Summary

• A post hoc analysis of the RECORD studies^1-4 compared event rates for symptomatic venous thromboembolism (VTE) plus all-cause mortality with nonfatal major bleeding in patients being treated with XARELTO or enoxaparin to determine number needed to treat (NNT), number needed to harm (NNH), and net clinical benefit (NCB).⁵
  • In patients who underwent total hip arthroplasty (THA), the NNT was 262 and the NNH was 1711.
  • In patients who underwent total knee arthroplasty (TKA), the NNT was 102 and NNH was 442.
• A benefit-risk analysis of the EINSTEIN-Choice study found that compared to aspirin, extended anticoagulation with once daily XARELTO reduced recurrent VTE with a favorable benefit-risk profile.⁶
• A benefit-risk analysis of the EINSTEIN-Extension study compared recurrent VTE and major bleeding events in patients treated with XARELTO or placebo for prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE). Benefits and risks were assessed using NNT, NNH, and clinical benefit.⁷
  • In a population of 10,000 patients treated for 1 year, XARELTO treatment would have resulted in 665 fewer recurrent VTE events vs placebo (NNT=15) and 68 more major bleeding events vs placebo (NNH=147).
• In an analysis of the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) study⁸, NNT was calculated for the primary efficacy endpoint of major cardiovascular (CV) events (composite of CV death, myocardial infarction [MI], and stroke) in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD) treated either with XARELTO 2.5 mg twice daily (BID) plus aspirin 100 mg once daily or aspirin 100 mg once daily alone. NNH was also calculated for the safety endpoint of the composite of fatal bleeding, symptomatic bleeding into a critical organ, or surgical site bleeding requiring reoperation.
  • In a population of 18,278 with stable CAD or PAD (9152 patients in XARELTO-plus-aspirin arm, 9126 patients in aspirin alone arm) over a mean study duration of 1.9 years, the NNT to prevent one major CV event with XARELTO plus aspirin versus aspirin alone was 77. The NNH for the same population was 461.⁸
  • In a prespecified analysis of the COMPASS population cohort (intention-to-treat population), the NNT to prevent one NCB outcome, defined as the composite of major CV events, fatal bleeding, or symptomatic bleeding into a critical organ, with XARELTO plus aspirin versus aspirin alone was 52.⁹
  • In a post hoc analysis of the COMPASS study, the absolute risk reduction (ARR) for total MACE events was 1.6% with a NNT (2 years) of 63 in the XARELTO plus aspirin group, and 1.3% with a NNT (2 years) of 77 for the first MACE event.¹⁰
• The VOYAGER PAD study used XARELTO 2.5 mg BID plus aspirin 100 mg once daily to evaluate the risk reduction of major atherothrombotic vascular outcomes consisting of both CV and limb events in patients with symptomatic PAD undergoing lower-extremity revascularization (LER).¹¹
  • The study estimated XARELTO would prevent 181 primary efficacy outcome events for every 10,000 patients treated for 1 year. For the same timeframe, the study estimated a total of 29 principal safety outcome events.
• In a subanalysis of VOYAGER PAD, at 3 years, XARELTO plus aspirin reduced unplanned index limb revascularization (UILR) by an absolute risk reduction of 3.4% in patients with critical limb-threatening ischemia (CLTI) compared to aspirin alone, which equates to a NNT of 30.¹²
• A benefit-risk analysis was conducted for a subpopulation of the MAGELLAN study. The NNT and NNH for different components of the primary efficacy and safety endpoints were explored in this analysis and calculated based on event rates in the MAGELLAN study.¹³
  • Overall, the benefit-risk profile was improved in the MAGELLAN subpopulation compared to the MAGELLAN overall population.
• In the MARINER study, in a population of 12,019 high-risk medically ill patients, the number needed to prevent one symptomatic VTE event was 430, while the number needed to cause one major bleed was 856.¹⁴
• In a systematic review and meta-analysis of randomized controlled trials evaluating the efficacy and safety of low-dose XARELTO plus aspirin vs aspirin alone, the NNT (range) for low-dose XARELTO plus aspirin to prevent 1 CV event was 63 (43-103) with a NNH (range) to cause 1 major bleed of 107 (77-183).¹⁵
• Other pivotal XARELTO studies are noninferiority studies and are therefore not included in this summary.¹⁶
• Additional citations identified are included for your review.^17-25

