Summary

• The PIONEER AF-PCI study demonstrated that in stented atrial fibrillation (AF) patients, XARELTO, either at a dose of 15 mg daily plus P2Y12 inhibitor monotherapy for 1 year or 2.5 mg twice daily (BID) plus 1, 6, or 12 months of dual antiplatelet therapy (DAPT), reduced the risk of clinically significant bleeding and the combined endpoint of all-cause mortality or recurrent hospitalization for adverse events (AEs; ie, bleeding or cardiovascular [CV] events) compared with standard-of-care vitamin K antagonist (VKA) plus 1, 6, or 12 months of DAPT.^1,2
• A prespecified analysis of the COMPASS³ study evaluated whether treatment with XARELTO 2.5 mg BID plus aspirin (ASA) 100 mg once daily (QD) or XARELTO 5 mg BID alone is more effective than ASA 100 mg QD alone for prevention of graft occlusion in patients undergoing coronary artery bypass grafting (CABG) surgery. The primary outcome, the proportion of coronary bypass grafts that had failed with complete occlusion of the graft (vessel-level analysis), was similar among all three groups: 9.1% in the XARELTO plus ASA group (vs ASA alone; odds ratio [OR]: 0.95; 95% confidence interval [CI]: 0.67-1.33), 7.8% in the XARELTO alone group (vs ASA alone; OR: 1.13; 95% CI: 0.82-1.57), and 8.0% in the ASA alone group. Major bleeding rates were similar across the XARELTO plus ASA and ASA alone groups.⁴
• A prespecified analysis of COMPASS³, COMPASS-PCI, evaluated whether dual pathway inhibition (DPI) with XARELTO 2.5 mg BID plus ASA 100 mg QD or ASA 100 mg QD alone is more effective in preventing the primary outcome of first occurrence of CV death, myocardial infarction (MI), or stroke in patients with or without previous percutaneous coronary intervention (PCI). The safety and efficacy of XARELTO plus ASA vs ASA alone were consistent with the overall COMPASS study results, regardless of prior history of PCI.⁵
• An assessment of the use and outcomes of DAPT in those undergoing PCI in the ROCKET-AF study found that patients treated with XARELTO had higher rates of major bleeding (15.01 vs 8.05, respectively) and lower rates of stroke (1.62 vs 4.08, respectively) and vascular death (3.12 vs 11.05, respectively) in comparison to warfarin-treated patients.⁶
• In the ATLAS ACS-TIMI 51 study, at baseline, there were 3138 (60.6%) patients in the XARELTO 2.5 mg BID group and 3123 (60.3%) patients in the XARELTO 5 mg BID group who underwent a PCI or CABG for their index event.⁷
  • In a pooled analysis of the ATLAS ACS-TIMI 51 study, XARELTO significantly reduced stent thrombosis compared to placebo in the pooled group (both 2.5-mg and 5-mg BID doses; hazard ratio [HR]: 0.65; P=0.017) and the XARELTO 2.5-mg BID group (HR: 0.61; P=0.023).⁸
• The RIVA-PCI (Rivaroxaban in Patients With Atrial Fibrillation Undergoing PCI) study included patients with NVAF who underwent PCI during a hospital stay. In-hospital events in patients treated with XARELTO included death (n=2; 0.3%), MI (n=1; 0.1%), stent thrombosis (n=3; 0.4%), ischemic stroke (n=2; 0.2%), major bleeding as per the International Society on Thrombosis and Haemostasis (ISTH) (n=8; 1.1%), and minor bleeding complications (n=13; 1.8%).⁹
• Additional citations identified during a literature search have been included in the REFERENCES section for your review.^10-23

CLINICAL STUDIES

PIONEER AF-PCI

PIONEER AF-PCI (An OPen-label, Randomized, Controlled, Multicenter Study ExplorIng TwO TreatmeNt StratEgiEs of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) was an exploratory study that evaluated the safety of 2 XARELTO treatment strategies and 1 VKA strategy in 2124 patients with NVAF who underwent a PCI. The study was not statistically powered to evaluate the efficacy of these treatment strategies.^1,2

