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(rivaroxaban)

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XARELTO® (rivaroxaban)
Medical Information

Use of XARELTO in Peripheral Artery Disease

Last Updated: 07/03/2026

Summary

  • VOYAGER PAD (Vascular Outcomes Study of ASA alonG with Rivaroxaban in Endovascular or Surgical Limb Revascularization for peripheral artery disease [PAD]) 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 cardiovascular (CV) and limb events in patients with symptomatic PAD undergoing lower-extremity revascularization (LER).1
    • The primary efficacy outcome 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%]; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76-0.96; P=0.009) based on Kaplan-Meier (K-M) estimates of the cumulative incidence at 3 years.
    • The principal safety outcome occurred in more patients in the XARELTO-plus-aspirin group vs 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 K-M estimates of the cumulative incidence at 3 years.
    • A prespecified subanalysis of 4379 (66.7%) patients who underwent endovascular revascularization was performed. Compared to the aspirin-alone group, the primary outcome occurred in fewer patients in the XARELTO-plus-aspirin group, but it did not reach statistical significance. A significant reduction in major adverse limb events (MALE) and acute limb ischemia (ALI) occurred in the XARELTO-plus-aspirin group. No heterogeneity was noted with concomitant clopidogrel use or when comparing patients receiving endovascular revascularization to surgically treated patients.2
    • An exploratory analysis of the VOYAGER PAD trial evaluated the net clinical benefit using alternative statistical approaches, including a global rank analysis and win ratio methods. The global rank analysis showed a benefit with XARELTO vs placebo (P=0.0158 for the primary hierarchy and P=0.0155 for the alternative hierarchy; Van Elteren test). In the win ratio analysis, XARELTO “won” 14.8% of pairings, whereas placebo “won” 12.8% of pairings, with ties occurring in 72.4% of the time. In pairwise comparisons, with CV death ranked as the most severe event, XARELTO was superior to placebo, with a win ratio of 1.16 (95% CI, 1.03-1.30; P=0.0167) and a loss ratio of 0.86 (95% CI, 0.77-0.97). At 3 years, cardiovascular death, ischemic stroke, myocardial infarction (MI), ALI, major amputation, or intracranial/fatal bleeding: cumulative incidence at 3 years was 14.1% with XARELTO vs 17.9% with placebo (HR, 0.76; 95% CI, 0.66-0.87; P<0.001; NNT=26). For the net clinical outcome of thrombolysis in myocardial infarction (TIMI) major bleeding, 15.4% of patients receiving XARELTO vs 18.5% of patients receiving placebo experienced events (HR, 0.80; 95% CI, 0.70-0.92; P=0.0012), with an NNT of 32. For the net clinical outcome of primary efficacy endpoints and all-cause death (instead of CV death) and the safety outcome of intracranial/fatal bleeding, cumulative incidence at 3 years was 15.0% with XARELTO vs 19.2% with placebo (HR, 0.75; 95% CI, 0.66-0.86; P<0.001; NNT=24). For the net clinical outcome of primary efficacy outcome including all-cause death and the safety outcome of TIMI major bleeding, 16.3% vs 19.7% of patients experienced events, respectively (HR, 0.79; 95% CI, 0.70-0.90; P<0.001; NNT=29).3
    • A prespecified subanalysis of the VOYAGER PAD trial was conducted to evaluate whether a history of prior LER was associated with increased risk of MACE and MALE and whether the efficacy and safety of XARELTO plus aspirin differed between patients with and without prior LER. For the primary efficacy outcome, the 3-year K-M rate with XARELTO vs placebo was 18.1% vs 23.8% (HR, 0.73; 95% CI, 0.60-0.88; P interaction=0.036) in patients with prior LER and 16.9% vs 17.7% (HR, 0.94; 95% CI, 0.81-1.10) in those without prior LER. For MALE, the 3-year K-M rate with XARELTO vs placebo was 8.7% vs 12.9% (HR, 0.66; 95% CI, 0.51-0.86; P interaction=0.28) in patients with prior LER and 6.5% vs 8.0% (HR, 0.80; 95% CI, 0.63-1.01) in those without prior LER. For ALI, the 3-year K-M rate with XARELTO vs placebo was 6.6% vs 10.8% (HR, 0.59; 95% CI, 0.44-0.80; P interaction=0.29) in patients with prior LER and 4.5% vs 6.0% (HR, 0.74; 95% CI, 0.56-0.98) in those without prior LER. For major adverse cardiovascular events (MACE), the 3-year K-M rate with XARELTO vs placebo was 11.1% vs 13.5% (HR, 0.82; 95% CI, 0.64-1.05; P interaction=0.08) in patients with prior LER and 12.5% vs 11.4% (HR, 1.08; 95% CI, 0.90-1.31) in those without prior LER.4
  • COMPASS (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 twice daily (BID) and aspirin 100 mg once daily or XARELTO 5 mg BID alone is more effective than aspirin 100 mg once daily alone for prevention of MI, stroke, or CV death in 27,395 patients with a history of stable atherosclerotic vascular disease (coronary artery disease [CAD] or PAD).5
    • A prespecified subanalysis of 7470 (~27%) patients with a history of PAD at baseline was conducted. The effects of XARELTO plus aspirin vs aspirin alone on the primary composite outcome of CV death, stroke, or MI and the safety outcome of modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding were consistent with the overall COMPASS study results.6
      • The primary outcome occurred in 126 (5%) of 2492 patients who received XARELTO plus aspirin and in 174 (7%) of 2504 patients who received aspirin alone (HR, 0.72; 95% CI, 0.57-0.90; P=0.0047).
      • The XARELTO plus aspirin group had increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 patients vs 48 [2%] of 2504 patients; HR, 1.61; 95% CI, 1.12-2.31; P=0.0089).
      • MALE were lower in the XARELTO plus aspirin group compared with the aspirin alone group (30 [1%] of 2492 patients vs 56 [2%] of 2504 patients; HR, 0.54; 95% CI, 0.35-0.84, P=0·0054).
      • Major amputations were fewer in the XARELTO plus aspirin group when compared with the aspirin alone group (HR, 0.30; 95% CI, 0.11-0.80).
      • For every 1000 patients treated, 27 MACE or MALE including major amputation would be prevented, and 1 fatal and 1 critical organ bleed would be caused over a 21-month period.
    • Results were consistent in a prespecified subgroup of 6391 (~23%) patients with lower-extremity PAD at baseline. Compared with aspirin alone, the combination of XARELTO 2.5 mg BID plus aspirin reduced the risk of MALE, total vascular amputation, major vascular amputation, and vascular intervention and increased the risk of major bleeding.7
    • Results were consistent in a subset of 4129 (15%) patients with symptomatic lower-extremity PAD. Compared to aspirin alone, the combination of XARELTO 2.5 mg BID plus aspirin reduced the risk of MACE, MALE (including major amputation), or both and increased the risk of major bleeding.8
  • COMPASS LTOLE (Long Term Open Label Extension) was a long-term open-label extension of the COMPASS trial that assessed the safety and efficacy of XARELTO 2.5 mg BID plus aspirin 75 or 100 mg once daily in patients with CAD and/or PAD.9
    • The primary efficacy outcome (composite of stroke, MI, or CV death) occurred in 115 patients with PAD at a rate of 2.85 (95% CI, 2.35-2.42) per 100 patient-years (PY), and in 72 patients with CAD plus PAD at a rate of 2.93 (95% CI, 2.29-3.69) per 100 PY.
  • An analysis was conducted to determine high-risk patients among patients with CAD and/or PAD selected to receive low-dose XARELTO and aspirin in a prospective, postapproval registry study called XATOA (Xarelto plus Acetylsalicylic acid: Treatment Patterns and Outcomes in Patients with Atherosclerosis).10
    • The cumulative incidence risk of primary outcomes (MACE or MALE) was the highest among patients with polyvascular disease at 13.58% over 24 months. The incidence risk was 9.16 per 100 PY in patients with polyvascular disease vs 2.48 per 100 PY in patients without polyvascular disease.
  • A subgroup analysis of the XATOA study was conducted to evaluate the characteristics and clinical outcomes of patients with lower-extremity PAD based on prior LER status, comparing outcomes between patients with prior LER and those without prior LER.11
    • The incidence rate (95% CI) for MACE was 2.55 (1.90-3.34) in patients with prior LER and 2.89 (2.03-4.01) in patients without prior LER and for MALE was 9.06 (7.77-10.50) in patients with prior LER and 4.09 (3.04-5.39) in patients without prior LER.
  • Zeymer et al (2025)12 reported the characteristics and clinical outcomes of patients with CAD with or without PAD in the German XATOA subgroup and compared clinical events with those in the COMPASS CAD subgroup.
    • The incidence of treatment-emergent clinical events in XATOA CAD + PAD (n, %) was as follows: MACE, 35 (3.9); MALE, 63 (7.0); and major bleeding, 13 (1.4). The corresponding incidence in COMPASS CAD (n, %) was as follows: MACE, 347 (4.2); MALE, data not published; and major bleeding, 263 (3.2).
  • Cornejo-Avendaño et al (2026)13 presented XATOA data from Latin America (LATAM), with an incidence rate (95% CI) of 1.72 (0.63-3.75) for MACE, 1.15 (0.31-2.94) for CV death, and 1.15 (0.31-2.95) for MALE.
  • XARELTO is not indicated for the reduction of symptoms related to PAD, such as intermittent claudication. The COMPASS study did not evaluate the efficacy of XARELTO alone or XARELTO in combination with aspirin for the reduction of intermittent claudication symptoms.5
  • A retrospective cohort study was conducted using Merative MarketScan databases to evaluate the effectiveness and safety of low-dose rivaroxaban (LDR) after peripheral vascular intervention (PVI) in insured adult patients with PAD (2017-2024), comparing outcomes between patients receiving LDR and those not receiving XARELTO.14
    • LDR was associated with an HR of 0.66 (95% CI, 0.50-0.87) for major amputation, 0.76 (95% CI, 0.55-1.06) for MALE, and 1.85 (95% CI, 1.24-2.76) for bleeding complications.
  • Additional references identified during the literature search are included in the REFERENCES section for your review.15-29

