Summary

• In ROCKET AF, 40.0% (n=5695) of patients had diabetes mellitus (DM).¹
  • In a prespecified subgroup analysis of the ROCKET AF study in patients with DM, the relative efficacy and safety of XARELTO vs warfarin were similar in patients with and without DM.
• In a large population-based cohort study that evaluated the effectiveness and safety of XARELTO vs apixaban in patients with nonvalvular atrial fibrillation (NVAF) and type 2 DM (T2DM), comparable efficacy was found between apixaban and XARELTO in the prevention of stroke (hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.79-1.23). Apixaban was associated with a decreased risk of major bleeding compared with XARELTO (HR, 0.68; 95% CI, 0.59-0.78); however, no difference in the risk of major adverse limb events (MALEs) was observed between the 2 groups (HR, 0.75; 95% CI, 0.54-1.04).²
• In a subanalysis of a retrospective study (RIVA-DM) that evaluated the impact of age (<80 vs ≥80 years) on the effectiveness and safety of XARELTO vs warfarin in patients with NVAF and T2DM, no significant interaction for XARELTO vs warfarin by age was observed for any outcome, including stroke/systemic embolism (SSE; HR, 0.95; 95% CI, 0.87-1.04 vs HR, 1.05; 95% CI, 0.92-1.19) and hospitalization for major bleeding or clinically relevant nonmajor bleeding (CRNMB; HR, 0.90; 95% CI, 0.84‑0.96 vs HR, 1.06; 95% CI, 0.96-1.18).³
• In a retrospective cohort analysis conducted in patients with NVAF and comorbid T2DM, XARELTO was associated with an ~10% relative reduction in vascular mortality and fewer bleeding-related hospitalizations vs warfarin.⁴
• A retrospective, observational study conducted on patients with NVAF and DM newly initiating apixaban, dabigatran, XARELTO, or warfarin found that non-vitamin K oral anticoagulants (NOACs) were associated with variable rates of SSE and major bleeding when compared to warfarin.⁵
• In a study utilizing electronic health records, XARELTO was associated with reduced incidence rates of kidney and limb complications, and death in patients with NVAF and T2DM vs warfarin.⁶
• A retrospective review of electronic medical records found that diabetic patients on XARELTO had a higher incidence of major bleeding compared with nondiabetics.⁷
• A retrospective, administrative claims database analysis conducted in patients with NVAF and diabetes found that compared with warfarin, XARELTO was associated with nonsignificant 32% and 22% hazard reductions in SSE and ischemic stroke, respectively. No differences in major bleeding were observed between groups.⁸
• In COMPASS (N=27,895):
  • A total of 37.7% (n=10,341) of patients in COMPASS had DM at baseline.^9,10
  • A total of 31.2% (n=8555) of patients in COMPASS were on at least 1 hypoglycemic agent at baseline.¹¹
  • The efficacy and safety of XARELTO plus aspirin vs aspirin alone were consistent in patients with and without DM at baseline.^9,12
• In VOYAGER PAD, 40.0% (n=2629) of patients had DM at baseline.¹³
  • The efficacy and safety of XARELTO plus aspirin vs aspirin alone were consistent in patients with and without DM at baseline.¹⁴
• A post hoc analysis of the COMMANDER-HF study compared the efficacy and safety of low-dose XARELTO in heart failure patients with sinus rhythm and coronary disease with diabetes vs without diabetes. The event rates per 100 person-years (PY) for the primary efficacy outcome (a composite of death, nonfatal myocardial infarction [MI], or nonfatal stroke) were 16.23 vs 11.81 for patients with vs without diabetes (adjusted HR, 1.34; 95% CI, 1.19-1.50). The event rates per 100 PY for the primary safety outcome (a composite of fatal bleeding and bleeding into a critical space with the potential for permanent disability) were 0.47 vs 0.38 for patients with vs without diabetes (adjusted HR, 1.06; 95% CI, 0.56-2.01).¹⁵
• In EINSTEIN DVT/PE (N=8281)¹⁶:
  • A total of 10.2% (n=843) of patients in EINSTEIN DVT/PE had DM at baseline, of whom 415 (10.0%) were in the XARELTO group and 428 (10.4%) were in the enoxaparin/vitamin K antagonist (VKA) group.
  • The efficacy and safety data for this subgroup of patients are not available.
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^17,18-25