• Patients were randomized to 1 of the following groups within 72 hours of sheath removal and after achieving an international normalized ratio (INR) of ≤2.5, with a treatment duration of 12 months:
  • Group 1 (reduced-dose XARELTO plus P2Y₁₂ inhibitor): XARELTO 15 mg daily + a P2Y₁₂ inhibitor for 12 months; XARELTO dose was 10 mg daily for patients with a CrCl of 30-50 mL/min.
  • Group 2 (very low-dose XARELTO plus DAPT): XARELTO 2.5 mg BID plus ASA 75-100mg daily plus a P2Y₁₂ inhibitor for a prespecified duration of 1, 6, or 12 months, followed by XARELTO 15 mg daily plus ASA 75-100mg.
  • Group 3 (VKA plus DAPT): dose-adjusted VKA (target INR: 2.0-3.0) plus ASA 75-100 mg daily plus a P2Y₁₂ inhibitor for the duration of 1 or 6 months, followed by dose-adjusted VKA plus ASA 75-100mg.
• The investigator prespecified the intended P2Y₁₂ inhibitor (ticagrelor 90 mg BID or prasugrel 10 mg daily or clopidogrel 75 mg daily; 95% received clopidogrel) and the intended duration of DAPT (1, 6, or 12 months).
• Primary safety outcome: Thrombolysis in Myocardial Infarction (TIMI) clinically significant bleeding events (composite of TIMI major bleeding, minor bleeding, or bleeding requiring medical attention) during the treatment-emergent period (first study drug administration up to 2 days following drug discontinuation through 12 months of therapy)
• Secondary outcomes included: components of TIMI clinically significant bleeding events; major adverse CV events (MACE; composite of CV death, MI, or stroke); individual components of the MACE outcome; and stent thrombosis.
  • All secondary outcomes that included efficacy events were adjudicated by an independent committee blinded to study medication.
• Compared to group 3, clinically significant bleeding occurred in significantly fewer patients in group 1 and 2.
• Compared to group 3, significantly less bleeding requiring medical attention occurred in group 1 and 2. See table: Cumulative Incidence of the Primary Safety Outcome and its Components

• Group 1 and group 2 patients had consistently reduced clinically significant bleeding across subgroups of radial vs femoral arterial access and vascular closure device use vs group 3 patients.²⁴
• A post hoc analysis used a time-to-multiple-event method to compare the incidence of all clinically significant bleeding events from the PIONEER AF-PCI study. Group 1 patients had a significant reduction in overall clinically significant bleeding events vs group 3 patients (21.8% vs 31.0%; HR, 0.64; 95% CI, 0.49-0.85; P<0.001), as did group 2 patients vs group 3 patients (20.7% vs 31.0%; HR, 0.62; 95% CI, 0.48-0.80; P<0.001).²⁵
• MACE occurred in 6.5% of patients in group 1, in 5.6% of patients in group 2, and in 6.0% of patients in group 3 (P>0.05 for both comparisons). Stent thrombosis occurred in <1% of patients, regardless of treatment strategy.¹
  • When stratified by ischemia-driven revascularization, urgency of revascularization, location of culprit artery, presence of angiographic stenosis, presence of bifurcation lesion, presence of thrombus, type of stent, length of stent, and number of stents, treatment effect on MACE in groups 1 and 2 did not vary significantly (P>0.05).²⁴
• A non-prespecified post hoc analysis assessed the outcomes of all-cause mortality and rehospitalization due to an AE. Two physicians blinded to study drug assignment were provided with a list of AE terms associated with rehospitalization. All AEs were classified as potentially attributable to bleeding, CV causes, or other causes through consensus. All patients who received 1 dose of study medication were included in the analysis.²
  • The risk of all-cause mortality or recurrent hospitalization was 34.9% in group 1 (HR: 0.79; 95% CI: 0.66–0.94; P=0.008 vs group 3; number needed to treat: 15), 31.9% in group 2 (HR: 0.75; 95% CI: 0.62-0.90; P=0.002 vs group 3; number needed to treat: 10), and 41.9% in group 3.² See Figure: Time to All-Cause Death or First Recurrent Hospitalization

• • Both all-cause death plus hospitalization potentially for bleeding and all-cause death plus rehospitalization potentially for a CV cause were significantly reduced in groups 1 and 2 compared with group 3.
  • See Figure: Time to First Recurrent Hospitalization Related to CV or Bleeding Event.