CLINICAL STUDIES

VOYAGER PAD

VOYAGER PAD 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.1

Study Design/Methods

  • A total of 6,564 patients were recruited from 542 centers in 34 countries between August 2015 and January 2018.
  • Dosing interventions were as follows:
    • XARELTO 2.5 mg BID and aspirin 100 mg once daily
    • Placebo BID and aspirin 100 mg once daily
  • Eligible participants with symptomatic PAD underwent successful revascularization for a lesion distal to the external iliac artery within the last 10 days
  • Patients were stratified according to the type of index procedure underwent (endovascular vs. surgical) and according to clopidogrel use or nonuse within the group of patients who underwent an endovascular procedure
  • Key Inclusion Criteria: Age 50 or older; moderate to severe PAD; abnormal ABI ≤0.80 or toe-brachial index (TBI) ≤0.60 without prior history of limb revascularization; abnormal ABI ≤0.85 or TBI ≤0.65 with prior history of limb revascularization.
  • Key Exclusion Criteria: Patients without functional limitation of the index leg; prior revascularization on the index leg within 10 days of the qualifying revascularization; patients with major tissue loss; patients requiring treatment with aspirin >100 mg; planned DAPT use for >6 months after revascularization procedure
  • The median follow-up period was 28 months.
  • Primary Efficacy Outcome: the composite of ALI, major amputation of vascular etiology, MI, ischemic stroke, or CV death.
  • Principal Safety Outcome: Major bleeding according to TIMI classification.

Results

Baseline Characteristics
  • Median age was 67 years; ~26.0% of patients were female; ~81% of patients were Caucasian.
  • Baseline medical history: 40% had diabetes mellitus; ~20% had an eGFR less than 60 mL/min/1.73m2; ~35.0% were current smokers; ~31.0% had a history of symptomatic CAD; ~11.0% had a MI; median ABI was 0.56; ~6.0% had a prior amputation; ~96.0% had a history of claudication
  • Qualifying revascularization: ~65.0% had an endovascular procedure; ~35.0% treated surgically; ~36.0% had a history of a prior LER
  • Baseline medication: ~80.0% used a statin; ~63.0% were on an angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker
  • Approximately 51% of patients were given clopidogrel at randomization.
Outcomes

For efficacy and safety outcomes, see Tables: Efficacy Outcomes and Safety Outcomes.


Efficacy Outcomesa,1
Outcome
XARELTO
(n=3286)
Placebo
(n=3278)
HR
(95% CI)
P Value
Patients with Event
no. (%)
K-M Estimate at 3 Years
(%)
Patients with Event
no. (%)
K-M Estimate
at 3 Years
(%)
Primary efficacy outcome: ALI, major amputation for vascular causes, MI, ischemic stroke, or death from CV causes
508 (15.5)
17.3
584 (17.8)
19.9
0.85 (0.76-0.96)
0.009
   ALI
155 (4.7)
5.2
227 (6.9)
7.8
0.67 (0.55-0.82)
   Major amputation for
   vascular causes
103 (3.1)
3.4
115 (3.5)
3.9
0.89 (0.68-1.16)
   MI
131 (4.0)
4.6
148 (4.5)
5.2
0.88 (0.70-1.12)
   Ischemic stroke
71 (2.2)
2.7
82 (2.5)
3.0
0.87 (0.63-1.19)
   Death from CV causes
199 (6.1)
7.1
174 (5.3)
6.4
1.14 (0.93-1.40)
Secondary efficacy outcomes
   ALI, major amputation for a
   vascular cause, MI, ischemic
   stroke, or death from
   coronary heart disease
433 (13.2)
14.7
528 (16.1)
18.2
0.80 (0.71-0.91)
<0.001
   Unplanned index-limb
   revascularization for
   recurrent limb Ischemia
584 (17.8)
20.0
655 (20.0)
22.5
0.88 (0.79-0.99)
0.03
   Hospitalization for coronary
   or peripheral event of a
   thrombotic nature
262 (8.0)
8.7
356 (10.9)
12.1
0.72 (0.62-0.85)
<0.001
   ALI, major amputation for a
   vascular cause, MI, ischemic
   stroke, or death from any
   cause
614 (18.7)
20.6
679 (20.7)
23.2
0.89 (0.79-0.99)
0.03
   ALI, major amputation for a
   vascular cause, MI, stroke
   from any cause, or death
   from any cause
514 (15.6)
17.5
588 (17.9)
20.1
0.86 (0.76-0.96)
0.01
   Death from any cause
321 (9.8)
11.1
297 (9.1)
10.9
1.08 (0.92-1.27)
0.34
   Venous thromboembolism
25 (0.8)
0.8
41 (1.3)
1.7
0.61 (0.37-1.00)
Abbreviations: ALI, acute limb ischemia; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; K-M, Kaplan-Meier; MI, myocardial infarction.
aAll efficacy outcomes were analyzed on an intention-to-treat basis.

