once daily
  • XARELTO 2.5 mg BID plus clopidogrel 75 mg once daily
  • ASA 100 mg once daily plus ticagrelor 90 mg BID
  • XARELTO 2.5 mg tablet BID plus ticagrelor 90 mg BID

Results

• Of 3037 patients analyzed, the average age was 62 years, 49% of patients presented with STEMI, 40% presented with NSTEMI, and 11% presented with unstable angina. Nearly all of the patients had cardiac catheterization and 87% were treated with percutaneous coronary intervention (PCI) for their index ACS event prior to randomization.
• Of patients treated with a P2Y12 inhibitor, those taking ticagrelor were younger; less likely to have diabetes mellitus, prior MI, prior PCI; and more likely to undergo PCI for the index ACS event.
• 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 aspirin (HR, 1.09; 95% CI, 0.80-1.50; P=0.5840).
• The most common type of bleed in both groups was TIMI bleeding requiring medical attention; TIMI major bleeding was 1% for both groups, and intracranial hemorrhage was <1% for XARELTO and 0% for aspirin.
• The frequency of TIMI non-CABG clinically significant bleeding for XARELTO vs aspirin was similar in the ticagrelor stratum (7% vs 6%, HR, 1.15; 95% CI, 0.79 -1.68) compared with the clopidogrel stratum (3% vs 3%, HR, 0.95; 95% CI, 0.53-1.71), with no significant treatment interactions observed (P=0.5889).
• The frequency of the composite ischemic endpoint of CV death, MI, stroke, or definite stent thrombosis was 5.0% with XARELTO versus 5.0% with aspirin (HR, 1.06; 95% CI, 0.77-1.46; P=0.7316). The frequencies of all-cause death and the component ischemic endpoints were also similar by treatment assignment.

ATLAS ACS 2-TIMI 51

ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with/without thienopyridine therapy in Subjects with Acute Coronary Syndrome ─ Thrombolysis In Myocardial Infarction 51) was a randomized, double-blind, event-driven study designed to determine whether XARELTO (2.5 mg BID or 5 mg BID), when added to SOC, was safe and reduced the risk of the composite of CV death, MI, or stroke in patients with ACS compared with placebo.^3,17

Methods

• Inclusion criteria: Patients ≥18 years of age with symptoms suggestive of an ACS event and diagnosed with STEMI, NSTEMI, or unstable angina; patients <55 years of age needed to have comorbid diabetes mellitus or prior MI to be included
• Exclusion criteria: Patients with platelets <90,000/µL, hemoglobin <10 g/dL, or creatinine clearance <30 mL/min at screening; clinically significant gastrointestinal bleeding within 12 months of randomization, prior intracranial hemorrhage, and prior ischemic stroke or transient ischemic attack (TIA) in patients who were taking both aspirin and thienopyridine
• Patients were stabilized with initial management strategies (eg, revascularization) before enrollment. First dose of study drug was given no sooner than 4 hours after the final dose of intravenous unfractionated heparin, 2 hours after the final dose of bivalirudin, and 12 hours after the final dose of intravenous or subcutaneous anticoagulants (eg, enoxaparin or fondaparinux).¹⁸
• Details of the study group are presented in Figure: Study Design.
• Patients who experienced a primary or secondary efficacy endpoint event (other than death) continued to receive blinded study drug and completed all assessments at all scheduled visits.

Statistical Analysis

• The primary safety analysis included all randomized patients who received at least 1 dose of study drug and underwent evaluation from the time of administration of the first dose until 2 days following discontinuation.
• Testing was prespecified to occur between pooled doses of XARELTO and placebo (alpha=0.05), based on the stratified log-rank test, stratified by intention to use a thienopyridine. If this comparison achieved statistical significance in favor of XARELTO, each XARELTO dose was to be compared with placebo.

Results

Demographics

• A total of 15,526 patients were randomized and had similar baseline characteristics. See Table: Baseline Demographics.
• The mean duration of treatment with a thienopyridine was 13.3 months. The median time from index ACS event to randomization was 4.7 days. The mean duration of treatment with study drugs was 13.1 months.
• In the safety population, premature discontinuation rates were 26.9%, 29.4%, and 26.4% in the XARELTO 2.5 mg, XARELTO 5 mg, and placebo groups, respectively. The rates of withdrawal of consent and rates of lost-to-follow up were 8.7% and 0.2%; 8.5% and 0.3%; and 7.8% and 0.3%, respectively.

Efficacy

• Compared to placebo, XARELTO significantly reduced CV death, MI, or stroke (P=0.008) in the modified intent-to-treat (mITT) population. See Table: Efficacy Endpoints In addition, see Figure: Risks of the Primary Efficacy Endpoint According to Subgroups.

Safety

• See Table: Safety Endpoints.
• The rates of TIMI major bleeding not related to CABG were lower with the 2.5 mg BID dose as compared with the 5 mg BID dose (P=0.12). Adverse events not related to bleeding, including clinical and laboratory liver abnormalities, were comparable in patients treated with XARELTO and placebo.