• A sub analysis of the PIONEER AF-PCI study characterized the occurrence, location, and severity of post-PCI, clinically significant bleeds within 30 days of cardiac catheterization in patients with AF. Of the 146 clinically significant bleeds that occurred 30 days post-PCI, 5 (3.4%) were access-site bleeds and 141 (96.6%) were nonaccess-site bleeds. TIMI major nonaccess-site bleeds accounted for 6.8% of all clinically significant bleeds, while 7.5% were TIMI minor nonaccess-site bleeds and 82.2% were nonaccess-site bleeds requiring medical attention. The most frequent types of nonaccess-site TIMI major bleeds were GI (n=5) and intracranial hemorrhage (n=4). Overall, GI bleeds represented 19.9% of all post-PCI clinically significant bleeds within 30 days.²⁶
• A PIONEER-AF PCI sub-group analysis was conducted to compare the occurrence of bleeding events. Groups 1 and 2 were compared against Group 3 according to a patient’s time in the therapeutic range (TTR) and time spent with an INR > 3. Mean TTR, 65.0+24.8%, was available for 93.4% (n=651) of patients in group 3, of which 63.1% (n=411) had a TTR_2.0-3.0 > 60% and 36.9% (n=240) had a TTR_2.0-3.0 < 60%.  A significant decrease in clinically significant bleeding was associated with group 1 and 2 compared to group 3 TTR_2.0-3.0 < 60%, HR=0.53, 95% CI,0.39-0.73 P<0.001; HR=0.57, 95% CI, 0.42-0.78, P<0.001 respectively and group 3 TTR_2.0-3.0 > 60%, HR=0.71, 95% CI, 0.53-0.93, P=0.013. Regardless of the proportion of time spent with an INR > 3, groups 1 and 2 saw a significant reduction in bleeding compared to group 3, HR ranges 0.59-0.67 and 0.42-0.69; P<0.5 for all.²⁷
• A PIONEER-AF PCI sub analysis focused on patients receiving a single anticoagulant and a single antiplatelet (SAPT), DAPT, after prior randomization to a pre-specified duration of DAPT (1, 6, or 12 months). Post pre-specified duration, patients in Group 1 continued XARELTO 15mg plus P2Y₁₂ inhibitor, Group 2 switched to XARELTO 15mg plus low dose ASA and Group 3 switched to VKA plus low dose ASA. A total of 612 patients received at least one dose of XARELTO plus SAPT and 294 patients received warfarin plus SAPT for 1 or 3 months.  Total bleeding or CV rehospitalization events occurred in significantly fewer patients in the pre-specified XARELTO plus SAPT group compared to the warfarin plus SAPT group (20.3% vs 29.6%); respectively (HR=0.65, 95% CI: 0.45-0.93, p = 0.008). Multiple rehospitalizations occurred in 3.3% (n=20) assigned to XARELTO plus SAPT compared to 17.2% (n=11) assigned to the warfarin plus SAPT.²⁸

COMPASS

COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) was a phase 3, event-driven, double-blind, randomized, controlled study designed to evaluate whether treatment with XARELTO 2.5 mg BID plus ASA 100 mg QD or XARELTO 5 mg BID alone is more effective than ASA 100 mg QD alone for prevention of MI, stroke, or CV death in patients with a history of stable atherosclerotic vascular disease (CAD or peripheral artery disease [PAD]).³

A prespecified analysis per protocol (COMPASS-CABG) was conducted to evaluate the impact of XARELTO plus ASA and XARELTO alone vs ASA alone in prevention of graft occlusion in patients who had recent CABG surgery.⁴

• The primary outcome of this sub analysis was the proportion of coronary bypass grafts that had failed with complete occlusion of the graft (vessel-level analysis). The clinical efficacy outcomes were the COMPASS primary composite of CV death, MI, or stroke. The primary safety outcome was a modification of the ISTH criteria for major bleeding.
• Of the 27,395 patients randomized in the COMPASS study, a total of 1488 were randomized within 4 to 14 days after CABG surgery (XARELTO plus ASA group, n=502; XARELTO alone group, n=483; and ASA alone group, n=463).
• The clinical efficacy outcome, a composite of MI, stroke, or CV death, occurred in fewer patients within the XARELTO plus ASA (2.4%) and XARELTO alone (3.3%) groups vs the ASA alone group (3.5%), but the difference was not statistically significant. There was no difference in the individual components of the clinical efficacy outcome among the three groups.
• The incidence of major bleeding in the first 30 days after CABG in this sub analysis occurred in 2 (0.4%) participants who were randomized to XARELTO plus ASA, 1 (0.2%) of those who received XARELTO alone, and 5 (1.1%) of those who received ASA alone. There was no increased risk of major bleeding among the three groups.
  • Compared to the ASA alone group, patients who received XARELTO alone were more likely to have had a major bleed 30 days after the CABG surgery (3.9% vs. 1.7%; HR, 2.43; 95% CI, 1.06-5.54) and a bleed leading to hospitalization (3.5% vs. 1.5%; HR, 2.49; 95% CI, 1.03-6.01). There was no increased risk in the XARELTO plus ASA group vs the ASA alone group (2.4% vs. 1.7%; HR, 1.41; 95% CI, 0.58-3.45) for major bleeding 30 days following CABG surgery or bleeding leading to hospitalization (2.4% vs. 1.5%; HR, 1.61; 95% CI, 0.63-4.08).
• No benefit was observed in regards to graft patency. See Table: Rates of Graft Occlusion in COMPASS-CABG.