Safety Outcomesa,1
Outcome
XARELTO
(n=3256)
Placebo
(n=3248)
HR
(95% CI)
P Value
Patients with Event
no. (%)
K-M Estimate at 3 Years
(%)
Patients with Event
no. (%)
K-M Estimate at 3 Years
(%)
Principal safety outcome: TIMI major bleeding
62 (1.90)
2.65
44 (1.35)
1.87
1.43
(0.97-2.10)
0.07
   Intracranial hemorrhage
13 (0.40)
0.60
17 (0.52)
0.90
0.78
(0.38-1.61)
   Fatal bleeding
6 (0.18)
0.21
6 (0.18)
0.21
1.02
(0.33-3.15)
   Intracranial or fatal bleeding
17 (0.52)
0.74
19 (0.58)
0.97
0.91
(0.47-1.76)
Secondary safety outcomes
   BARC major bleedingb
93 (2.86)
3.86
73 (2.25)
2.92
1.29
(0.95-1.76)
0.10
   ISTH major bleeding
140 (4.30)
5.94
100 (3.08)
4.06
1.42
(1.10-1.84)
0.007
Abbreviations: BARC, Bleeding Academic Research Consortium; CI, confidence interval; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; K-M, Kaplan-Meier; TIMI, Thrombolysis in Myocardial Infarction.
aSafety analyses included all patients who underwent randomization and had received at least one dose of trial medication (on-treatment).
bBARC major bleeding is defined as grade 3b or higher.

Subanalysis of VOYAGER PAD2-4
Study Objective
Patients
Outcomes
Rymer et al (2023)2 conducted a subanalysis of a prespecified subgroup of 4379 (66.71%) patients who underwent endovascular revascularization* included in the VOYAGER PAD trial.
*Endovascular revascularization included endovascular-only procedures and those deemed hybrid that included endovascular procedures.
Study Groups
  • XARELTO 2.5 mg BID plus aspirin 100 mg once daily: n=2202.
  • Placebo BID plus aspirin 100 mg once daily: n=2177
Inclusion Criteria
  • Key inclusion criteria were same as VOYAGER PAD and are described in the VOYAGER PAD trial above (see VOYAGER PAD1).

Key Demographics
  • Median age was 67 years, 28.7% were female, 32.4% had CAD, and 68.6% were on clopidogrel at randomization.

PAD Characteristics:
  • 38.7% had a history of previous limb revascularization (35.0% had peripheral PTA and 6.8% had undergone surgical bypass).
  • Of the endovascular procedures, 288 (6.6%) were hybrid procedures.
XARELTO plus Aspirin
(n=2202)
Placebo plus Aspirin
(n=2177)
Patients With Event, n (%)
K-M Rate
at 3 Years,
%
Patients With Event,
n (%)
K-M Rate
at 3 Years,
%
Primary efficacy outcome (acute limb ischemia, major amputation for vascular causes)
309 (14.0)
16.1
342 (15.7)
17.8
HR, 0.89 (95% CI 0.76-1.03); Pa=0.12
No heterogeneity noted between endovascularly and surgically treated patients (P interaction=0.43)
Results consistent regardless of background clopidogrel use (concomitant clopidogrel use, HR 0.86 (95% CI 0.71-1.04); P interaction=0.63)
MALE
100 (4.5)
5.3
142 (6.5)
7.5
HR, 0.70 (95% CI, 0.54-0.90); P=0.005
Acute limb ischemia
75 (3.4)
4.0
114 (5.2)
6.0
HR, 0.65 (95% CI, 0.49-0.87); P=0.004
Major amputation of vascular pathogenesis
40 (1.8)
2.0
48 (2.2)
2.6
HR, 0.83 (95% CI, 0.55-1.27); P=0.39
MACE
234 (10.6)
12.4
224 (10.3)
11.9
HR, 1.04 (95% CI, 0.87-1.25); P=0.68
Safety Outcomes
XARELTO plus Aspirin
(n=2184)
Placebo plus Aspirin
(n=2149)
Patients With Event, n (%)
K-M Rate
at 3 Years %
Patients With Event, n (%)
K-M Rate
at 3 Years %
Primary safety outcome: TIMI major bleeding
51 (2.3)
3.3
31 (1.4)
2.1
HR, 1.66 (95% CI, 1.06-2.59); P=0.02
No heterogeneity noted between endovascularly and surgically treated patients (P interaction=0.17)
Results consistent regardless of background clopidogrel use (concomitant clopidogrel use, HR, 1.4 (95% CI 0.81-2.42); P interaction=0.31)
Hogan et al (2025)3 conducted an exploratory analysis that included 3 alternative analysis methods prespecified in VOYAGER PAD.
Study Groups
  • Overall, 6564 participants were randomized 1:1 to receive XARELTO 2.5 mg BID or placebo, on a background of aspirin 100 mg daily; clopidogrel use was at the physician’s discretion.
Inclusion Criteria
  • Key inclusion criteria were the same as those in VOYAGER PAD and are described in the VOYAGER PAD trial above (see VOYAGER PAD1).