Subgroup Analyses of ATLAS ACS 2-TIMI 51

Gibson et al (2018)⁴ conducted a subanalysis of the ATLAS ACS 2-TIMI 51 study to compare fatal and irreversible efficacy and safety events with XARELTO vs placebo, when added to SOC, and subsequently assess net clinical outcome and overall risk-benefit.

• Fatal and irreversible efficacy endpoints included CV death (not due to bleeding), MI, and ischemic stroke; these were considered separately and as a composite endpoint. Fatal and irreversible safety endpoints included fatal and intracranial bleeding.
• Net clinical outcome was measured as a composite of CV death, MI, ischemic stroke, and non-CABG TIMI major bleeding.
• Net clinical benefit (CV death, MI, ischemic stroke, non-CABG TIMI major bleeding) occurred in 10.3% of XARELTO-treated patients and in 10.7% of placebo-treated patients (HR, 0.95; 95% CI, 0.82-1.10; P=0.473).
• In patients treated with aspirin and clopidogrel/ticlopidine, compared with placebo, XARELTO 2.5 mg BID was associated with 115 (95% CI, 18-212) fewer fatal or irreversible ischemic events (548 vs 663) and 10 (95% CI: -11 to 32) additional fatal or irreversible seriously harmful events (33 vs 23) per 10,000 patient-years of exposure.

Daaboul et al (2016)⁵ conducted a subgroup analysis to evaluate the effects of XARELTO on neurological outcomes in patients with ACS who experienced a stroke.

• A total of 128 stroke events with investigator-reported Modified Rankin Scale Score (mRS score) were identified. Of these, 69.5% (n=89) were ischemic, 26.6% (n=34) were hemorrhagic, and 3.9% (n=5) were of uncertain cause.
• Patients treated with XARELTO 2.5 mg BID experienced fewer strokes that were disabling or had fatal outcomes (mRS score 3 to 6) vs placebo-treated patients (17.1% [7/41] vs 52.6% [20/38], respectively; P=0.001).
  • When specifically analyzing ischemic stroke, XARELTO 2.5 mg BID was associated with significantly fewer disabling or fatal ischemic strokes vs placebo (3.9% [1/26] vs 48.4% [15/31], respectively; P<0.001).
  • Incidence of hemorrhagic strokes was also lower with XARELTO 2.5 mg BID vs placebo, but the difference was not statistically significant (38.5% [5/13] vs 80.0% [4/5], P=0.29).
• A logistic regression model, which adjusted for imbalances in age, antiplatelet stratum (DAPT vs aspirin monotherapy), and stroke type, found that patients treated with XARELTO 2.5 mg BID were 9 times less likely to experience a disabling or fatal outcome vs placebo-treated patients (P=0.002).
• No differences were observed between patients treated with XARELTO 5 mg BID and placebo-treated patients.

Mega et al (2013)⁶ conducted a prespecified subgroup analysis to evaluate the safety and efficacy of XARELTO in 7817 patients who were stabilized (1 to 7 days) after a STEMI. The baseline characteristics were well matched across the treatment groups. The median time from the STEMI event to randomization was 4.7 days.

• XARELTO reduced the primary efficacy endpoint by 15% vs placebo (P=0.09), which began to emerge in the first 30 days (P=0.042). See Table: STEMI Subgroup Efficacy and Safety Endpoints.
• XARELTO 2.5 mg reduced CV death (P=0.006) and all-cause death (P=0.007); this was not seen with XARELTO 5 mg. The observation of the 2.5-mg dose was consistent during treatment with DAPT and regardless of MI location and treatment strategy.⁶
• XARELTO 5 mg BID had higher rates of TIMI minor bleeding compared to placebo (1.9% vs 0.5%, respectively; P=0.005). Both doses of XARELTO were associated with higher rates of TIMI medical attention bleeds compared to placebo (P<0.001 for both doses) and higher rates of intracranial hemorrhage (P=0.031 for XARELTO 2.5 mg BID vs placebo; P=0.008 for XARELTO 5 mg BID vs placebo).⁶

Mega et al (2014)⁸ performed a subgroup analysis of 12,626 patients who had cardiac biomarker elevations during their index ACS event.

• In the pooled XARELTO group of patients with cardiac biomarker elevations, the combined incidence of CV death, MI, or stroke was significantly lower compared to the placebo group (HR, 0.81; 95% CI, 0.71-0.93; P=0.003). A significant difference was not observed between the XARELTO and placebo groups for this endpoint in patients who did not have cardiac biomarker elevations (HR, 1.06; 95% CI, 0.74-1.51; P=0.74).
• In 12,353 patients with cardiac biomarker elevations and no prior stroke/TIA:
  • The combined endpoint of CV death, MI, or stroke was significantly lower with XARELTO than with placebo (P=0.01).
  • XARELTO 2.5 mg BID resulted in a significantly higher rate of non-CABG TIMI major bleeding than placebo (1.9% vs 0.7%; P<0.001). There was no difference in the rates of fatal bleeding (0.1% vs 0.3%), intracranial hemorrhage (0.4% vs 0.2%), or fatal intracranial hemorrhage (0.1% vs 0.2%). In addition, the 2.5 mg BID dose resulted in a lower incidence of fatal hemorrhage than 5 mg BID (0.1% vs 0.5%, P=0.006).