A prespecified subgroup analysis (COMPASS-PCI) was conducted to evaluate the efficacy and safety of DPI (or low-dose XARELTO plus ASA) in patients who had stable CAD (chronic coronary syndrome) with or without previous PCI (PCI: N=9862; no PCI: N=6698).⁵

• There was a consistent relative risk reduction in the primary outcome, a composite of the first occurrence of CV death, MI, or stroke, regardless of previous PCI (PCI: HR, 0.74; 95% CI, 0.61-0.88; no PCI: HR, 0.76; 95% CI, 0.61-0.94; P-interaction=0.85). There was no heterogeneity between previous single-vessel PCI and previous multivessel PCI with DPI vs. ASA alone (P-interaction=0.31) or between bare-metal and drug-eluting stents (P-interaction=0.95).
• Effects were consistent among subgroups for secondary outcomes including all-cause mortality and the individual end points of the primary composite, and definite or probable stent thrombosis. Relative risk reductions were observed for all-cause death, CV mortality, and stroke. See Table: COMPASS PCI Subgroup Analysis.⁵
• DPI vs ASA alone did not impact the rate of definite stent thrombosis (0.6% vs. 0.6%; HR, 1.06; 95% CI, 0.0.64-1.75; P-interaction=0.40 between previous single-vessel or multivessel PCI) or probable stent thrombosis (0.2% vs. 0.2%; HR, 1.30; 95% CI, 0.63-2.67; P-interaction=0.72 between previous single-vessel or multivessel PCI) in those with previous PCI.
• There was a consistent relative increase in the primary safety outcome, modified ISTH major bleeding defined as: fatal bleeding or symptomatic bleeding in a critical organ or bleeding into the surgical site requiring reoperation or bleeding leading to hospitalization (PCI: HR, 1.72; 95% CI, 1.34-2.21; no PCI: HR, 1.58; 95% CI, 1.15-2.17; P-interaction=0.68).
• Effects were consistent across all other bleeding events, including a relative increase in minor bleed (PCI: HR, 1.71; 95% CI, 1.48-1.98; no PCI: HR, 1.78; 95% CI, 1.47-2.16; P-interaction=0.74). See Table: COMPASS PCI Subgroup Analysis.⁵
• The lower risk of the net-clinical benefit outcome, a composite of CV death, MI, stroke, fatal bleeding, or symptomatic bleeding into a critical organ, was consistent across subgroups (PCI: HR, 0.78; 95% CI, 0.65-0.93; no PCI: HR, 0.79; 95% CI, 0.65-0.98; Pinteraction=0.98).

ROCKET-AF

ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was a phase 3, randomized, double-blind, double-dummy, multicenter, event-driven, noninferiority study designed to evaluate the efficacy and safety of XARELTO 20 mg QD (15 mg for patients with CrCl 30-49 mL/min) and dose-adjusted warfarin (target INR: 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with NVAF and moderate-to-high risk of stroke.²⁹

Sherwood et al (2014)⁶ assessed the use of DAPT and related outcomes in patients undergoing PCI within the ROCKET-AF study.

• Of the 14,171 patients in the ITT group, 153 (1.1%) underwent PCI (61 XARELTO-treated patients, 92 warfarin-treated patients).
• PCI was performed with balloon angioplasty alone (16%), bare-metal stents (44%), and drug-eluting stents (34%).
• Long-term DAPT (≥30 days) was used in 37% of patients.
• A higher rate of major bleeding was observed in XARELTO-treated patients and a higher rate of stroke and vascular death (based on very few events) was observed in warfarin-treated patients. See Table: Events in Patients Undergoing PCI in the ROCKET AF Study.

ATLAS ACS-TIMI 51

ATLAS ACS-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 51) was a randomized, multicenter, double-blind, event-driven study designed to determine whether XARELTO (2.5 mg BID or 5 mg BID), when added to standard care, is safe and reduces the risk of the composite of CV death, MI, or stroke compared with placebo in stabilized patients after an acute coronary syndrome (ACS) event. Standard medical therapy included low-dose ASA (75-100 mg) with or without a thienopyridine. Patients were stratified by the investigator’s intention to administer a thienopyridine (clopidogrel or ticlopidine) at the time of enrollment. A total of 93% of patients received a thienopyridine.⁷

• At baseline, there were 3138 (60.6%) patients in the XARELTO 2.5-mg BID group, 3123 (60.3%) patients in the XARELTO 5-mg BID group, and 3126 (60.4%) patients in the placebo group who underwent a PCI or CABG for their index event.