CLINICAL STUDIES

NVAF

ROCKET AF Study

The ROCKET AF study was a phase 3, randomized, double-blind, double-dummy, activecontrolled, parallel-group, multicenter, event-driven, noninferiority study designed to evaluate the efficacy and safety of XARELTO 20 mg once daily with the evening meal (15 mg once daily with the evening meal in patients with creatinine clearance 30 to <50 mL/min) to warfarin (international normalized ratio 2.0 to 3.0) for the prevention of stroke and systemic embolism (SE) in patients with NVAF at moderate-to-high risk for stroke.²⁶

Patients were included, but not limited to the following in this study²⁶:

• Documented paroxysmal, persistent, or permanent atrial fibrillation (AF) with moderateto-high risk of stroke
• History of prior stroke, transient ischemic attack (TIA), or SE, or had ≥2 of the following risk factors (CHADS₂ ≥2): heart failure or left ventricular ejection fraction ≤35%; hypertension; age ≥75 years; DM

Bansilal et al (2015)¹ conducted a prespecified subgroup analysis of the ROCKET AF study to compare the efficacy and safety of XARELTO and warfarin in patients with (n=5695; 40%) or without (n=8569, 60%) DM.

• The diagnosis of DM was based either on prior documentation of DM or treatment with glucose-lowering medications.
• The primary efficacy endpoint was the composite of stroke (ischemic or hemorrhagic) and SE. The primary safety endpoint was the composite of both major bleeding and CRNMB.
• After dose adjustments for renal function, 84% and 16% of patients with DM were assigned to XARELTO 20 mg and XARELTO 15 mg, respectively, as compared with 76% and 24% of patients without DM.
• See Table: Efficacy and Safety Endpoints in Diabetic and Nondiabetic Patients.
• In patients with DM randomized to XARELTO or warfarin, primary efficacy outcome rates were similar to those in patients without DM (interaction P=0.53).
• In patients with DM randomized to XARELTO or warfarin, primary safety outcome rates (composite of major and nonmajor clinically relevant bleeding) were similar to those in patients without DM.
• Major bleeding rates in patients with DM randomized to XARELTO or warfarin were similar to those in patients without DM (interaction P=0.43; HR: 0.98; 95% CI: 0.791.21; P=0.84). Nonmajor clinically relevant bleeding rates in patients with DM randomized to XARELTO or warfarin were similar to those in patients without DM (interaction P=0.17).

Chowdhury et al (2022)² conducted a large population-based cohort study using the United Kingdom’s Clinical Practice Research Datalink (CPRD) to evaluate the effectiveness and safety of XARELTO vs apixaban in patients with NVAF and T2DM.

• Adult patients with NVAF and T2DM who were newly initiated on XARELTO or apixaban between January 1, 2013, and March 31, 2020, were included in the study. Patients with a history of valvular surgery or rheumatic valvular disease and hyperthyroidism were excluded. Additionally, patients who were diagnosed with venous thromboembolism (VTE) or underwent hip or knee surgery ≤30 days prior to the cohort entry date (ie, the date of the first XARELTO or apixaban prescription following AF diagnosis) were excluded.
• The primary effectiveness outcome was a composite of hospitalization with incident ischemic stroke (or stroke not otherwise specified), TIA, or SE. The secondary effectiveness outcome included MALEs, a composite of major limb amputation and surgical or endovascular revascularization.
• The safety outcome was major bleeding, defined as any bleeding requiring hospitalization or resulting in death.
• After propensity score weighting, the XARELTO and apixaban groups consisted of 11,695 and 11,561 patients, respectively.²⁷
  • After weighting, all baseline characteristics were well balanced across both groups.
• The median duration of follow-up for the XARELTO and apixaban groups ranged from 300 to 313 and 285 to 293 days, respectively.
• Incidence rates of stroke, major bleeding, and major limb events in the XARELTO and apixaban groups are presented in Table: XARELTO and Apixaban Comparisons.

Coleman et al (2022)³ conducted a subanalysis of a retrospective study (RIVA-DM) that used data from the Optum^® De-Identified electronic health record database from November 2010 to December 2019 to evaluate the impact of age (<80 vs ≥80 years) on the effectiveness and safety of XARELTO vs warfarin in patients with NVAF and T2DM.

