Summary

• ROCKET AF: In a prespecified subgroup analysis of this phase 3 study in patients with nonvalvular atrial fibrillation (NVAF), efficacy and safety of XARELTO and warfarin in patients with previous stroke or transient ischemic attack (TIA) were consistent with those in patients without previous stroke or TIA and with the overall study population.¹
  • The number of events per 100 person-years (PY) for the primary endpoint in patients treated with XARELTO versus warfarin was consistent among patients with prior stroke or TIA (XARELTO, 2.79% vs warfarin, 2.96%; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.77-1.16) and those without (XARELTO, 1.44% vs warfarin, 1.88%; HR, 0.77; 95% CI, 0.58-1.01; P-value for interaction=0.23).¹
  • The number of major bleeding (MB) and nonmajor clinically relevant bleeding (NMCRB) events per 100 PY in patients treated with XARELTO versus warfarin was consistent among patients with prior stroke or TIA (XARELTO, 13.31% vs warfarin, 13.87%; HR, 0.96; 95% CI, 0.87-1.07) and those without (XARELTO, 16.69% vs warfarin, 15.19%; HR, 1.10; 95% CI, 0.99-1.21; P-value for interaction=0.08).¹
• J-ROCKET AF: Consistent safety and efficacy results between the secondary prevention subgroup with the overall study population in Japanese patients with NVAF.²
• ATLAS ACS-2 TIMI 51: Increased risk of the primary efficacy endpoint in patients with a prior stroke or TIA that received XARELTO compared to placebo.³
• NAVIGATE ESUS: XARELTO was associated with comparable efficacy to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source, and was associated with a higher risk of bleeding.⁴
  • Prior stroke and TIA was identified as an independent predictor of recurrent ischemic stroke and ESUS in this population.⁵
• COMPASS: In this phase 3 study of patients with stable atherosclerotic vascular disease (coronary artery disease [CAD] or peripheral artery disease [PAD]), 3.8% of patients had a history of stroke. The primary efficacy outcome (cardiovascular [CV] death, stroke, or myocardial infarction [MI]) occurred in fewer patients treated with XARELTO plus aspirin than in those treated with aspirin alone, but MB events occurred in more patients treated with XARELTO plus aspirin. Among patients with prior stroke, benefits of the combination of XARELTO and aspirin in prevention of CV death, stroke, or MI were consistent with those observed in the overall population.^6,7
  • In a prespecified subanalysis of 7470 (~27%) COMPASS patients with stable PAD at baseline and a prespecified subanalysis of 24,824 (~91%) COMPASS patients with stable CAD at baseline, 6.7% and 3% of patients had a history of stroke, respectively. The effects of XARELTO plus aspirin vs aspirin alone on the primary efficacy outcome of CV death, stroke, or MI and on the primary safety outcome of modified International Society on Thrombosis and Hemostasis (ISTH) MB were consistent with the overall COMPASS study results.^8,9
  • In a subanalysis of the COMPASS study, which assessed stroke outcomes based on previous stroke status, compared to aspirin alone, XARELTO plus aspirin reduced the risk of stroke in patients with a history of stroke and ischemic or uncertain stroke. The effect was consistent among patients with or without a history of stroke. There was an increased risk of major bleeding in patients receiving XARELTO plus aspirin regardless of stroke status.¹⁰
• COMPASS MIND, which was conducted in a subset of COMPASS patients (n=1905) across 86 sites in 16 countries, examined the effect of antithrombotic treatment (XARELTO plus aspirin or XARELTO alone vs aspirin alone) on magnetic resonance imaging (MRI) outcomes (incident covert brain infarcts), cognitive and functional outcomes, and biomarkers and genetics. A total of 2.5% of patients had a history of TIA and 4.5% had a history of stroke.¹¹
  • After a mean of 2.0 (0.7) years, incident covert infarcts occurred in 2.7% of patients on XARELTO and aspirin vs 3.5% of patients on aspirin alone (odds ratio [OR] 0.77, 0.37-1.60).
  • Incident cerebral microbleeds occurred in 6.6% of patients (with combination vs aspirin OR, 1.49; 0.88-2.52).¹²
• In an open-label, single-arm study of patients with NVAF treated with XARELTO initiated ≤14 days after TIA or moderate ischemic stroke, no patients developed symptomatic hemorrhagic transformation or parenchymal hemorrhage (PH) with follow-up MRI on day 7.¹³
• Additional references identified by literature search are included in the REFERENCES section for your review.^14-22