Key Demographics
  • Median age was 67 years; 74% of participants were men, and 82% of participants were White.
  • Treatment groups had similar rates of risk factors (including diabetes, current tobacco use, and non-PAD) and similar PAD-related history and medication regimens.
  • A global rank analysis showed consistent benefit when a predefined ranked hierarchy of outcomes was compared, with cardiovascular death as the worst event; XARELTO was superior to placebo, with P=0.0158  for primary hierarchy and P=0.0155 for alternative hierarchy, based on a Van Elteren test stratified by procedure type and clopidogrel use.
  • In the win ratio analysis
    • XARELTO “won” 14.8% of pairings (i.e., the patient taking placebo experienced the event first [4.4% cardiovascular death events and 10.4% nonfatal events]), whereas placebo “won” 12.8% of pairings (4.9% cardiovascular death events and 7.9% nonfatal events); ties occurred in 72.4% of time.
  • In pairwise comparisons, with cardiovascular death ranked as the most severe event followed by noncardiovascular ischemic events, XARELTO was superior to placebo; the win ratio was 1.16 (95% CI, 1.03-1.30; P=0.0167), and the corresponding loss ratio was 0.86 (95% CI, 0.77-0.97).
Outcomes Measured at 3 Years
XARELTO
Placebo
NNT
Primary net clinical outcome
(cardiovascular death, ischemic stroke, myocardial infarction, acute limb ischemia, major amputation, intracranial/fatal bleeding)
14.1
17.9
26
HR, 0.76; 95% CI, 0.66-0.87; P<0.001
Net clinical outcome including TIMI major bleeding
15.4
18.5
32
HR, 0.80; 95% CI, 0.70-0.92; P=0.0012
Net clinical outcome
(all-cause death [instead of cardiovascular death] + intracranial/fatal bleeding)
15.0
19.2
24
HR, 0.75; 95% CI, 0.66-0.86; P<0.001
Net clinical outcome
(all-cause death + TIMI major bleeding)
16.3
19.7
29
HR, 0.79; 95% CI, 0.70-0.90; P<0.001
  • Correlations of log HR among the primary efficacy endpoint and the 4 net clinical benefit outcomes were highly consistent.
Canonico et al (2026)4 conducted a prespecified analysis to evaluate whether a prior history of LER was associated with a risk of MACE and MALE and to assess whether the efficacy and safety of XARELTO 2.5 mg BID were consistent in patients with vs without prior LER.
Study Groups
  • Overall, 6564 patients were randomized to receive XARELTO 2.5 mg BID plus aspirin or placebo plus aspirin; clopidogrel use (≤6 months) was at the operator’s discretion; the prior LER group comprised 2336 patients, and the no prior LER group comprised 4226 patients.
Inclusion Criteria
  • Key inclusion criteria were the same as those in VOYAGER PAD and are described in the VOYAGER PAD trial above (see VOYAGER PAD1).

Key Demographics
  • Median age (IQR), years, for prior LER vs no prior LER: 67 (61-73) vs 67 (61-73).
  • Female, for prior LER vs no prior LER: 594 (25.4%) vs 1110 (26.2%).
XARELTO
Placebo
HR (95% CI)
P Interaction
K-M Rate at 3 Years, %
K-M Rate at 3 Years, %
Primary efficacy outcome
Prior LER
18.1
23.8
0.73 (0.60-0.88)
0.036
No prior LER
16.9
17.7
0.94 (0.81-1.10)
MALE
Prior LER
8.7
12.9
0.66 (0.51-0.86)
0.28
No prior LER
6.5
8.0
0.80 (0.63-1.01)
Acute limb ischemia
Prior LER
6.6
10.8
0.59 (0.44-0.80)
0.29
No prior LER
4.5
6.0
0.74 (0.56-0.98)
Major amputation
Prior LER
3.7
4.5
0.86 (0.56-1.31)
0.84
No prior LER
3.3
3.4
0.91 (0.65-1.27)
MACE
Prior LER
11.1
13.5
0.82 (0.64-1.05)
0.08
No prior LER
12.5
11.4
1.08 (0.90-1.31)
Myocardial infarction
Prior LER
4.5
6.4
0.74 (0.51-1.07)
0.20
No prior LER
4.6
4.6
1.01 (0.74-1.37)
Ischemic stroke
Prior LER
2.8
2.9
1.02 (0.60-1.72)
0.48
No prior LER
2.6
3.1
0.80 (0.54-1.19)
Cardiovascular death
Prior LER
5.4
6.9
0.87 (0.61-1.23)
0.06
No prior LER
8.1
6.2
1.32 (1.03-1.70)
  • XARELTO reduced total (i.e., first and subsequent) MALE events in the prior LER group (HR, 0.66; 95% CI, 0.50-0.87) compared with the no prior LER group (HR, 0.80; 95% CI, 0.62-1.03); in patients with prior LER, it also reduced unplanned index limb revascularization for recurrent limb ischemia in those with claudication (HR, 0.83; 95% CI, 0.70-0.99) and chronic limb‑threatening ischemia (HR, 0.92; 95% CI, 0.67-1.26; P interaction=0.39).
  • After multivariable adjustment, the relative reduction in the primary efficacy endpoint with XARELTO vs placebo was greater in patients with prior LER (HR, 0.71; 95% CI, 0.60-0.83) than in those with no prior LER (HR, 0.92; 95% CI, 0.81-1.05; P interaction=0.013).
XARELTO
Placebo
HR (95% CI)
P Value
Patients with Event Number
K-M Rate at 3 Years, %
Patients with Event Number
K-M Rate at 3 Years,
%
TIMI major bleeding
Prior LER
26
3.2
24
3.1
1.08
(0.62-1.89)
0.16
No prior LER
36
2.3
20
1.2
1.88
(1.09-3.25)
TIMI minor bleeding
Prior LER
24
2.9
13
1.4
1.83
(0.93-3.60)
0.41
No prior LER
22
1.3
18
1
1.24
(0.67-2.32)
Intracranial or fatal bleeding
Prior LER
6
0.6
9
1.4
0.66
(0.23-1.84)
0.38
No prior LER
11
0.9
10
0.7
1.19
(0.50-2.80)
ISTH major bleeding
Prior LER
65
8
46
5.4
1.41
(0.97-2.06)
0.92
No prior LER
75
4.6
54
3.3
1.44
(1.02-2.05)
BARC type 3B and above bleeding
Prior LER
41
4.7
41
4.7
1.00
(0.65-1.55)
0.09
No prior LER
52
3.3
32
1.9
1.70
(1.09-2.64)
  • XARELTO was associated with a higher risk of ISTH major bleeding irrespective of background clopidogrel use in patients with prior LER and no prior LER.
Abbreviations: BARC, Bleeding Academic Research Consortium; BID, twice daily; CAD, coronary artery disease; CI, confidence interval; HR, hazard ratio; IQR, interquartile range; ISTH, International Society on Thrombosis and Haemostasis; K-M, Kaplan-Meier; LER, lower-extremity revascularization; MACE, major adverse cardiovascular events; MALE, major adverse limb events; NNT, number needed to treat; PAD, peripheral artery disease; PTA, percutaneous transluminal angioplasty; TIMI, Thrombolysis in Myocardial Infarction.
aAll reported P values are 2-sided.

COMPASS

COMPASS was a phase 3, event-driven, double-blind, randomized study designed to evaluate whether treatment with XARELTO 2.5 mg BID and aspirin 100 mg once daily or XARELTO 5 mg BID alone is more effective than aspirin 100 mg once daily alone for prevention of MI, stroke, or CV death in 27,395 patients with a history of stable atherosclerotic vascular disease (CAD or PAD).5

