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Concomitant Use of XARELTO With Aspirin

Last Updated: 05/30/2023

Summary

  • Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin (ASA), P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.1
  • ROCKET AF trial: ASA use at doses of >100 mg per day was excluded from the trial.2 A subgroup analysis investigating the relationship between baseline ASA use and clinical outcomes showed that there were no significant differences in treatment effect for XARELTO or warfarin between patients with and without baseline ASA use for any efficacy or safety outcomes.3
  • EINSTEIN program: Patients were allowed to take ASA (up to 100 mg per day), if indicated.4, 5 Approximately 14% of patients in the safety population took ASA. A subanalysis demonstrated a hazard ratio (HR) of 1.81 (1.36-2.41) for XARELTO and 1.59 (1.17-2.17) for the enoxaparin-vitamin K antagonist (VKA) group for clinically relevant bleeding events in patients with and without concomitant ASA use. For major bleeding events, the subanalysis demonstrated a HR of 1.50 (0.63-3.61) for XARELTO and 1.50 (0.74-3.05) for the enoxaparin-VKA group in patients with and without concomitant ASA use.6
  • RECORD program: In patients taking platelet function inhibitors (PFIs) or ASA over the total at-risk period, the analysis of pooled data from RECORD 1-4 studies demonstrated similar relative rate ratios for any bleeding events (XARELTO 1.32, 95% confidence interval [CI]: 0.85-2.05; enoxaparin 1.40, 95% CI, 0.87-2.25), and similar relative rate ratios of major and nonmajor clinically relevant (NMCR) bleeding events (XARELTO 1.11, 95% CI, 0.55-2.55; enoxaparin 1.13, 95% CI, 0.47-2.75) between the XARELTO and enoxaparin groups, respectively.7
  • COMPASS: Patients in the COMPASS study received enteric-coated ASA at a dose of 100 mg daily. The primary outcome of the composite of cardiovascular (CV) death, myocardial infarction (MI) and stroke occurred in fewer patients in the XARELTOplusASA group than in the ASA-alone group (379 patients [4.1%] vs 496 patients [5.4%]; HR, 0.76; 95% CI, 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the XARELTO-plus-ASA group (288 patients [3.1%] vs 170 patients [1.9%]; HR, 1.70; 95% CI, 1.40 to 2.05; P<0.001).8
    • A sub-analysis of the COMPASS trial compared the efficacy and safety outcomes of XARELTO plus ASA with those of ASA alone between Asian and non-Asian patients with chronic coronary artery disease (CAD)/ peripheral artery disease (PAD). The primary efficacy composite of MI, stroke, or CV death was less common with XARELTO + ASA vs ASA alone in the Asian (risk reduction, 36%; HR, 0.64; 95% CI, 0.45-0.90) and non-Asian (risk reduction, 22%; HR, 0.78; 95% CI, 0.67-0.90) groups, respectively [P (for interaction) =0.29]. Major bleeding was more common with XARELTO plus ASA vs ASA alone in the Asian (>2-fold; HR, 2.24; 95% CI, 1.40–3.58) and non-Asian (1.6-fold; HR:1.60; 95% CI: 1.30–1.97) groups, respectively [P (heterogeneity) =0.20].9
  • VOYAGER PAD: Based on Kaplan-Meier estimates of the cumulative incidence at 3 years, the primary composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or CV death occurred in fewer patients in the XARELTO plus ASA group than in the ASA alone group (508 patients [17.3%] vs 584 patients [19.9%]; HR, 0.85; 95% CI, 0.76-0.96; P=0.009), but major bleeding events occurred in more patients in the XARELTO plus ASA group than in the ASA alone group (62 patients [2.65%] vs 44 patients [1.87%]; HR, 1.43; 95% CI, 0.97-2.10; P=0.07).10
  • A randomized, nonblinded, 2-way crossover, drug-drug interaction study demonstrated that there was no clinically relevant interaction between XARELTO 15 mg once daily and ASA (loading dose of 500 mg followed by a maintenance dose of 100 mg once daily) and that the two drugs could be administered concomitantly at the doses used in the study.11
  • A registry-based cohort study of adult patients with nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE) who were started on a direct oral anticoagulant therapy (DOAC) at 4 medical centers in Michigan, showed that patients receiving concomitant ASA therapy had increased bleeding events (31.6 vs. 26.0 bleeds per 100 patient years, P=0.01), and hospitalizations (9.1 versus 6.5 admissions per 100 patient years, P=0.02), compared to those receiving DOAC monotherapy. Thrombosis rates between both groups were similar (2.5 vs. 2.3 per 100 patient years, P=0.80).12
  • An additional citation identified during a literature search is included in the REFERENCES section for your review.13