CLINICAL STUDIES

Stroke Prevention in NVAF

Hankey et al (2012)¹ conducted a prespecified subgroup analysis of the ROCKET AF study to assess whether the efficacy and safety of XARELTO compared with warfarin among patients with previous stroke or TIA was consistent with results among patients without previous stroke or TIA and the entire study population. ROCKET AF was a phase 3, randomized, double-blind, active-controlled, multicenter, event-driven, noninferiority study designed to evaluate efficacy and safety of oral, fixed-dose XARELTO and dose-adjusted warfarin (target international normalized ratio [INR]: 2.0-3.0) for the prevention of stroke and systemic embolism (SE) in patients with NVAF at moderate-to-high risk for stroke.

• Patients were randomized to receive fixed-dose XARELTO (20 mg daily or 15 mg daily in patients with creatinine clearance [CrCl] 30-49 ml/min) or adjusted-dose warfarin. Patients in each group also received a placebo tablet to maintain blinding.
• The primary objective of the study was the composite of adjudicated stroke (both ischemic and hemorrhagic) and noncentral nervous system (CNS) SE.
  • Stroke was defined as a sudden, focal neurological deficit of presumed cerebrovascular cause that was neither reversible within 24 hours nor due to another readily identified cause, such as tumor, trauma, or seizure.
  • An event with this definition, but lasting less than 24 hours, was classified as TIA.
• The primary safety endpoint was the composite of both MB and NMCRB.
  • MB was defined as clinically overt bleeding that was associated with the following: fatal outcome; occurred at a critical site (intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal site); decrease of ≥2 g/dL in hemoglobin; required a transfusion of ≥2 units of whole blood or packed red blood cells; or permanent disability.
  • NMCRB was defined as overt bleeding not meeting the criteria for MB but requiring medical intervention, unscheduled contact with a physician, temporary interruption of study drug, pain, or impairment of daily living.
  • All CNS bleeding events that met the definition of acute stroke were included as hemorrhagic strokes in the primary endpoint analysis and were counted both as efficacy and safety events.
• Patients with a prior TIA within 3 days, acute stroke within 14 days, or severe disabling stroke within 3 months of randomization were excluded.
• Patients that had a previous stroke or TIA were determined by their clinical history and enrolling physician. Clinical or imaging records were not adjudicated nor required.
• A total of 14,264 patients were randomized in ROCKET AF.
  • A total of 7468 (52%) patients had experienced a stroke or TIA before study entry.
    • 2561 patients had TIA
    • 4907 patients had ischemic or hemorrhagic stroke, stroke of unknown type, or both stroke and TIA
  • A total of 6796 (48%) patients had no previous stroke or TIA.
  • Among all patients with a previous stroke or TIA, 3754 were allocated to receive XARELTO and 3714 to receive warfarin.
• Regardless of treatment exposure, the number of stroke or non-CNS SE events per 100 PY of all study patients was significantly higher among patients with (2.87%) than without (1.66%) previous stroke or TIA (HR, 1.70; 95% CI, 1.44-2.02; P<0.0001).
• The number of events per 100 PY for the primary endpoint in patients treated with XARELTO compared with warfarin was consistent among patients with previous stroke or TIA (XARELTO, 2.79% vs warfarin, 2.96%; HR, 0.94; 95% CI, 0.77-1.16) and those without (XARELTO, 1.44% vs warfarin, 1.88%; HR, 0.77; 95% CI, 0.58-1.01; P-value for interaction=0.23).
• The number of MB  and NMCRB events per 100 PY in patients treated with XARELTO compared with warfarin was consistent among patients with previous stroke or TIA (XARELTO, 13.31% vs warfarin, 13.87%; HR, 0.96; 95% CI, 0.87-1.07) and those without (XARELTO, 16.69% vs warfarin, 15.19%; HR, 1.10, 95% CI, 0.99-1.21; P-value for interaction=0.08).
  • The number of MB events per 100 PY among patients who received at least 1 dose of study drug was significantly lower among those with previous stroke or TIA (n=361, 3.18%) than in those without previous stroke or TIA (n=420, 3.89%; HR, 0.81, 95% CI, 0.70-0.93; P=0.0037).
  • MB events in the XARELTO patients compared to the warfarin patients showed no interaction between the patients with previous stroke or TIA (XARELTO, 3.13% vs warfarin, 3.22%; HR, 0.97; 95% CI, 0.79-1.19) and those without (XARELTO, 4.10% vs warfarin, 3.69%; HR, 1.11; 95% CI, 0.92-1.34; P-value for interaction=0.36).