Study Design/Methods

  • A total of 27,395 patients were recruited from 602 centers in 33 countries between February 2013 and May 2016.
  • 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 estimated glomerular filtration rate (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% of New York Heart Association class III or IV symptoms; need for dual antiplatelet therapy (DAPT), other nonaspirin antiplatelet therapy, or oral anticoagulant therapy; eGFR <15 mL/min; systemic treatment with strong inhibitors of both cytochrome P (CYP)3A4 and P-glycoprotein or strong inducers of CYP3A4. Patients with atrial fibrillation (AF) requiring anticoagulation were also excluded.
  • CAD was defined as previous MI or history of angina with multivessel disease, or multivessel revascularization.30
  • Dosing interventions were as follows:
    • XARELTO 2.5 mg BID and aspirin 100 mg once daily
    • XARELTO 5 mg BID and placebo once daily
    • Placebo BID and aspirin 100 mg once daily
  • Patients who were not already receiving a proton pump inhibitor were randomized, using a partial factorial design, to receive 40 mg pantoprazole once daily or placebo for prevention of upper gastrointestinal (GI) complications.
  • Eligible participants (except those who underwent randomization 4 to 14 days after coronary artery bypass graft [CABG] surgery) entered a run-in phase during which they received a XARELTO-matched placebo BID and aspirin at a dose of 100 mg once daily.
  • Primary efficacy outcome: the composite of MI, stroke, or CV death
  • Primary safety outcome (based on modified ISTH criteria): major bleeding, including fatal bleeding, symptomatic bleeding into 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)

Results

Baseline Characteristics
  • Mean age was 68.2 years, 22.0% of patients were female, 90.6% had a history of CAD, and 27.3% had a history of PAD.
  • Vital status was available for 27,331 (99.8%) patients up to February 6, 2017; the mean duration of follow-up for these patients was 21 months (maximum duration of 47 months).2
Efficacy/Safety

Primary Efficacy and Safety Outcomes in Overall COMPASS Patients5
Outcome
XARELTO plus Aspirin
(n=9152)
XARELTO Alone
(n=9117)
Aspirin Alone
(n=9126)
XARELTO plus Aspirin vs Aspirin Alone
XARELTO Alone vs Aspirin Alone
n (%)
HR
(95% CI)
P Value
HR
(95% CI)
P Value
Primary Efficacy Outcome
   MI, stroke, or CV
   deatha
379 (4.1)
448 (4.9)
496 (5.4)
0.76
(0.66-0.86)
<0.001
0.90
(0.79-1.03)
0.12
Primary Safety Outcome
   Major bleeding
288 (3.1)
255 (2.8)
170 (1.9)
1.70
(1.40-2.05)
<0.001
1.51
(1.25-1.84)
<0.001
Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
aP value for the primary efficacy outcome is confirmatory.

Subanalyses of COMPASS6-8
Study Objective
Patients
Outcomesb
Anand et al (2018)6,16 conducted a prespecified subanalysis of 7470 (27.3%) patients in the COMPASS study that had stable PAD at baseline.
Investigated:
Efficacy and safety of XARELTO
Study Groups
  • Aspirin alone (n=2504)
  • Low dose XARELTO plus aspirin (n=2492)
  • XARELTO alone (n=2474)a
Inclusion Criteria
Patients with PAD were required to have 1 of the following:
  • Aortofemoral/limb bypass surgery, PTAR of the iliac or infrainguinal arteries.
  • Limb or foot amputation for AVD
  • Intermittent claudication and ≥1 of either an ABI <0.90 or PAS (≥50%); carotid revascularization or asymptomatic CAS of at least 50%, both diagnosed by angiography or duplex ultrasound.
  • Patients with CAD who had an ABI <0.90 were included in the PAD cohort.

Key Demographics
  • Mean age: 67.8 years
  • 72% were men
  • 74% were current or former smokers.
  • 66% also had a history of CAD.
  • 55% had symptomatic PAD of the lower extremities.
  • 26% had previous carotid revascularization or a carotid stenosis of at least 50%.
  • 4.5% had a previous limb or foot amputation.
XARELTO Plus Aspirin (n=2492)
Aspirin
(n=2504)
Patients With Event
n (%)
Patients With Event
n (%)
Primary efficacy outcome (CV death, Stroke, MI)
126 (5)
174 (7)
HR, 0.72 (95% CI, 0.57-0.90); P=0.0047
Prespecified PAD Outcomec
ALI
19 (1)
34 (1)
HR, 0.56 (95% CI, 0.32-0.99); P=0.042
Chronic limb ischemia
16 (1)
24 (1)
HR, 0.67 (95% CI, 0.35-1.26); P=0.21
MALE
30 (1)
56 (2)
HR, 0.54 (95% CI, 0.35-0.84); P=0.0054
Major amputationd
5 (<1)
17 (1)
HR, 0.30 (95% CI, 0.11-0.80); P=0.011
Primary Safety Outcome
Major bleeding
77 (3)
48 (2)
HR, 1.61 (95% CI, 1.12-2.31); P=0.0089
Prespecified Net Benefit
CV death, MI, stroke, and critical organ or fatal bleeding
140 (6)
185 (7)
HR, 0.75 (95% CI, 0.60-0.94); P=0.011
The effects of XARELTO plus aspirin vs aspirin alone on the combined outcome of MACE and MALE including major amputation were consistent in patients with and without diabetes, patients who were current vs former or never smokers, those with lower-extremity PAD vs other PAD, those who had an ABI <0.90 vs ≥0.90, those with symptomatic PAD vs those with CAD who had an ABI <0.90, and those with and without CAD.
Anand et al (2018)7 conducted a subanalysis of 6391 (23%) patients in the COMPASS study that had lower-extremity PAD at baseline.
Investigated
  • If hospitalizations, MACE, amputations, and deaths are higher following the first episode of MALE compared with patients with PAD who do not experience MALE.
  • Impact of treatment with low dose XARELTO and aspirin compared with aspirin alone on vascular outcomes.

Study Groups
  • XARELTO plus aspirin (n=2139)
  • XARELTO alone (n=2129)a
  • Aspirin alone (n=2123)
Inclusion Criteria
Lower-extremity PAD reported on baseline case record forms as a:
  • History of previous aortofemoral bypass surgery, limb bypass surgery, PTAR of the iliac or infrainguinal arteries.
  • Limb or foot amputation for AVD.
  • Intermittent claudication confirmed by objective measures (evidence of PAD according to ABI, ultrasound, or angiogram).
  • CAD who had an ABI of <0.90 at baseline.