• Adult patients with NVAF and T2DM who were newly initiated on XARELTO and warfarin were stratified into 2 subgroups, <80 and ≥80 years.
• The primary outcomes included the incidence rates of developing SSE (effectiveness outcome) and hospitalization due to major or CRNMB (safety outcome).
• Secondary outcomes included the composite of SSE/vascular death, any major bleeding, and MALEs.
• Overall, 32,078 XARELTO and 83,971 warfarin users were identified and included in the main analysis.
  • A total of 25,472 XARELTO and 58,636 warfarin users were <80 years old, and 6606 XARELTO and 25,335 warfarin users were ≥80 years old.
• After propensity score-overlap weighting, the mean (±standard deviation [SD]) age in the <80 and ≥80 years subgroups were 67 (±9) and 83 (±2) years, respectively.
• The mean (±SD) duration of follow-up for XARELTO and warfarin was 2.9 (±1.9) and 2.9 (±2.0) years, respectively.
• Incidence rates of SSE, hospitalization for major or CRNMB are referenced in Table: XARELTO and Warfarin Comparisons in Patients Aged <80 vs ≥80 Years.
• No significant interaction for XARELTO vs warfarin by age was observed for any of the secondary outcomes, including vascular death (HR, 0.90 vs 0.92), MALE (HR, 0.76 vs 0.80), major bleeding (HR, 0.82 vs 0.77), or ICH (HR, 0.75 vs 0.68).

Coleman et al (2021)⁴ conducted a retrospective cohort analysis using Optum^® DeIdentified electronic health record data from November 2010 to December 2019 to evaluate the effectiveness and safety of XARELTO vs warfarin in NVAF patients with T2DM.

• Adult patients with NVAF and comorbid T2DM, who were oral anticoagulant-naïve, newly started on XARELTO or warfarin, and had ≥12 months of prior electronic health record activity, were included in the analysis. Pregnant patients, patients with alternative indications for oral anticoagulation, and those with valvular heart disease were excluded.
• The co-primary outcomes included the incidence rates (%/year) of developing the composite of SSE or vascular death (effectiveness) and major or CRNMB resulting in hospitalization (safety). Individual components of the composite outcomes were also assessed.
• A total of 32,078 XARELTO (31% initiated on 15-mg dose) and 83,971 warfarin users (time-in-therapeutic range = 47 ± 28%) were identified and included in the analysis.
• XARELTO was associated with a reduced risk of SSE or vascular death vs warfarin (3.79 vs 4.19, respectively; HR: 0.91; 95% CI: 0.88-0.95), driven primarily by reductions in vascular death (2.81 vs 3.18, respectively; HR: 0.90; 95% CI: 0.86-0.95) and SE (0.13 vs 0.16, respectively; HR: 0.82; 95% CI: 0.66-1.02).
• Hospitalization for any type of major or CRNMB was less frequent with XARELTO vs warfarin (2.17 vs 2.31, respectively; HR: 0.94; 95% CI: 0.89-0.99) due to decreased critical organ bleeding (including intracranial hemorrhage) (0.35 vs 0.54, respectively; HR: 0.63; 95% CI: 0.55-0.72).

Lip et al (2020)⁵ conducted a retrospective, observational study comparing between newly initiated apixaban, dabigatran, XARELTO, or warfarin in diabetic NVAF patients. The study analyzed data from the diabetes subgroup of the ARISTOPHANES study, 4 United States (US) commercial claims databases, and Centers for Medicare and Medicaid Services data to compare SE and major bleeding among a large NVAF population with diabetes. Patients were selected for analysis between January 01, 2013, to September 30, 2015.

Study Design/Methods

• A total of 154,324 patients were included in the study. Following propensity score matching, the patients were included in 6 matched cohorts, the XARELTO cohorts are referenced in Table: Matched Cohorts.

• Primary outcomes included time to first SSE, including ischemic stroke, hemorrhagic stroke, and SE, and time to first major bleeding, which included gastrointestinal bleeding, intracranial hemorrhage, and bleeding at other key sites.
• Baseline characteristics related to demographic and clinical characteristics were well balanced for the matched populations.

Results

Rates of SSE and major bleeding of XARELTO compared to warfarin are referenced in Table: XARELTO and Warfarin Comparisons.

• Rates of SSE and major bleeding compared across the NOACs and XARELTO are referenced in Table: XARELTO and NOAC Comparisons.

• When compared to warfarin, this study found that apixaban and XARELTO were associated with a lower rate of SSE, whereas apixaban and dabigatran were associated with a lower rate of major bleeding compared to warfarin.