Tanahashi et al (2012)² conducted a substudy of J-ROCKET AF to assess the safety and efficacy of XARELTO compared with dose-adjusted warfarin among the subgroup of patients with AF and prior history of stroke or TIA or non-CNS SE (secondary prevention subgroup) who at increased risk of thromboembolism, as well as hemorrhage.

• The J-ROCKET AF study was a prospective, randomized, double-blind comparison to confirm the noninferiority of XARELTO vs warfarin for the prevention of stroke in regard to the primary safety outcome in Japanese patients with NVAF (n=1280).²³
  • Doses of XARELTO were optimized for the pharmacokinetic and pharmacodynamic profile of Japanese patients.
  • Patients were randomized to either 15 mg XARELTO once daily (10 mg in patients with moderate renal impairment [CrCl 30–49 mL/min]) or warfarin (target INR 2.0-3.0 for patients aged <70 or 1.6-2.6 for those aged ≥70).
  • The principal safety outcome was the composite of MB or NMCRB.
  • The primary efficacy endpoint was stroke or non-CNS SE.
• A total of 813 of 1278 patients (63%) comprised the secondary prevention subgroup. A total of 465 of 1278 patients (36%) comprised the primary prevention subgroup.
  • In the secondary prevention group, 408 patients were allocated to receive XARELTO and 405 to receive warfarin.
  • In the primary prevention (without prior history) group, 231 patients were allocated to receive XARELTO and 234 to receive warfarin.
• The number of MB or NMCRB events per 100 PY for the primary safety endpoints in patients treated with XARELTO compared with warfarin was consistent among patients in the secondary prevention group (XARELTO, 17.02% vs warfarin, 18.26%; HR, 0.95; 95% CI, 0.70-1.29) and those in the primary prevention group (XARELTO, 19.76% vs warfarin, 13.46%; HR, 1.48; 95% CI, 0.98-2.22; P-value for interaction=0.090).
• The number of stroke, TIA, or non-CNS SE events per 100 PY for the primary efficacy endpoints in patients treated with XARELTO compared with warfarin was consistent among patients in the secondary prevention group (XARELTO, 1.66% vs warfarin, 3.25%; HR, 0.51; 95% CI, 0.23-1.14) and those in the primary prevention group (XARELTO, 0.61% vs warfarin, 1.56%; HR, 0.39; CI, 0.08-2.02; P-value for interaction=0.776).

Gioia et al (2016)¹³ conducted a prospective, open-label, single-arm study of patients with NVAF treated with XARELTO initiated ≤14 days after TIA or moderate ischemic stroke (National Institute of Health [NIH] Stroke Scale <9).

• Dosing of XARELTO was based on renal function (estimated glomerular filtration rate [eGFR] 30-50 mL/min: 15 mg daily, eGFR >50 mL/min: 20 mg daily).
• All patients underwent MRI at baseline and on day 7.
• The primary endpoint was symptomatic hemorrhagic transformation on day 7 (defined as PH2 associated with ≥4-point increase in NIH Stroke Scale score).
• Sixty patients (n=49, ischemic stroke; n=11, TIA) were enrolled in the study.
• The median (interquartile range) time from symptom onset to XARELTO initiation was 3 (1.5-6) days.
• At baseline, hemorrhagic transformation was present in 25 (42%) patients (hemorrhagic infarct [HI]1, n=19; HI2, n=6).
• On follow-up MRI on day 7, no patients developed symptomatic hemorrhagic transformation or PH.
• New asymptomatic HI1 developed in 3 patients, and asymptomatic progression from H1 to H2 occurred in 5 patients.
• Recurrent ischemic events included 1 TIA (day 5, MRI negative) and 1 ischemic stroke (small cerebellar infarcts on day 28 computed tomography scan in a 95-year-old patient who never left the hospital after initial stroke and later died after withdrawal of care).
• Additionally, 1 patient died from aspiration pneumonia.
• No systemic bleeding complications or other serious adverse events occurred.