CLINICAL STUDIES

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

The RECORD clinical development program, a comprehensive program of 4 phase III studies with over 12,000 patients, studied XARELTO for the prophylaxis of VTE in patients undergoing knee (RECORD 3 and 4) or hip (RECORD 1 and 2) replacement surgery. The data from the RECORD program were submitted to the Food and Drug Administration (FDA). XARELTO was approved on July 1, 2011 by the FDA for the indication studied in the RECORD program. In the RECORD 4 study, patients received either oral XARELTO 10 mg once daily, beginning at least 6–8 h after surgery, or subcutaneous enoxaparin 30 mg every 12 hours, starting 12–24 hours after surgery. Data from RECORD 4 are not included in the approved product labeling for XARELTO.

Since publication of RECORD 4 findings, the sponsor company conducted a verification of the data for all patients in this clinical trial. With respect to study findings, additional adverse events/serious adverse events were identified; however, the distribution of those was balanced between study groups. In the company’s view, verification findings did not appreciably change the conclusions of the study. Thus, the RECORD 4 findings reported in the publication remain consistent with the overall results from the total RECORD program.^1-4

Levitan et al (2014)

Levitan et al (2014)⁵ conducted a post hoc analysis to quantitatively assess the benefit-risk assessment of XARELTO vs enoxaparin for the prevention of VTE after THA or total knee arthroplasty (TKA) in patients enrolled in the RECORD studies.

• The primary analysis compared the temporal course of event rates and rate differences between XARELTO and enoxaparin prophylaxis for symptomatic VTE plus all-cause mortality (efficacy events) vs nonfatal major bleeding (safety events).
• Data from the 2 THA studies and 2 TKA studies were pooled separately to allow for assessment of the different time course of benefit-risk after both types of procedures. Rate differences between XARELTO and enoxaparin treatment were used to more clearly show the number of events caused vs those prevented.
  • NCB, NNT, and NNH were derived from these rates. (See Table: Kaplan-Meier Event Rates, Rate Difference, NNT/NNH, and NCB for THA and TKA Patients)
• Following THA, XARELTO therapy prevented more harmful events, but was associated with more safety events.
  • The NNT=262. For every 262 patients receiving XARELTO vs enoxaparin, 1 fewer symptomatic VTE or death would be expected to occur.
  • The NNH=1711. 1711 patients would need to be treated to see 1 more nonfatal major bleeding event.
  • NCB was 32 fewer symptomatic VTE, all-cause mortality, or nonfatal major bleeding events with XARELTO compared to enoxaparin.
• Following TKA, XARELTO therapy prevented more harmful events, but was associated with more safety events.
  • The NNT=102. For every 102 patients receiving XARELTO vs enoxaparin, 1 fewer symptomatic VTE or death would be expected to occur.
  • The NNH=442. 442 patients would need to be treated to see 1 more nonfatal major bleeding event.
  • NCB was 76 fewer symptomatic VTE, all-cause mortality, or nonfatal major bleeding events with XARELTO compared to enoxaparin.
• If surgical site bleeding was included, the NNH would be 345 for THA and 208 for TKA.

Reduction in the Risk of Recurrence of DVT and of PE

EINSTEIN-Choice

EINSTEIN-Choice was a phase 3, randomized, double-blind, event-driven, superiority study that compared the efficacy and safety of 2 doses of XARELTO (20 mg and 10 mg, once daily) with aspirin (100 mg once daily) in patients with VTE who had completed 6 to 12 months of anticoagulation therapy and for whom there was equipoise with respect to the need for ongoing anticoagulation.²⁶

Prandoni et al (2018)⁶ evaluated data from EINSTEIN-Choice to compare the benefit-risk profiles of extended XARELTO treatment (20 mg or 10 mg once daily) and extended aspirin treatment (100 mg once daily) in patients with VTE who had completed 6 to 12 months of anticoagulation.