Costa et al (2021)⁶ conducted a study utilizing Optum de-Identified electronic health record data (November 2010 to December 2019) to evaluate the incidence rate of kidney, limb, and/or ophthalmic complications in patients with NVAF and T2DM newly prescribed XARELTO or warfarin.

• Patients >18 years old, diagnosed with both NVAF and T2DM, and had a new prescription for XARELTO or warfarin were included in the study. Patients were excluded if they had previously received XARELTO for an indication other than NVAF, had valvular heart disease, prior oral anticoagulant use, or pregnant. Additional exclusion criteria included estimated glomerular filtration rate (eGFR) <15mL/min/1.73m², a history of dialysis or kidney transplant, previous limb revascularization or amputation or diabetic retinopathy.
• The primary outcome evaluated incidence rate of developing a composite outcome of >40% decrease in eGFR from baseline, eGFR <15mL/min/1.73m², new diagnosis for dialysis or renal transplant, limb revascularization or major amputation, diabetic retinopathy development or all-cause mortality.
• Included in the study were 24,912 XARELTO patients and 58,270 warfarin patients.
• XARELTO was associated with a reduced hazard of the composite outcome (HR: 0.93, 95% CI: 0.91–0.95; absolute risk reduction: 1.97 events per 1000 patient-years; number needed-to-treat: 51) vs warfarin.
• Additionally, XARELTO vs warfarin showed a significant reduction in the relative hazard of >40% decrease in eGFR from baseline (HR: 0.96), need for dialysis or renal transplant (HR: 0.81), and limb revascularization or major amputation (HR: 0.85). Allcause mortality occurred in 10.3/1000 PY fewer XARELTO vs warfarin users (HR: 0.92, 95% CI: 0.89-0.95).

Patel et al (2016)⁷ retrospectively reviewed approximately 10 million electronic medical records from the Department of Defense Healthcare System to evaluate MB-related hospitalizations in 44,793 patients prescribed XARELTO between 1/1/2013 and 6/30/2015 for NVAF.

• A total of 12,039 (26.9%) XARELTO patients concomitantly had DM. Diabetic patients were more likely to be male, younger, and have more comorbidities and higher CHA₂DS₂VASc scores relative to nondiabetics.
• Higher major bleeding rates were observed in diabetic patients compared to nondiabetics (3.68 vs 2.51 per 100 PY), with gastrointestinal bleeding as the most common site. Major bleeding fatality rate occurred in 2.3% in diabetics vs 3.7% in nondiabetics.

Coleman et al (2018)⁸ conducted a retrospective, administrative claims database analysis to assess efficacy and safety of XARELTO vs warfarin in patients with NVAF and diabetes treated in routine practice.  

• Using US Truven MarketScan claims data from November 2011 to December 2016, oral anticoagulant-naïve patients with NVAF and diabetes (type 1 or 2) and ≥12 months of continuous insurance coverage prior to the qualifying oral anticoagulant dispensing (index date) were identified.
• XARELTO users (20 mg or 15 mg once daily) were 1:1 propensity score-matched to warfarin users and were followed until an event, oral anticoagulant switch/discontinuation, insurance disenrollment, or end of follow-up.
  • The standard XARELTO dose was defined as 20 mg. The reduced XARELTO dose was defined as 15 mg.  
• Primary efficacy outcome: combination of SSE, including ischemic stroke, hemorrhagic stroke, or SE; primary safety outcome: MB
• Of the 8424 XARELTO users and 11,348 warfarin users with NVAF and diabetes that were initially identified, 5517 XARELTO users (20% received the reduced 15-mg oncedaily dose) and 5517 warfarin users were matched. Median follow-up was 1.5 years and ~97% had T2DM.
• All baseline covariates evaluated were well balanced after propensity score-matching.
• XARELTO-treated patients experienced nonsignificant reductions in SSE (0.87 vs 1.35/100 PY, respectively; HR: 0.68; 95% CI: 0.44-1.05) and ischemic stroke (0.69 vs 0.93/100 PY, respectively; HR: 0.78; 95% CI: 0.48-1.30) compared with warfarin-treated patients. No differences in overall major bleeding were observed (2.7 vs 3.0/100 PY, respectively; HR: 0.96; 95% CI: 0.74-1.25).
• Results were similar when the analysis was limited to standard-dose XARELTO. Reduced dose XARELTO was associated with a significantly decreased hazard of SSE and ischemic stroke, without an increase in risk of MB.