Gibson et al (2013)⁸ conducted a pooled analysis of the reduction in stent thrombosis in patients with ACS treated with XARELTO in ATLAS ACS-TIMI 51. This analysis was restricted to patients with a history of stent placement, including patients who received stents before study enrollment and patients who received stents during the index PCI.

• Stent thrombosis was a predefined endpoint that was reported by the enrolling physician and was independently adjudicated based upon the Academic Research Consortium (ARC) designation of definite, probable, or possible.
• Of the 15,342 patients included in the modified ITT (mITT) population, 9,631 (63%) had ≥1 stent inserted before randomization or during the index event.
• In the pooled group of patients treated with XARELTO (2.5 mg BID and 5 mg BID), the rate of stent thrombosis was significantly reduced in the ARC-defined definite/probable groups (1.5% vs 1.9%; P=0.017) and the definite/probable/possible groups (2.3% vs 2.9%; P=0.016) compared to placebo.
• When limited to patients with ARC-defined definite/probable stent thrombosis, there was a reduction among all patients treated with XARELTO compared with placebo.
  • In both the pooled (HR: 0.65; 95% CI: 0.46-0.93; P=0.017) and XARELTO 2.5-mg BID (HR: 0.61; 95% CI: 0.39-0.94; P=0.023) groups, this reduction achieved statistical significance, while reduction in the 5-mg group did not (HR: 0.70; 95% CI: 0.46-1.06; P=0.089).
• The reduction in stent thrombosis was consistent among patients with bare-metal stents (HR: 0.69; P=0.042) and patients with drug-eluting stents (HR: 0.68; P=0.170). No reduction was noted in patients who received stents prior to randomization.
• Within 30 days of randomization, definite/probable/possible stent thrombosis tended to be reduced in the pooled group of XARELTO patients (HR: 0.65; 95% CI: 0.41-1.03; mITT and ITT P=0.067).
• The magnitude of HR reduction with XARELTO administration from 30 days to 2 years after enrollment was comparable (HR: 0.72; 95% CI: 0.46-1.13; mITT P=0.154 and ITT P=0.081).
• In patients with stents who were treated with DAPT (ASA and a thienopyridine), there was a reduction in mortality in patients receiving XARELTO 2.5 mg (HR: 0.56; 95% CI: 0.35-0.89; P=0.014), but not XARELTO 5 mg BID.

Gibson et al (2018)³⁰ conducted an additional analysis of a comparison of efficacy and safety limited to fatal or irreversible ischemic events (CV death, MI, and ischemic stroke) and adverse or seriously harmful events (fatal and intracranial bleeding) in ATLAS ACS 2-TIMI 51.

• XARELTO 2.5 mg BID was associated with 115 fewer fatal or irreversible ischemic events per 10,000 patients-years of exposure (95% CI: 18 to 212; 663 CV deaths not due to bleeding, MIs, or ischemic strokes for placebo vs 548 events for XARELTO 2.5 mg BID).
• XARELTO 2.5 mg BID was associated with 10 excessive, fatal, or irreversible seriously harmful events per 10,000 patient-years of exposure (95% CI: -11 to 32; 23 fatal bleeds or intracranial hemorrhages for placebo vs 33 events for XARELTO 2.5 mg BID).

RIVA-PCI

RIVA-PCI was a prospective, noninterventional, multicenter, observational study designed to evaluate the use of antithrombotic therapies in patients with AF who underwent PCI, follow-up in patients treated with XARELTO at discharge (3 and 14 months) for adherence, and ischemic, embolic, and bleeding events.⁹

• XARELTO was administered at doses of 15, 20, and 10 mg in 86%, 5.2%, and 8.8% of patients, respectively.
• A total of 1636 patients were enrolled between January 2018 and March 2020, of whom 700 received XARELTO and 936 did not receive XARELTO after PCI.
• In-hospital events in patients treated with XARELTO included death, MI, stent thrombosis, ischemic stroke, and ISTH major bleeding and minor bleeding complications in 2 (0.3%), 1 (0.1%), 3 (0.4%), 2 (0.2%), and 8 (1.1%) and 13 (1.8%) patients, respectively.
• The clinical event rates through the 14-month follow-up in the total population discharged with XARELTO and events occurring under XARELTO therapy are presented in Table: Rates of Clinical Events Through the 14-Month Follow-up in Patients Who Received XARELTO.

• For comparison of events in patients receiving XARELTO with elective PCI vs PCI for ACS, see Table: Rates of Clinical Events Through the 14-Month Follow-up in Patients Receiving XARELTO Therapy With Elective PCI vs PCI for ACS.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 17 September 2024.