• One-year cumulative incidences of recurrent VTE and major bleeding were estimated, and net clinical benefit (composite of symptomatic recurrent VTE and major bleeding) was calculated by determining between-group differences in a hypothetical population of 10,000 VTE patients treated for 1 year.
• Baseline characteristics were similar among the 3 treatment groups.
• Compared to aspirin, for 10,000 patients treated for 1 year with XARELTO 20 mg and XARELTO 10 mg:
  • There would be 312 (95% confidence interval [CI], 144 to 479) and 341 (95% CI, 175 to 507) fewer recurrent VTE, respectively.
    • The NNT to prevent 1 episode of DVT or PE with XARELTO rather than with aspirin was 33 for XARELTO 20 mg and 30 for XARELTO 10 mg.
  • There would be 28 (95% CI, -43 to 99) and 0 (95% CI, -60 to 59) more major bleeding events, respectively.
    • The NNH to cause 1 major bleeding event with XARELTO rather than with aspirin was 356 for XARELTO 20 mg and >10,000 for XARELTO 10 mg.
  • There would be 284 (95% CI, 106 to 462) and 339 (95% CI, 165 to 512) fewer NCB events, respectively.
    • Compared with aspirin, 1 additional symptomatic recurrent VTE or major bleed would be avoided for every 36 patients treated with XARELTO 20 mg and 30 patients treated with XARELTO 10 mg.

EINSTEIN-Extension

The EINSTEIN-Extension study was a phase 3, randomized, double-blind, event-driven superiority study comparing XARELTO 20 mg once daily to placebo in patients with confirmed symptomatic PE or DVT who had been treated with XARELTO or a vitamin K antagonist for 6 to 12 months.²⁷

Wells et al (2016)⁷ conducted a benefit-risk analysis of the EINSTEIN-Extension study, which compared use of continued oral XARELTO (20 mg once daily) vs placebo for the prevention of recurrent DVT and PE in patients who had completed 6 to 12 months of anticoagulation with XARELTO or a vitamin K antagonist (N=1197).

• The analysis compared 1-year Kaplan-Meier event rates and rate differences between XARELTO and placebo for symptomatic, recurrent VTE (efficacy events) and major bleeding (safety events). (See Table: Rate Differences and NNT/NNH for Key Benefits and Risks in EINSTEIN-Extension Patients)
  • Symptomatic, recurrent VTE was defined as the composite of DVT or nonfatal or fatal PE.
  • An overt bleeding event was defined as major if it was fatal, occurred in a critical location (eg, intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial), was associated with a decrease in hemoglobin level of ≥2 g/dl, or required a transfusion of ≥2 units of whole blood or red cells.
• Benefits and risks were assessed using rate differences scaled to a population size of 10,000 patients treated for 1 year.
• Of the 1197 patients that were enrolled, 602 were assigned to XARELTO and 595 to placebo.
• Recurrent VTE occurred in 8 (Kaplan-Meier rate, 3.0%) XARELTO-treated patients (3 PEs and 5 DVTs) and in 42 (Kaplan-Meier rate, 9.6%) placebo-treated patients (13 PEs and 29 DVTs).
  • These rates correspond to a 1-year Kaplan-Meier rate difference of 6.7% (95% CI, 2.46-10.84), in favor of XARELTO.
  • In a population of 10,000 patients treated over 1 year, XARELTO treatment would have resulted in 665 (95% CI, 246-1084) fewer recurrent VTE events vs placebo (NNT=15).
• Major bleeding occurred in 4 (Kaplan-Meier rate, 0.7%) XARELTO-treated patients (3 gastrointestinal and 1 menorrhagia, none of which were fatal or in a critical organ) and in 0 placebo-treated patients.
  • XARELTO treatment would have resulted in 68 (95% CI, 2-134) more major bleeding events vs placebo (NNH=147).
• NCB (the composite of symptomatic, recurrent VTE and major bleeding events) was observed in 12 XARELTO-treated patients (Kaplan-Meier rate, 3.6%) and in 42 placebo-treated patients (Kaplan-Meier rate, 9.6%), resulting in a difference of 6.0% (95% CI, 1.8%-10.2%), in favor of XARELTO. XARELTO treatment would result in 598 (95% CI, 175-1021) fewer NCB outcomes vs placebo (NNT=17).
• Early recurrent VTE reduction with XARELTO was demonstrated through Kaplan-Meier analysis, and continued to improve throughout treatment. Major bleeding increased gradually, plateauing at ±100 days.