Key Demographics
  • Mean age: 67.6 years
  • 27.9% were women
  • 32% had a history of peripheral revascularization surgery or angioplasty.
  • 5.2% had a history of amputation.
  • 64.9% had a history of CAD.
  • A total of 128 (2.0%) patients experienced MALE
    • Incidence of MALE was 3.8% in patients with PAD and a history of intervention (peripheral revascularization or amputation), 1.37% among those with PAD and intermittent claudication with no prior intervention, and 0.35% among those with asymptomatic PAD (defined as an ABI of <0.90).
  • Following an incident of MALE, the 1-year cumulative risk of a subsequent hospitalization was 61.5%; for total vascular amputations, it was 20.5%; for death, it was 8.3%; and for MACE, it was 3.7%.
  • The MALE index event increased the risk of experiencing subsequent hospitalizations (HR, 7.21; P<0.0001), subsequent total vascular amputations (HR: 197.5; P<0.0001), death (HR, 3.23; P<0.0001), and the composite of MACE or total vascular amputations (HR, 7.56; P<0.0001).
XARELTO Plus Aspirin (n=2139)
Aspirin
(n=2123)
Prespecified PAD Outcomec
n (%)
n (%)
MALE
32 (1.5)
56 (2.6)
HR, 0.57 (95% CI 0.37-0.88); P=0.01
Total vascular amputation
11 (0.5)
26 (1.2)
HR, 0.42 (95% CI 0.21-0.85); P=0.01
Major vascular amputation
5 (0.2)
15 (0.7)
HR, 0.33 (95% CI 0.12-0.92); P=0.03
Vascular interventions
117 (5.5)
150 (7.1)
HR, 0.76 (95% CI 0.60-0.97); P=0.03
Major bleeding
68 (3.2)
42 (2.0)
HR, 1.61 (95% CI 1.09-2.36); P=0.01
Kaplovitch et al (2020)8 conducted a subanalysis of a subset of PAD patients from the COMPASS trial, in 4129 (15%) patients with symptomatic lower-extremity PAD.
Investigated
The efficacy and safety of the combination of low dose XARELTO plus aspirin compared with aspirin alone.
Study groups
  • XARELTO Plus Aspirin (N=1409)
  • Aspirin Alone (N=1359)
Inclusion Criteria
Symptomatic lower-extremity PAD included patients with a history of:
  • Aortofemoral bypass surgery, limb bypass surgery, or PTAR of the iliac or infrainguinal arteries.
  • Limb or foot amputation for AVD
  • Intermittent claudication with an ABI <0.90
  • PAS (>50%)
  • Patients were further classified by symptom severity at baseline utilizing the Fontaine classification and by high-risk limb presentation (incidence risk of MACE or MALE >10% over 30 months) or high-risk comorbidities (polyvascular disease [vascular disease in 2 or more vascular beds]; history of diabetes; history of HF; and kidney insufficiency, defined as eGFR <60 mL/min).

Key Demographics
  • Mean age: 66.8 years
  • 71.0% were men, 31.9% were currently smokers
  • 53.6% had CAD
  • 16.8% had peripheral artery bypass surgery, 29.3% had peripheral percutaneous angioplasty, 41.9% had previous peripheral artery revascularization or surgery, 7.7% had limb or foot amputation, and 71.8% had intermittent claudication.
XARELTO Plus Aspirin
(n=1409)e
Aspirin Alone
(n=1359)e
XARELTO Plus Aspirin vs Aspirin Alone
First Events,
n (%)
30-month K-M incidence risk, %
First Events,
n (%)
30-month K-M incidence risk, %
HR
(95% CI)
MACE
73 (5.2)
6.9
98 (7.2)
10.8
0.71
(0.53-0.97)
MALE, including major amputation
26 (1.8)
2.5
46 (3.4)
4.7
0.55
(0.34-0.88)
MACE or MALE, including major amputation
98 (7.0)
9.2
136 (10.0)
14.6
0.69
(0.53-0.89)
Major Bleeding
46 (3.3)
4.5
26 (1.9)
2.8
1.71
(1.06-2.77)
Fatal or critical organ bleeding
15 (1.1)
1.2
7 (0.5)
0.8
2.06 (0.84-5.05)
Net clinical benefitf
107 (7.6)
9.6
137 (10.1)
14.4
0.75
(0.58-0.96)
  • In patients with high-risk limb presentation, the 30-month K-M incidence risk of MACE or MALE, including amputation was highest among patients with a prior amputation (22.6%, n=54), followed by patients with Fontaine III or IV symptoms (17.6%, n=15), and patients with previous lower limb revascularization (11.8%, n=142).
  • In patients with any high-risk comorbidity, the 30-month K-M incidence risk of MACE or MALE, including amputation, was highest among patients with kidney insufficiency (14.1%, n=118), followed by patients with HF (13.5%, n=67), patients with diabetes (13.4%, n=199), and patients with polyvascular disease (12.8%, n=222).
  • The 30-month K-Meier incidence risk of major bleeding and its subset, fatal or critical organ bleeding was higher among patients with any high-risk limb presentation (1.0% [n=17] and 4.7% [n=67] for fatal or critical organ bleeding and modified ISTH major bleeding, respectively) and in patients with a high-risk comorbidity (1.2% [n=30] and 4.0% [n=92] for fatal or critical organ bleeding and modified ISTH major bleeding, respectively) compared to patients with neither high-risk limb presentation nor high-risk comorbidity (0.4% [n=1] and 2.0% [n=4] for fatal or critical organ bleeding and modified ISTH major bleeding, respectively).
Abbreviations: ABI, ankle-brachial index; ALI, acute limb ischemia; AVD, arterial vascular disease; CAD, coronary artery disease; CAS, carotid artery stenosis; CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; K-M, Kaplan-Meier; MACE, major adverse cardiovascular events; MALE, major adverse limb events; MI, myocardial infarction; PAD, peripheral artery disease; PAS, peripheral artery stenosis; PTAR, percutaneous transluminal angioplasty revascularization.
aSince the primary efficacy was not statistically significant between XARELTO alone and aspirin alone, only including outcomes for XARELTO plus aspirin vs aspirin.
bProvisions to address multiple testing for subgroups, such as PAD, were not specified and therefore any HRs, corresponding CIs, and P values reported for subgroup analyses cannot be interpreted as statistically significant.31
cPrespecified PAD outcome; ALI: limb threatening ischemia with evidence of acute arterial obstruction by radiological criteria or a new pulse deficit leading to an intervention within 30 days of symptoms onset; Chronic limb ischemia: severe limb ischemia leading to a vascular intervention; Major amputation: amputations due to a vascular event above the forefoot; MALE: development of acute or chronic limb ischemia over the course of the study follow-up, including any additional major amputations due to a vascular event that was not included in acute or chronic limb ischemia; Peripheral vascular interventions: interventions (including peripheral angioplasty, vascular surgery, or amputation) not meeting the definition for acute or chronic limb ischemia.
dMajor amputation: amputations due to a vascular event above the forefoot or defined as minor amputation if involving the forefoot and digits.
eIntent-to-treat population.
fNet clinical benefit defined as MACE, MALE (including major amputation), or fatal or critical organ bleeding.