Acute Coronary Syndrome (ACS)

ATLAS ACS-2 TIMI-51³ was a randomized, placebo-controlled, multicenter, event-driven study designed to determine whether XARELTO (2.5 mg twice daily [BID] or 5 mg BID), when added to standard care, was safe and reduced the risk of the composite of CV death, MI, or stroke (primary efficacy endpoint) in patients with ACS compared with placebo in stabilized patients after an ACS event. Standard medical therapy included low-dose aspirin (75-100 mg) with or without thienopyridine. Patients were stratified by the investigator's intention to administer thienopyridine (clopidogrel or ticlopidine) at the time of enrollment. A total of 93% of patients received thienopyridine.

• One of the exclusion criteria included previous ischemic stroke or TIA in patients who were taking both aspirin and thienopyridine. Subjects with a prior hemorrhagic stroke were excluded.
• There was an increased risk of the primary efficacy endpoint in patients with a prior stroke or TIA that received XARELTO (both doses combined) compared to those that received placebo (Refer to Figure: Risk of the Primary Efficacy Endpoint, According to Prior Stroke or TIA).
• Among the patients who had a history of stroke of TIA, 198 received aspirin alone and 217 received aspirin and thienopyridine. The latter was a deviation from the study protocol.

Due to the lack of primary safety events (Thrombosis in Myocardial Infarction [TIMI] MB not related to coronary artery bypass graft [CABG]) in the prior stroke or TIA subgroup, the HRs and interaction terms were not generated (Refer to Figure: Risk of TIMI Major Bleeding Not Related to CABG, According to Prior Stroke or TIA).

Embolic Stroke of Undetermined Source (ESUS)

NAVIGATE ESUS⁴ was an international, double-blind, randomized, phase 3 study evaluating the efficacy and safety of XARELTO for the prevention of recurrent stroke and SE in 7213 patients with a recent ESUS.^24,25 The primary efficacy endpoint was the first recurrence of stroke and SE in a time to event analysis; the primary safety endpoint was MB. This study was stopped early on the recommendation of the study’s Independent Data Monitoring Committee due to comparable efficacy between XARELTO 15 mg once daily and aspirin 100 mg once daily (standard of care), and lack of benefit with regard to stroke risk and because of bleeding associated with XARELTO.⁸

• Patients were assigned 15 mg XARELTO with placebo once daily (n=3609) or 100 mg aspirin with placebo once daily (n=3604). Follow-up was conducted at 1 month, 6 months, 12 months and every 6 months after that, when patients were assessed for safety and efficacy events, adverse events and adherence.
• Patients who had ischemic stroke, as identified on cerebral imaging, that had occurred between 7 days and 6 months before screening, were eligible if the stroke was not lacunar and was not associated with extracranial vessel atherosclerosis causing more than 50% luminal stenosis in arteries supplying the area of ischemia or with identified risk factors for a cardiac source of embolism (AF, left ventricular thrombus, mechanical prosthetic cardiac valve, or severe mitral stenosis) and if no other cause of stroke could be found.
• In the entire cohort, there was history of previous stroke or TIA in 18% of patients.
• The primary efficacy outcome (first recurrent stroke or SE in a time-to-event analysis) occurred in 172 patients in the XARELTO group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (HR, 1.07; 95% CI, 0.87-1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the XARELTO group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%)
• The primary safety outcome was MB at any site in the body, which occurred in 62 patients in the XARELTO group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (HR, 2.72; 95% CI, 1.68-4.39; P<0.001).
  • The rate of life-threatening or fatal bleeding was significantly higher in the XARELTO group than in the aspirin group (HR, 2.34; 95% CI, 1.28-4.29; P=0.004), as were the rates of symptomatic intracranial hemorrhage (HR, 4.02; 95% CI, 1.51-10.7; P=0.003) and NMCRB (HR, 1.51; 95% CI, 1.13-2.00; P=0.004).

Hart et al (2019)⁵ conducted an analysis to identify independent predictors of recurrent stroke during treatment in the NAVIGATE ESUS population.