CAD or PAD

COMPASS

• COMPASS⁸ was a phase 3, event-driven trial designed to evaluate whether treatment with XARELTO 2.5 mg BID (N=9152) in combination with aspirin 100 mg once daily (N=9126) or XARELTO 5 mg BID alone (N=9117) is more efficacious and safe than aspirin 100 mg alone for secondary prevention of atherosclerotic events in patients with stable CAD or PAD.
• Primary efficacy outcome: MACE (composite of CV death, MI, or stroke)
• Primary safety outcome: Modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding (composite of fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization including presentation to an acute care facility without an overnight stay).
• Additional safety outcome: fatal bleeding, symptomatic bleeding into a critical organ, or surgical site bleeding requiring reoperation.
• 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%]; hazard ratio [HR], 0.76; 95% CI, 0.66 to 0.86; P<0.001; z=-4.126).
  • The NNT=77. For every 77 patients on XARELTO 2.5 mg BID plus aspirin 100 mg once daily versus aspirin alone treated for the mean study duration of 1.9 years, one fewer major CV event would be expected to occur.
• The primary safety outcome of major bleeding occurred in more patients in the XARELTO-plus-aspirin group than aspirin alone (288 patients [3.1%] vs. 170 patients [1.9%]; HR, 1.70; 95% CI 1.40 to 2.05; P<0.001).
  • The NNH=83. For every 83 patients on XARELTO 2.5 mg BID plus aspirin 100 mg once daily versus aspirin alone treated for the mean study duration of 1.9 years, one more major bleed would be expected to occur.
• The net clinical benefit (composite of MI, stroke, CV death, fatal bleeding, or symptomatic bleeding into critical organ) was lower with XARELTO plus aspirin than with aspirin alone (431 patients [4.7%] vs. 534 patients [5.9%]; HR, 0.80; 95% CI, 0.71 to 0.91; P<0.001).
• The net-clinical-benefit outcome was not significantly lower with rivaroxaban alone than with aspirin alone.

Steffel et al (2020)⁹ conducted a prespecified analysis of the COMPASS study cohort (N=27,395) to evaluate the NCB of adding XARELTO 2.5 mg BID to aspirin monotherapy vs aspirin monotherapy in the overall COMPASS study population (intention-to-treat) and in select high-risk subgroups.

• The prespecified NCB was defined as the composite of CV death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ.
• Previously identified high-risk subgroups included patients with polyvascular disease (>2 vascular beds affected with atherosclerosis), impaired renal function (estimated glomerular filtration rate <60 mL/min), heart failure (HF), diabetes mellitus, or a combination of these risk characteristics. An additional subgroup included in this analysis were patients aged >65 and <65 years of age.
• Due to the clear benefit of rivaroxaban 2.5 mg BID plus aspirin over aspirin alone, this analysis was limited to that population (n =18,278).
• Overall, significantly fewer NCB adverse outcomes were observed in the group receiving XARELTO 2.5 mg BID plus aspirin vs aspirin alone (4.7% vs. 5.9%; HR, 0.80; 95% CI, 0.70-0.91). The absolute risk reduction based on Kaplan-Meier estimates of cumulative risk at 30 months was -19.5 events (95% CI, -28.9 to -10.0) prevented per 1000 patients, resulting in an NNT of 52.
• There was no significant interaction in the relative impact of the combination of XARELTO plus aspirin versus aspirin alone in any of the identified high-risk subgroups.

Branch et al (2023)¹⁰ conducted a post hoc analysis of the COMPASS trial to evaluate the effects of combination XARELTO and aspirin, XARELTO alone, and aspirin alone on recurrent and total (first and recurrent) MACE, bleeding outcomes, and NCB outcomes in patients with chronic CAD or PAD.

• The ARR for total (first and recurrent) MACE events was 1.6% with a NNT (2 years) of 63 in the XARELTO plus aspirin group, and 1.3% with a NNT (2 years) of 77 for the first MACE event.
• In the exploratory analysis, the prespecified NCB events were primary MACE outcomes (composite of CV death, stroke, MI) and severe bleeding (symptomatic bleeding into a critical oral or fatal bleeding).
  • The total number of NCB events was 496 (5.4%) in the XARELTO plus aspirin group and 616 (6.7%) in the aspirin alone group, and the total number of NCB events was improved by 20% in the XARELTO plus aspirin group compared with the aspirin alone group (HR, 0.80; 95% CI, 0.700.91; P=0.001).