Extension of COMPASS9
Study Objective
Patients
Outcomes
COMPASS LTOLE
Eikelboom et al (2022)9 conducted a LTOLE of the COMPASS trial to assess the efficacy and safety of XARELTO plus aspirin in patients with chronic CAD and/or PAD
Study Groups
  • First cohort: patients enrolled in the LTOLE from the start to the end (n=12,964)
  • Second cohort: patients who were randomized to receive XARELTO 2.5 mg BID in combination with aspirin 75 or 100 mg once daily (n=9152) from the start to the end of randomized treatment, who served as a comparator group
Inclusion Criteria
Patients who completed the follow-up until the end of antithrombotic randomization and who met the inclusion and exclusion criteria of the COMPASS trial.
Key Demographics
  • Mean age: 67.2 years
  • 22.2% were women
  • 90.7% had CAD at baseline
  • 26.4% had PAD at baseline
During LTOLEa
n; Events/100 PY (95% CI)
(n=12,964)
During Randomized Treatmentb
n; Events/100 PY
(95% CI)
(n=9,152)
Efficacy
MI, stroke, or CV death overall
353; 2.35 (2.11-2.61)
379; 2.18 (1.97-2.41)
MI, stroke, or CV death in PAD subgroup
115; 2.85 (2.35-2.42)
126; 2.82 (2.35-3.36)
MI, stroke, or CV death in CAD+PAD subgroup
72; 2.93 (2.29-3.69)
94; 3.06 (2.47-3.75)
Safety
Major bleeding per modified ISTH
152; 1.01 (0.86-1.19)
288; 1.67 (1.48-1.87)
Fatal
9; 0.06 (0.03-0.11)
15; 0.09 (0.05-0.14)
Critical organ bleeding (non-fatal)
40; 0.27 (0.19-0.36)
73; 0.42 (0.33-0.52)
Requiring reoperation (non-fatal and non-critical organ)
12; <0.1 (0.04-0.14)
15; 0.09 (0.05-0.14)
Hospitalization (non-fatal, for non-critical organ, not leading to reoperation)
90; 0.60 (0.48-0.73)
259; 1.50 (1.32-1.69)
Abbreviations: BID, twice daily; CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; ISTH, International Society on Thrombosis and Haemostasis; LTOLE, long-term open-label extension; MI, myocardial infarction; PAD, peripheral artery disease; PY, patient-years.
aEvents/100 PY: Incidence rate estimated as number of patients with incident events divided by the cumulative at-risk time in the reference population, where a patient is no longer at risk once an incident event has occurred.
bPatients randomized to the combination of XARELTO and aspirin are also included in the LTOLE population.

Subanalysis of XATOA Registry Study10-13
Study objectives
Patients
Outcomes
Anand et al (2024)10 conducted an analysis to determine highest risk patients among patients with CAD and/or PAD selected to receive low-dose XARELTO and aspirin in a prospective postapproval XATOA (Xarelto plus Acetylsalicylic acid: Treatment Patterns and Outcomes in Patients with Atherosclerosis) registry study.
Study Groups
  • Patients taking XARELTO 2.5 mg BID plus aspirin within 4 weeks before study enrollment (n=5532).
Inclusion Criteria
  • Patients with a diagnosis of CAD, PAD, or both

Key Demographics
  • Mean age: 68 years
  • 74.46% were men
  • 72.7% had CAD, 58.9% had PAD, and 31.6% had both.
  • Patients with polyvascular disease (>2 vascular beds affected); (n=2889) and patients with no polyvascular disease (n=2643).
  • The cumulative incidence risk for MACE or MALEa was the highest among patients with polyvascular disease at 13.58% over 24 months. The incidence risk was 9.16 per 100 PY in patients with polyvascular disease vs 2.48 per 100 PY in patients without polyvascular disease.
  • The high-risk COMPASS-identified sub-groups that included patients with polyvascular disease, history of diabetes, HF, chronic renal insufficiency, or with age >75 years had a higher incidence of MACE and MALE.
  • The cumulative incidence of major bleedingb over 2 years was 1.62% with an incidence rate of 0.95 (95% CI, 0.70-1.21) per 100 PY. There was a higher incidence rate of major bleeding in patients with polyvascular disease compared with patients without polyvascular disease 1.40 (95% CI, 1.03-1.86) vs 0.49 (95% CI, 0.28-0.79) per 100 PY, respectively.
Debus et al (2024)11
performed a subgroup analysis of XATOA to evaluate the characteristics and clinical outcomes of patients with lower-extremity PAD based on prior LER history, and the results were compared with those reported in COMPASS and VOYAGER PAD for symptomatic lower-extremity PAD.
Study Groups
  • Of 5532 XATOA patients receiving XARELTO 2.5 mg BID plus aspirin within 4 weeks before enrollment, 1736 (61.6%) had lower-extremity PAD with prior LER and 1084 (38.4%) had lower-extremity PAD without prior LER.
Inclusion Criteria
  • Patients ≥18 years with CAD, PAD, or both

Key Demographics
  • Lower-extremity PAD with prior LER (n=1736): mean±SD age, 68.2±9.0 years; female, 446 (25.7%)
  • Lower-extremity PAD without prior LER (n=1084): mean±SD age, 69.1±9.2 years; female, 305 (28.1%)
Clinical Outcome
Lower-Extremity PAD With Prior LER
Lower-Extremity PAD Without Prior LER
Incidence Rate (95% CI)
MACE
2.55 (1.90-3.34)
2.89 (2.03-4.01)
MI
1.03 (0.63-1.57)
0.80 (0.38-1.48)
Stroke
0.59 (0.30-1.03)
0.72 (0.33-1.37)
CV death
1.12 (0.71-1.68)
1.6 (0.98-2.47)
MALE
9.06 (7.77-10.50)
4.09 (3.04-5.39)
ALI
3.93 (3.11-4.89)
1.54 (0.92-2.40)
CLI
5.46 (4.48-6.59)
2.76 (1.91-3.85)
Amputationc
0.29 (0.11-0.64)
0.16 (0.02-0.58)
TIA
0.20 (0.05-0.50)
0.24 (0.05-0.70)
Major bleedingd
1.17 (0.75-1.74)
1.49 (0.90-2.33)
Nonmajor bleeding
4.87 (3.95-5.93)
5.26 (4.06-6.71)
Zeymer et al (2025)12 reported characteristics and clinical outcomes of patients with CAD with or without PAD in the German XATOA subgroup (n=1641), comparing clinical events (MACE) and safety outcomes (major bleeding) with the those of the COMPASS CAD subgroup.
Study Groups
  • German XATOA subgroup: 2780 enrolled; patients received XARELTO 2.5 mg BID plus aspirin once daily; FAS, n=2566; SAS, n=2604
Inclusion Criteria
  • Patients ≥18 years with chronic CAD, PAD, or both

Key Demographics
  • Mean observation period in the FAS population: 477.4±209.3 days (maximum, 890 days)
  • FAS population: CAD, n=1641 (63.9%); PAD, n=1819 (70.8%)
  • Among German XATOA patients: CAD only, n=747 (29.1%); CAD + PAD, n=894 (34.8%); PAD only, n=925 (36.0%)
  • CAD + PAD (n=894): mean±SD age, 69.8±8.53 years; female, n=184 (20.6%)
Clinical Event, n (%)
XATOA CAD + PAD
(n=894)
COMPASS CAD
(n=8313)
MACE
35 (3.9)
347 (4.2)
MI
19 (2.1)
169 (2.0)
Stroke
5 (0.6)
74 (0.9)
TIA
4 (0.4)
No data published
CV death
15 (1.7)
139 (1.7)
Major bleedinge
13 (1.4)
263 (3.2)
MALE
63 (7.0)
No data published
Acute/severe limb ischemia
20 (2.2)
13 (0.2)
CLI
44 (4.9)
No data published
Peripheral artery ischemia (excluding MALE and TIA)
11 (1.2)
No data published
Interventions during follow-up
   PCI
40 (4.5)
No data published
   CABG
4 (0.4)
No data published
   Peripheral arterial intervention
100 (11.2)
No data published
   Lower-extremity amputation
6 (0.7)
No data published
   Carotid intervention
8 (0.9)
No data published
   Cerebrovascular intervention
3 (0.3)
No data published
   Other
48 (5.4)
No data published
Cornejo-Avendaño et al (2026)13 presented XATOA data from LATAM.
Study Groups
  • Patients receiving at least 1 dose of DPI with XARELTO 2.5 mg BID and aspirin within 4 weeks before enrollment (n=317)
Inclusion Criteria
  • Patients ≥18 years with chronic CAD, PAD, or both