• Several characteristics were evaluated for association with increased risk of recurrent stroke, but 7 were significantly predictive in the stepwise multivariate analysis:
  • Prior stroke or TIA (HR, 2.03; 95% CI, 1.58-2.60)
  • Current tobacco user (HR, 1.62; 95% CI, 1.24- 2.12)
  • Age (HR, 1.02 per year increase; 95% CI, 1.01-1.03)
  • Diabetes (HR, 1.28; 95% CI, 1.01-1.64)
  • Multiple acute infarcts on neuroimaging (HR, 1.49; 95% CI, 1.09-2.02)
  • Aspirin use prior to qualifying stroke (HR, 1.34; 95% CI, 1.02-1.70)
  • Time from qualifying stroke to randomization (HR per 5 days, .98; 95% CI, 0.97 0.99)
• The strongest and most consistent predictor of recurrent ischemic stroke (and recurrent ESUS) was prior stroke or TIA.

Risk Reduction of Major CV Events in Stable CAD and PAD

COMPASS

COMPASS⁷ (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 BID plus aspirin 100 mg once daily or XARELTO 5 mg BID alone is more effective than aspirin 100 mg once daily alone for prevention of CV death, stroke, or MI in patients (N=27,395) with a history of stable atherosclerotic vascular disease (CAD or PAD).

• Key inclusion criteria included: PAD; CAD with ≥1 of the following: age ≥65 years or age <65 years and documented atherosclerosis or revascularization involving ≥2 vascular beds or ≥2 additional risk factors: current smoker (within 1 year of randomization), diabetes mellitus, renal dysfunction with eGFR <60 mL/min, heart failure (HF), or nonlacunar ischemic stroke ≥1 month ago.
• Key exclusion criteria included: stroke within 1 month or any history of hemorrhagic or lacunar stroke; severe HF with known ejection fraction <30% or New York Heart Association class III or IV symptoms; need for dual antiplatelet therapy, other nonaspirin antiplatelet therapy, or oral anticoagulant therapy; eGFR <15 mL/min; or systemic treatment with strong inhibitors of both CYP3A4 and P-glycoprotein or strong inducers of CYP3A4.
• Primary efficacy outcome: the composite of CV death, stroke, or MI
• Primary safety outcome (based on modified ISTH criteria): the composite of fatal bleeding, symptomatic bleeding in 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)
• Mean age was 68.2 years, 22.0% of patients were female, 90.6% had a history of CAD, 27.3% had a history of PAD, and 3.8% had a history of stroke.
• The primary efficacy outcome occurred in fewer patients in the XARELTO-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs 496 patients [5.4%]; HR, 0.76; 95% CI, 0.66-0.86; P<0.001), but MB events occurred in more patients in the XARELTO-plus-aspirin group (288 patients [3.1%] vs 170 patients [1.9%]; HR, 1.70; 95% CI, 1.40-2.05; P<0.001).
• Among patients with prior stroke, the benefits of the combination of XARELTO and aspirin in prevention of CV death, stroke, or MI were consistent with those observed in the overall COMPASS population. See Table: Risk of Primary Efficacy and Safety Outcomes Based on Previous Stroke Status.^6,7
• Provisions to address multiple testing for subgroups were not specified and therefore, any HRs, corresponding CIs, and P values reported for subgroup analyses cannot be interpreted as statistically significant.²⁶

CAD and PAD Subgroup Analyses

Connolly et al (2018)⁹ conducted a prespecified subanalysis of patients (n=24,824 [~91%]) in the COMPASS study that had stable CAD at baseline. Anand et al (2018)⁸ conducted a prespecified subanalysis of patients (n=7470 [~27%]) in the COMPASS study that had stable PAD at baseline.

• In the CAD subgroup analysis, 3% of patients had a history of stroke. In the PAD subgroup analysis, approximately 6.7% of patients had a history of stroke.
• The effects of XARELTO plus aspirin vs aspirin alone on the primary efficacy and safety outcomes were consistent among the CAD (primary efficacy: 347 patients [4%] vs 460 patients [6%]; HR, 0.74; 95% CI, 0.65-0.86; P<0.0001; primary safety: 263 patients [3%] vs 158 patients [2%]; HR, 1.66; 95% CI, 1.37-2.03; P<0.0001) and PAD (primary efficacy: 126 patients [5%] vs 174 patients [7%]; HR, 0.72; 95% CI, 0.57-0.90; P<0.0047; primary safety: 77 patients [3%] vs 48 patients [2%]; HR, 1.61; 95% CI, 1.12-2.31; P<0.0089) subgroups and were similar to those observed in the overall COMPASS study.
• In both subanalyses, results were not stratified by baseline history of stroke.