VOYAGER PAD

VOYAGER PAD¹¹ was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate whether XARELTO 2.5 mg BID plus aspirin 100 mg once daily is more effective than aspirin 100 mg once daily alone for the risk reduction of major atherothrombotic vascular outcomes consisting of both CV and limb events in patients with symptomatic PAD undergoing LER.

• The median follow-up duration of the VOYAGER PAD study was 28 months.
• The primary efficacy outcome (composite of acute limb ischemia, major amputation of vascular etiology, MI, ischemic stroke, or CV death) occurred in fewer patients in the XARELTO plus aspirin group than in the aspirin alone group (508 patients [17.3%] vs 584 patients [19.9%]; HR, 0.85; 95% CI, 0.76-0.96; P=0.009) based on Kaplan-Meier estimates of the cumulative incidence at 3 years.
• The principal safety outcome (composite of major bleeding according to Thrombolysis in Myocardial Infarction [TIMI] classification) occurred in more patients in the XARELTO plus aspirin group than in the aspirin alone group (62 patients [2.65%] vs 44 patients [1.87%]; HR, 1.43; 95% CI, 0.97-2.10; P=0.07) based on Kaplan-Meier estimates of the cumulative incidence at 3 years.
• The study estimated XARELTO (dosed at 2.5 mg BID) plus aspirin (100 mg once daily) would prevent 181 primary efficacy outcome events for every 10,000 patients treated for 1 year. For this same timeframe, the study estimated a total of 29 principal safety outcome events.
• An additional citation regarding the VOYAGER PAD study has been identified for your review.²⁸

Hogan et al (2024)¹² conducted a subanalysis of VOYAGER PAD patients with CLTI who had the first occurrence of UILR. During the 3-year follow up, UILR events occurred in 26% and 14% of patients in the endovascular LER and surgical LER groups, respectively.

• At 3 years, XARELTO plus aspirin reduced UILR by an absolute risk reduction of 3.4% in patients with CLTI compared to aspirin alone, which equates to a NNT of 30.
  • The reduction in UILR in patients with CLTI was seen in both the endovascular and surgical LER groups, although only the endovascular group reached statistical significance.
    • Endovascular LER group: HR 0.75 (95% CI, 0.56-1.0); P=0.049; NNT=15.
    • Surgical LER group: HR 0.83 (95% CI, 0.55-1.25); P=0.37.

Medically Ill Patients

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 post-discharge periods.^29,30

• The study randomized 8101 patients to receive either subcutaneous placebo daily for 10±4 days plus XARELTO 10 mg daily for 35±4 days or subcutaneous enoxaparin 40 mg daily for 10±4 days plus oral placebo daily for 35±4 days. All enrolled study participants underwent mandatory bilateral lower limb venous ultrasonography at 2 time points, on day 10±4 and day 35±4.
• Primary efficacy outcome: composite of VTE or VTE-related death.
  • Noninferiority analysis at day 10
  • Superiority analysis at day 35
• Primary safety outcome: major bleeding or clinically relevant nonmajor bleeding (CRNMB) observed no later than 2 days after the last dose of study medication.
• Net clinical benefit/harm: composite of VTE, VTE-related death, major bleeding, or CRNMB. It included patients who met the criteria for modified intention-to-treat population, safety population, and those who had a primary safety outcome up to day 41 (for the 35-day analysis).
• At 35 days, the primary efficacy outcome occurred in fewer patients in the XARELTO group than in the enoxaparin group (131/2967 [4.4%] vs. 175/3057 [5.7%]; relative risk 0.77; 95% CI, 0.62 to 0.96; P=0.02).
  • The NNT=77. For every 77 patients on XARELTO for 35 days versus enoxaparin for 10 days, one fewer VTE or VTE-related death would be expected to occur.
• At 35 days, the primary safety outcome occurred in more patients in the XARELTO group than in enoxaparin (164/3997 [4.1%] vs. 67/4001 [1.7%]; relative risk 2.5; 95% CI, 1.85 to 3.25; P<0.001).
  • The NNH=41. For every 41 patients on XARELTO for 35 days versus enoxaparin for 10 days, one more major bleeding or CRNMB would be expected to occur.
• At 35 days, the net clinical benefit/harm occurred in more patients in the XARELTO group than in the enoxaparin group (286/3042 [9.4%] vs. 240/3082 [7.8%]; relative risk 1.21; 95% CI 1.03 to 1.43; P=0.02).