Coronary Artery Disease and Peripheral Artery Disease

COMPASS Study

COMPASS was a phase 3, event-driven, double-blind, randomized, controlled study that compared treatment with XARELTO (2.5 mg twice daily) plus aspirin (100 mg once daily) vs aspirin alone (100 mg once daily) or XARELTO alone (5 mg twice daily) vs aspirin alone (100 mg once daily) in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD).⁹

• A total of 27,395 patients were enrolled in the study and 37.7% (n=10,341) of patients had DM.
• At baseline, 8555 patients (31.2%) within the COMPASS study were on at least 1 hypoglycemic agent. Of those patients, 2840 had been in the XARELTO-plus-aspirin group, 2829 had been in the XARELTO-alone group, and 2886 had been in the aspirinalone group.¹¹
• Blood glucose levels and hemoglobin A1C (HbA1C) were not systematically collected at baseline.²⁸
• The primary efficacy outcome was the composite of cardiovascular (CV) death, stroke, and MI and the principal safety outcome was modified International Society on Thrombosis and Hemostasis Major Bleeding. Results were consistent when stratified by patients with or without DM at baseline. See Table: Primary Efficacy and Safety Outcomes for the Comparison of XARELTO Plus Aspirin vs Aspirin Alone, Stratified by Baseline DM.^9,12

Connolly et al (2018)²⁹ conducted a prespecified subanalysis of patients in the COMPASS study that had stable CAD. Of the total patients enrolled in the COMPASS study, 24,824 (91%) had CAD.

• In total, 37% of CAD patients had DM. The primary efficacy and safety outcomes were the same as in the overall COMPASS study, which were previously described.
• The effects of XARELTO plus aspirin vs aspirin alone for the primary efficacy and safety outcomes were consistent among subgroups stratified by baseline DM. Results are displayed in Table: Efficacy and Safety Outcomes for the Comparison of XARELTO Plus Aspirin vs Aspirin Alone, Stratified by Baseline DM.

Anand et al (2018)³⁰ conducted a prespecified subanalysis of patients in the COMPASS study that had stable PAD. Of the total patients enrolled in the COMPASS study, 7470 (27%) had a history of PAD at baseline.

• The primary efficacy and safety outcomes were the same as in the overall COMPASS study, which were previously described.
• Several composite outcomes specific to PAD were also evaluated, including major adverse CV events (CV death, stroke, and MI) and MALEs (defined as the development of acute or chronic limb ischemia over the course of study follow-up, including any major amputations due to a vascular event that was not included in acute or chronic limb ischemia).
• DM was reported at baseline in 44% (n=3287) of patients with PAD.
• The effects of XARELTO plus aspirin vs aspirin alone on the combined outcome of major adverse CV events and MALEs including major amputation were consistent in patients with and without DM, as shown in Table: The Composite of Major Adverse CV Events and Major Adverse Limb Events Including Major Amputation, Stratified by DM.

Bhatt et al (2020)³¹ conducted a prespecified subanalysis of patients in the COMPASS study to compare the effects of XARELTO (2.5 mg twice daily) plus aspirin (100 mg daily) vs placebo plus aspirin in patients with diabetes vs without diabetes.

• The primary efficacy and safety outcomes were the same as in the overall COMPASS study, which were previously described.
• Of the total patients enrolled in the COMPASS study, 10,341 patients had diabetes and 17,054 patients did not have diabetes.
• Patients with diabetes were significantly younger (mean age: 67.0 ± 8.2 years) and more likely female (24.4%) vs those without diabetes (mean age: 69.0 ± 7.7 years; female: 20.5%).³²
• A consistent and similar relative risk reduction for benefit of XARELTO plus aspirin (N=9152) vs placebo plus aspirin (N=9126) was observed both in patients with diabetes (N=6922) and without diabetes (N=11,356) for the primary efficacy outcome (HR: 0.74, P=0.002 and HR: 0.77, P=0.005, respectively; P interaction=0.77) and all-cause mortality (HR: 0.81, P=0.05 and HR: 0.84, P=0.09, respectively; P interaction=0.82). See Table: Outcomes in Patients with and without Diabetes for XARELTO Plus Aspirin vs Placebo Plus Aspirin.
• Although patients with diabetes had numerically larger absolute risk reductions compared to those without diabetes, similar benefit was observed among both subgroups (2.3% vs 1.4%, respectively, for the primary efficacy outcome at 3 years, Gail-Simon qualitative P interaction <0.0001; 1.9% vs 0.6%, respectively, for all-cause mortality, P interaction=0.02; 2.7% vs 1.7%, respectively, for major vascular events at 3 years, P interaction <0.0001).
• Similar to the overall COMPASS study, the dual pathway regimen was associated with a significant increase in major bleeding in both subgroups, with a similar degree of risk increase (without diabetes: major bleeding increased at 3 years from 3.2% to 4.4%, HR: 1.69, 95% CI: 1.33-2.15, P<0.0001; with diabetes: major bleeding increased at 3 years from 3.4% to 4.5%, HR: 1.70, 95% CI: 1.25-2.31, P=0.0006, P interaction=0.97). See Table: Outcomes in Patients with and without Diabetes for XARELTO Plus Aspirin vs Placebo Plus Aspirin.
  • As bleeding hazards were similar among patients with and without diabetes, the prespecified net clinical benefit for XARELTO appeared favorable in those with diabetes (2.7% vs 1.0%, respectively: Gail-Simon qualitative P interaction=0.001).