Stroke Subgroup Analysis – Previous Stroke Status and Outcomes

Sharma et al (2019)¹⁰ conducted a subanalysis of the COMPASS study, which assessed stroke outcomes (overall stroke, ischemic/uncertain, hemorrhagic) by treatment (XARELTO alone, XARELTO plus aspirin, or aspirin alone), modified Rankin Scale score at 7 days or at hospital discharge, selected predictors of stroke, and stroke outcomes based on previous stroke status.

• Of the 27,395 patients in the COMPASS study, 1032 (3.8%) had a history of stroke, which was observed to be a selected predictor of stroke.
  • All strokes: 2.6%/year; HR, 3.63; 95% CI, 2.65-4.97; P=0.0001
  • Ischemic/uncertain stroke: 2.4%/year; HR, 3.75; 95% CI, 2.69-5.23; P=0.0001
  • Hemorrhagic stroke: 0.3%/year; HR, 3.12; 95% CI, 1.22-7.98; P=0.02
• In patients with a history of stroke, compared to aspirin (100 mg once daily) alone, the combination of XARELTO (2.5 mg BID) plus aspirin (100 mg once daily) was associated with a lower incidence of stroke.  
  • XARELTO plus aspirin reduced the rate of all strokes from 3.4% to 0.7% per year (HR, 0.42; 95% CI, 0.19-0.92; P=0.03; interaction P=0.40).
  • XARELTO plus aspirin reduced the rate of ischemic/uncertain stroke from 3.4% to 1.1% per year (HR, 0.33; 95% CI, 0.14-0.77; P=0.01; interaction P=0.28), resulting in an ARR of 2.3% and an NNT of 36 for 1 year.
  • The absence of hemorrhagic stroke in patients assigned aspirin alone, as well as the small number of hemorrhagic strokes that occurred in patients assigned XARELTO plus aspirin (N=2) precluded testing of interaction by previous stroke status.
• In patients without a history of stroke, compared to aspirin (100 mg once daily) alone, the combination of XARELTO (2.5 mg BID) plus aspirin (100 mg once daily) was also associated with a lower incidence of stroke.
  • XARELTO plus aspirin reduced the rate of all strokes from 0.7% to 0.4% per year (HR, 0.60; 95% CI, 0.45-0.80; P=0.0006; interaction P=0.40).
  • XARELTO plus aspirin reduced the rate of ischemic/uncertain stroke from 0.7% to 0.4% per year (HR, 0.54; 95% CI, 0.40-0.74; P=0.0001; interaction P=0.28).
  • There was no difference in the rate of hemorrhage stroke in patients without a history of prior stroke, which occurred in 0.08% of patients in the XARELTO plus aspirin arm and 0.06% of patients in the aspirin alone arm (HR, 1.29; 95% CI, 0.57-2.94; P=0.54).
• An increased risk of major bleeding was observed in patients who received XARELTO plus aspirin vs aspirin alone in both patients with and without prior stroke.
  • XARELTO plus aspirin increased the rate of major bleeding from 0.5% to 1.9% per year (HR, 3.79; 95% CI, 1.07-13.4; P=0.04; interaction P=0.19) in patients with prior stroke.
  • XARELTO plus aspirin increased the rate of major bleeding from 1.0% to 1.7% per year (HR, 1.66; 95% CI, 1.37-2.01; P<0.0001; interaction P=0.19) in patients without prior stroke.
• An increased risk of minor bleeding was observed in patients who received XARELTO plus aspirin vs aspirin alone in patients who had not had a history of prior stroke.
  • XARELTO plus aspirin increased the risk of minor bleeding from 3.0% to 5.2% per year (HR, 1.73; 95% CI, 1.55-1.94; P<0.0001; interaction P=0.05).
• The composite outcome of CV death, stroke, or MI occurred less frequently in patients receiving XARELTO plus aspirin vs aspirin alone in patients with or without prior stroke.
  • XARELTO reduced the rate of the composite of CV death, stroke, or MI from 2.8% to 2.0% per year in patients without a history of prior stroke (HR, 0.77; 95% CI, 0.67-0.88; P=0.0002; interaction P=0.27).
  • XARELTO reduced the rate of the composite of CV death, stroke, or MI from 6.5% to 3.7% per year in patients with a history of prior stroke (HR, 0.57; 95% CI, 0.34-0.96; P=0.04; interaction P=0.27).