Spyropoulos et al (2018)¹³ conducted a retrospective, benefit-risk analysis in a subpopulation of the MAGELLAN study.

• Five risk factors for major bleeding 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. The exclusion criteria were: history of bronchiectasis/pulmonary cavitation, active cancer (i.e. undergoing acute, in-hospital treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy.^13,31
• For calculated NNT and NNH for the MAGELLAN overall population and subpopulation, see Table: MAGELLAN and MAGELLAN Subpopulation Benefit-Risk Analysis.¹³

MARINER

The MARINER^14,32 (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 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) vs placebo in the prevention of symptomatic VTE and VTE-related death in high-risk, medically ill patients for a period of 45 days post-hospital discharge.

• There were 12,019 patients randomized to XARELTO or placebo.
  • Of those randomized to XARELTO, 4909 patients had a CrCl ≥50 mL/min and received the 10 mg dose, and 1098 patients had CrCl 30 to <50 mL/min and received the 7.5 mg dose.
• There was no statistically significant difference between XARELTO and placebo for the primary efficacy and safety outcome. Therefore, the NNT and NNH are not calculated.¹⁴
  • Primary efficacy outcome (composite of symptomatic VTE or VTE-related death) in the XARELTO and placebo group: 50/6007 (0.83%) vs 66/6012 (1.1%); HR, 0.76; 95% CI, 0.52 to 1.09; P=0.14.
  • Primary safety outcome (major bleeding) in the XARELTO and placebo group: 17/5982 (0.28%) vs 9/5980 (0.15%); HR, 1.88; 95% CI, 0.84 to 4.23.

Systematic Review and Meta-Analysis

Bucci et al (2024)¹⁵ performed a systematic review and meta-analysis of randomized controlled trials that evaluated the efficacy and safety of low-dose XARELTO plus an antiplatelet compared to an antiplatelet alone in patients with CAD and/or PAD.

• The study analyzed 7 trials with 45,836 patients (mean age range: 54-70 years, >70% were men). Of these, 34,276 had CAD and 11,560 had PAD.
• Primary analysis was low-dose XARELTO plus any antiplatelet vs any antiplatelet.
  • Subgroup analysis evaluated low-dose XARELTO plus aspirin vs aspirin (N=30,193).
  • NNT and NNH were calculated for low-dose XARELTO plus aspirin vs aspirin.
• Efficacy endpoints: risk of CV events, MI, stroke, CV death, and all-cause mortality.
• Safety endpoints: risk of any bleeding, major bleeding, intracranial hemorrhage (ICH), and fatal bleeding.
• Primary and subanalysis results were consistent. The subanalysis and NNT/NNH were:
  • Compared with aspirin alone, low-dose XARELTO plus aspirin was:
    • associated with a statistically significant reduction in the risk of CV events (HR 0.86, 95% CI 0.78-0.94) and stroke (HR 0.68, 95% CI 0.55-0.84).
    • not associated with a statistically significant reduction in MI (HR 0.86, 95% CI 0.71-1.05), CV death (HR 0.96, 95% CI 0.86-1.06), or all-cause mortality (HR 0.95, 95% CI 0.84-1.07).
    • associated with a statistically significant higher risk of major bleeding (HR 1.71, 95% CI 1.38-2.11) and any bleeding (HR 1.53, 95% CI 1.36-1.73).
    • not associated with a statistically significant higher risk of ICH (HR 1.03, 95% CI 0.68-1.58) and fatal bleeding (HR 1.24, 95% CI 0.75-2.06).
  • Compared to aspirin alone, the low dose XARELTO plus aspirin group showed an NNT (range) to prevent 1 CV event of 63 (43-103), with an NNH (range) to cause 1 major bleeding of 107 (77-183).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 26 August 2024.