VOYAGER PAD

VOYAGER PAD was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate whether XARELTO 2.5 mg twice daily 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 lower extremity revascularization (LER).¹³

• Patients with poorly controlled diabetes (at the discretion of the investigator) were excluded.¹⁴
• Primary Efficacy Outcome: the composite of acute limb ischemia (ALI), major amputation of vascular etiology, MI, ischemic stroke, or CV death¹³
• Principal Safety Outcome: Major bleeding according to Thrombolysis in Myocardial Infarction (TIMI) classification¹³
• A total of 6,564 patients were enrolled in the study and 40.0% (n=2629) of patients had DM. Of those 2,629 patients, 40.0% (n=1313) had been in the XARELTO-plus-aspirin group and 40.1% (n=1316) had been in the aspirin-alone group.¹³
• Results were stratified by age and are presented in Table: Primary Efficacy and Safety Outcomes for the VOYAGER PAD study, stratified by DM.

Low Wang et al (2021)³³ evaluated the risk profile of critical limb ischemia (CLI) patients with diabetes (n=716) compared to CLI patients without diabetes (n=817) from the VOYAGER PAD study.

• Of the 6564 patients undergoing revascularization in the VOYAGER PAD study, 1533 presented with CLI.
• The HR for the primary outcome at 3 years in CLI patients (all high risk) was 0.85, 95% CI: 0.69-1.05, with higher risk in the patients with diabetes (28.8%) vs patients without diabetes (20.7%).
• The benefit and bleeding risk of XARELTO was consistent regardless of diabetes status in CLI patients.

Sharma et al (2023)¹⁵ conducted a post hoc analysis of the COMMANDER-HF study that compared the efficacy and safety of low-dose XARELTO in heart failure patients with sinus rhythm and coronary disease with diabetes vs without diabetes.

• Of the 5022 patients randomized in the COMMANDER-HF study, 2052 and 2970 were with and without diabetes, respectively.
• The median (interquartile range) age was 66 (59-74) years in both groups; 24.9% vs 21.5% of patients were female with vs without diabetes.
• The primary efficacy outcome was a composite of death, nonfatal MI, or nonfatal stroke. The primary safety outcome was a composite of fatal bleeding and bleeding into a critical space with a potential for permanent disability.
• The event rates per 100 PY for the primary efficacy outcome were 16.23 vs 11.81 for patients with vs without diabetes (adjusted HR, 1.34; 95% CI, 1.19-1.50).
• The event rates per 100 PY for the primary safety outcome were 0.47 vs 0.38 for patients with vs without diabetes (adjusted HR, 1.06; 95% CI, 0.56-2.01).
• The risk of CV death, nonfatal MI, or nonfatal stroke was similar in patients with diabetes (adjusted HR, 1.00; 95% CI, 0.85-1.18) and without diabetes (adjusted HR 0.90; 95% CI, 0.77-1.04; P_interaction=0.32).
• No interaction was found between diabetes and XARELTO treatment with respect to fatal bleeding or bleeding into a critical space with a potential for permanent disability in patients with diabetes (adjusted HR, 0.81; 95% CI, 0.32-2.06) and without diabetes (adjusted HR, 0.76; 95% CI, 0.33-1.74; P_interaction =0.92).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 11 November 2024.