Key Demographics
  • XATOA LATAM (n=311; 5.6%): mean±SD age, 67.74±11.63 years; female, n=92 (29.6%)
  • CAD only: n=185 (59.5%); CAD + PAD: n=46 (14.8%); PAD only: n=80 (25.7%)
  • Mean observation period in the complete analysis set (n=311): 445.2±145.7 days; 82.9% (n=258) of patients followed for >12 months
  • In the XATOA LATAM population, aspirin only was the most common pre-enrollment antithrombotic therapy (45% vs 70.7% in the overall XATOA population), with 51.9% use in CAD and 29.4% use in PAD.
  • DPI initiated due to existing/worsening/new risk characteristics, 74.9% (vs 85.9% overall); CAD, 68.0%; PAD, 88.1%
  • High CV risk as reason for DPI initiation, 54.0% (vs 70.7% overall); CAD, 49.4%; PAD, 61.9%.
  • Mean treatment duration: XARELTO, 433.5±164.1 days; aspirin, 442.2±151.1 days.
  • Permanent discontinuation: XARELTO, n=49 (15.8%); aspirin, n=10 (3.2%)
Outcome
Incidence Rate (95% CI), per 100 patient-years
MACE
1.72 (0.63-3.75)
CV death
1.15 (0.31-2.94)
MALE
1.15 (0.31-2.95)
ALI/severe limb ischemia
0.57 (0.07-2.07)
ISTH major bleeding
Not reported
Nonmajor bleeding
5.42 (3.27-8.47)
  • During follow-up, 13 of 311 patients (4.2%) in the XATOA LATAM population died, compared with 2.7% in the overall XATOA population.
  • Treatment-emergent adverse events (XARELTO-related), n=20 (6.4%); serious adverse events, n=1 (0.3%); all-cause fatal adverse events, n=11 (3.5%); COVID-19 events, n=12 (3.9%).
Abbreviations: ALI, acute limb ischemia; BID, twice daily; CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; CLI, chronic limb ischemia; COVID-19, coronavirus disease 2019; CV, cardiovascular; DPI, dual pathway inhibitioR; FAS, full analysis set; HF, heart failure; ISTH, International Society on Thrombosis and Haemostasis; LATAM, Latin America; LER, lower-extremity revascularization; MACE, major adverse cardiovascular events; MALE, major adverse limb events; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; PY, patient-years; SAS, safety analysis set; TIA, transient ischemic attack.
aMACE, defined as the composite of MI, stroke, and CV death; MALE, defined as the composite of ALI, chronic limb ischemia, or amputation above the forefoot due to a vascular cause.
bMajor bleeding events were defined by ISTH.
cAmputation was defined as amputation above the forefoot due to a vascular cause.
dBleeding rates are shown for SAS (LER, n=1757; no LER, n=1113).
eSAS.

Real-world Evidence Section14
Study Objective
Patients
Outcomes
Schurman et al (2026)14 conducted a retrospective cohort study using the Merative MarketScan Commercial and Medicare Supplemental databases to identify insured adult patients aged 40 to 90 years with PAD who underwent an index PVI between 2017 and 2024.
Study Groups
  • N=88,792: LDR, n=1285; no XARELTO, n=87,507
Inclusion Criteria
  • Patients who underwent PVI for claudication and CLTI, defined as rest pain, gangrene, or lower limb ulceration

Key Demographics
  • LDR (n=1285): age, 64 (59-74) years; male, 784 (61.01%)
  • No XARELTO (n=87,507): age, 65 (59-75) years; male, 54,604 (62.4%)
Variable
No XARELTO
(n=87,507)
LDR
(n=1285)
P Value
Indication for revascularization, n (%)
   CLTI
9502 (10.9)
136 (10.6)
0.788
   Claudication
78,005 (89.1)
1149 (89.4)
Target arterial lesion segment, n (%)
   Aorto-iliac
29,175 (33.3)
285 (22.2)
<0.001
   Femoropopliteal
35,575 (40.7)
524 (40.8)
   Tibial
22,757 (26.0)
476 (37.0)
Outcome
LDR Use
HR (95% CI)
P Value
Major amputation
No XARELTO
Ref
-
Any LDR use
0.66 (0.5-0.87)
0.004
LDR adherence
0.30 (0.10-0.91)
0.033
LDR nonadherence
0.91 (0.72-1.14)
0.402
MALE
No XARELTO
Ref
-
Any LDR use
0.76 (0.55-1.06)
0.11
LDR adherence
0.38 (0.13-1.12)
0.08
LDR nonadherence
1.02 (0.83-1.26)
0.862
Bleeding complications
No XARELTO
Ref
-
Any LDR use
1.85 (1.24-2.76)
0.002
LDR adherence
1.65 (1.08-2.53)
0.021
LDR nonadherence
2.00 (1.52-2.63)
<0.001
  • After propensity-score adjustment, SMDs for all comorbidities and procedure variables between patients prescribed LDR and those not on therapy were <0.1, resulting in a matched cohort with a similar risk profile.
  • The 1-year major amputation rate was similar in the LDR vs no-LDR group (2.8% vs 3.6%; P=0.159); however, patients’ adherent to LDR (>80% of days) showed a lower 1-year major amputation rate.
  • Reinterventions (LDR vs no-LDR: 1.0% vs 0.7%; P=0.303) and MALE (LDR vs no-LDR: 3.6% vs 4.2%; P=0.311) were comparable between the groups; LDR adherence (>80%) was associated with a lower MALE rate.
  • Patients receiving both LDR and P2Y12 inhibitors had a 68% lower likelihood of MALE (HR, 0.32; 95% CI, 0.10-1.02; P=0.054) compared with those on neither therapy.
  • Any bleeding complications within 1st year following revascularization were higher in the LDR vs no-LDR group (20.3% vs 11.2%; P<0.001); major bleeding complication (ISTH) occurred in 1.01% vs 0.53% of patients in the LDR vs no-LDR group (P=0.034).
  • Patients’ adherent to LDR (>80% of days) showed similar 1-year rates of bleeding complications to nonadherent patients; rates in adherent and nonadherent patients were higher than those in patients not prescribed LDR.
  • Patients receiving both LDR and a P2Y12 inhibitor were associated with a higher likelihood of bleeding (HR, 2.21; 95% CI, 1.17-4.19; P=0.015) compared with those receiving LDR monotherapy (HR, 1.85; 95% CI, 0.95-3.59) or P2Y12 inhibitor monotherapy (HR, 1.17; 95% CI, 0.80-1.70), relative to patients receiving neither therapy.
Abbreviations: CI, confidence interval; CLTI, chronic limb-threatening ischemia; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; LDR, low-dose rivaroxaban; MALE, major adverse limb events; PAD, peripheral artery disease; PVI, peripheral vascular intervention; Ref, reference; SMD, standardized mean difference.

LITERATURE SEARCH

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 15 June 2026.

References

Show
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