Gibson et al (2013)⁷ conducted a subgroup analysis to evaluate the effect of XARELTO on the incidence of stent thrombosis. Stent thrombosis was independently adjudicated based on the Academic Research Consortium (ARC) criteria as definite, probable, or possible. A total of 9631 patients underwent PCI and had >1 stent placed and had at least 1 stent inserted either before randomization or during their index event. At baseline, the majority of patients in this subgroup were treated with aspirin (98%) and a thienopyridine (97%; stratum 2). The results are presented below as 2-year Kaplan-Meier estimates in the mITT population.

• ARC-defined definite or probable stent thrombosis was significantly lower for the pooled XARELTO group (stratum 1 and 2) than for the placebo group (1.5% vs 1.9%, P=0.017). There was a significant difference in the incidence of definite or probable stent thrombosis between the 2.5 mg BID group and the placebo group (P=0.023), but not between the 5 mg BID group and the placebo group (P=0.089).
• Reductions in stent stenosis occurred in patients with bare-metal and drug-eluting stents.
• There was no significant difference between the placebo group and XARELTO pooled groups in the occurrence of ARC-defined definite stent thrombosis.
• In stratum 2 patients, the benefit of XARELTO was seen during the period of active DAPT, before the thienopyridine was discontinued (HR, 0.68; 95% CI, 0.50-0.92) in the pooled XARELTO group.
• Mortality for stratum 2 patients was significantly lower with XARELTO 2.5 mg BID than with placebo (1.35% vs 2.27%; P=0.014 in the mITT group), but no difference from placebo was seen with XARELTO 5 mg BID.

XARELTO Dose Comparison from ATLAS ACS 2-TIMI 51

Mega et al (2013)¹⁹ directly compared the efficacy and safety of XARELTO 2.5 mg BID with XARELTO 5 mg BID. Endpoint rates were expressed as 2-year Kaplan-Meier estimates in the mITT population.

• There were no significant differences between the 2.5-mg BID dose and the 5-mg BID dose for the primary efficacy endpoint (P=0.89), or with regards to MI or stent thrombosis. Death and CV death were lower with the XARELTO 2.5 mg BID compared to 5 mg BID (2.9% vs 4.4%; P=0.009 for death; 2.7% vs 4.0%; P=0.009 for CV death). XARELTO 2.5 mg BID, compared to 5 mg BID, had lower rates of TIMI non-CABG major or minor bleeding (P=0.021), TIMI minor bleeding (P=0.046), and fatal bleeding (P=0.44).

Selection of 2.5 mg and 5 mg Doses for ATLAS ACS 2-TIMI 51

The selection of the 2.5 mg and 5 mg doses in the ATLAS ACS 2-TIMI 51 study was based primarily on the results from the ATLAS ACS-TIMI 46 phase 2 study.⁹

• The study evaluated 6 months of treatment with XARELTO once daily (5 to 20 mg) or BID (2.5 to 10 mg) in combination with aspirin alone or aspirin plus thienopyridine in stabilized patients with recent ACS.
• The primary efficacy endpoint was time to the first episode of death, MI, stroke, or severe recurrent ischemia requiring revascularization up to 6 months from enrollment. The primary safety endpoint was clinically significant bleeding (TIMI major bleeding, TIMI minor bleeding, and bleeding requiring medical attention).
• Results showed that bleeding events increased with increasing doses of XARELTO. Of all dosing regimens in this study, XARELTO 2.5 mg BID and XARELTO 5 mg BID were selected to be investigated in the phase 3 ATLAS ACS 2-TIMI 51 study due to their favorable balance of benefit and risk in ACS patients.

Pooled Analysis of ATLAS ACS 2-TIMI 51 and ATLAS ACS-TIMI 46

Gibson et al (2019)¹⁰ conducted a pooled analysis of the ATLAS ACS 2-TIMI 51 and ATLAS ACS-TIMI 46 studies to evaluate efficacy and safety of XARELTO plus aspirin compared with aspirin alone in the period immediately following an ACS.

• Among stabilized post-ACS patients (N=1477) on a background of aspirin monotherapy, XARELTO (combined doses) was associated with a significant reduction in the primary outcome compared with placebo (combined XARELTO doses, 11.4% vs placebo, 16.3%; HR, 0.65; 95% CI, 0.45-0.92; P=0.016).
• Although the combined XARELTO dose groups were associated with significantly higher rates of non-CABG TIMI major bleeding compared with placebo (P=0.018), the XARELTO 2.5 mg BID dose group was not (P=0.15), and the overall number of patients experiencing a non-CABG TIMI major bleeding event was 1.5%.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 04 June 2025.