COMPASS MIND

Sharma et al (2018)¹¹ conducted a prespecified subanalysis of COMPASS patients (n=1905), known as COMPASS MIND (MRI and Neurocognitive Deterioration substudy of COMPASS), to examine the effect of antithrombotic treatment (XARELTO plus aspirin or XARELTO alone vs aspirin alone) on MRI outcomes (incident covert brain infarcts), cognitive and functional outcomes, and biomarkers and genetics.

• COMPASS study patients were eligible for inclusion in COMPASS MIND if they had no contraindications to MRI and provided additional informed consent for the subanalysis.
• COMPASS MIND recruited COMPASS study patients across 86 sites in 16 countries.
• The primary outcome was incident covert brain infarcts (detected on imaging in the absence of an adjudicated stroke, consistent with the location of the infarct) detected by blinded comparison of baseline and end-of-study MRI.
• T1-weighted, T2-weighted, T2*-weighted, and FLAIR images were obtained close to randomization and near study drug termination; biomarker and genetic samples at randomization and 1 month; and cognitive and functional assessment at randomization, after 2 years, and at study end.
• A baseline MRI was completed in 1760/1905 (~92%) patients.
• Mean age of patients was 71.2 years (vs 68.2 years in COMPASS), 23.9% of patients were female, 90.3% had a history of CAD, 28.5% had a history of PAD, 2.5% had a history of TIA, and 4.5% had a history of stroke.
• Brain infarcts were present in 34.8% of patients, 29.3% had cerebral microbleeds, and 93.0% had white matter hyperintensities.
• The median Montreal Cognitive Assessment score was 26, similar to that seen in the overall COMPASS population.

Results

• Provisions to address multiple testing for subgroups, such as COMPASS MIND patients, were not specified and therefore any hazard ratios, corresponding confidence intervals, and P values reported for subgroup analyses cannot be interpreted as statistically significant.²⁶
• Of the total 27,395 patients recruited within the overall COMPASS trial, 1905 patients were recruited for the COMPASS MIND subgroup. Of these, 1761 patients had MRI scans that were readable at baseline. Of the baseline MRI scans, 34.8% had infarcts.¹¹
• Mean age was 71.2 years, 23.9% were female, 90.3% had a history of CAD, 28.5% had history of PAD, 7.9% had asymptomatic carotid stenosis ≥50% or had previous carotid revascularization, and 6.6% had a history of transient ischemic attack or stroke.¹¹
• After a mean of 2.0 (0.7) years, incident covert infarcts occurred in 2.7% of patients on XARELTO and aspirin vs 3.5% of patients on aspirin alone (OR, 0.77;95% CI, 0.37-1.60). Covert infarcts or ischemic stroke occurred in 2.9% on XARELTO and aspirin and 5.3% on aspirin alone (OR, 0.53, 95% CI, 0.27-1.03).
• Incident cerebral microbleeds occurred in 6.6% of patients (with combination vs aspirin OR 1.49; 95 % CI, 0.88-2.52).¹²

Retrospective Studies

Coleman et al (2017)²⁷ conducted a real-world study to compare XARELTO, dabigatran, and apixaban with warfarin in patients with NVAF with previous histories of ischemic stroke or TIA.

• A US administrative claims database (MarketScan) was used to identify patients from January 2012 to June 2015, and 3 propensity score-matched cohorts were compared: XARELTO vs warfarin (n=5208), apixaban vs warfarin (n=2514), and dabigatran vs warfarin (n=1962).
• Patients had to be free of oral anticoagulants for ≥180 days prior to the index date, then started 1 of the study medications (the index date) and were followed until they had an ischemic stroke or intracranial hemorrhage (ICH) (combined primary endpoint), a MB (primary safety endpoint), switched/discontinued oral anticoagulants, terminated insurance, or completed the follow-up period.
• The mean length of follow-up was 0.5 to 0.6 years.
• XARELTO significantly decreased the combined primary endpoint of ischemic stroke or ICH compared with warfarin (HR, 0.45; 95% CI, 0.29-0.72; P=0.001) without effecting the incidence of MB (HR, 1.07; 95% CI, 0.71-1.61).
  • When the events were analyzed separately, XARELTO significantly decreased ischemic stroke (HR, 0.48; 95% CI, 0.29-0.79) and non-significantly reduced ICH (HR, 0.40; 95% CI, 0.15-1.04) compared with warfarin.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 23 October 2024.