CLINICAL STUDIES

Stroke Prevention in NVAF

The ROCKET-AF trial was a phase 3, double-blind, double-dummy, parallel-group, eventdriven, noninferiority study to evaluate the efficacy and safety of oral XARELTO 20 mg once daily (15 mg for patients with creatinine clearance 30-49 ml/min) and doseadjusted warfarin (target international normalized ratio: 2.0-3.0) for the prevention of stroke and systemic embolism in patients with NVAF at moderate-to-high risk for stroke.2

  • In ROCKET AF, ASA use at doses of >100 mg per day was excluded from the trial.2

Shah et al (2016)3 conducted a subgroup analysis of patients who received ASA at baseline in the ROCKET AF study in order to investigate the relationship between ASA use and clinical outcomes, particularly in those with CAD.

  • The intention-to-treat population was used for analysis of efficacy endpoints and the ontreatment population was used for analysis of safety endpoints.
  • Primary efficacy endpoint: stroke or noncentral nervous system embolism; Secondary efficacy endpoints: MI, vascular death, and all-cause death; Primary safety endpoint: major or NMCR bleeding; Secondary safety endpoints: major fatal bleeding, intracranial hemorrhage, and hemorrhagic stroke.
  • Of the 14,264 patients in ROCKET AF, 5205 (36.5%) reported taking ASA at baseline (mean daily dose of 99.2 mg; 30.6% had known CAD). Of the 5205 patients who were on ASA at baseline, 2742 (53%) reported taking ASA during follow-up and 2083 (40%) patients were still taking ASA at the end of the study.
  • Those receiving ASA at baseline had significantly higher rates of prior MI (22% vs 14%; P<0.0001) and congestive heart failure (68% vs 59%; P<0.0001).
  • Significant differences in treatment effect for XARELTO or warfarin were not observed between patients with and without baseline ASA use for any of the efficacy or safety outcomes, including stroke/systemic embolism (P=0.95 for interaction) and major or NMCR bleeding (P=0.76 for interaction). See Table: ROCKET-AF: Efficacy and Safety Endpoints by Baseline ASA Use and Treatment.
  • A significant interaction was observed between treatment and continued ASA use for allcause death. The lower rates of all-cause death observed in patients treated with XARELTO vs warfarin were more pronounced in those with continued ASA use vs those without continued ASA use (P=0.043).

ROCKET-AF: Efficacy and Safety Endpoints by Baseline ASA Use and Treatment3,a
Endpoints
Baseline ASA Use
No Baseline ASA Use
P-value for Interaction of Baseline ASA and Treatment
XARELTO
Warfarin
XARELTO vs Warfarin Adjusted HR
(95% CI)

XARELTO
Warfarin
XARELTO vs Warfarin Adjusted HR
(95% CI)

Efficacy Endpoints
Stroke or SE
2.34
2.71
0.88 (0.68-‍1.14)
2.00
2.26
0.89 (0.72-‍1.10)
0.95
Stroke/SE/
vascular death

5.15
5.80
0.90 (0.75-‍1.08)
4.16
4.28
0.98 (0.84-‍1.14)
0.48
All-cause death
5.14
6.19
0.83 (0.70-‍0.99)
4.18
4.21
0.99 (0.86-‍1.15)
0.13
Vascular death
3.56
3.95
0.91 (0.74-‍1.13)
2.56
2.66
0.97 (0.80-‍1.17)
0.67
Stroke
2.23
2.52
0.89 (0.68-‍1.17)
1.86
2.05
0.91 (0.73-‍1.14)
0.91
SE
0.15
0.22
0.73 (0.28-‍1.91)
0.16
0.20
0.77 (0.37-‍1.59)
0.93
MI
1.37
1.24
1.14 (0.80-‍1.64)
0.82
1.04
0.80 (0.58-‍1.10)
0.15
Safety Endpoints
Major or NMCR bleeding
16.80
16.37
1.06 (0.95-‍1.19)
13.93
13.56
1.04 (0.95-‍1.14)
0.76
Major bleeding
4.52
4.12
1.14 (0.92-‍1.42)
3.11
3.11
1.02 (0.85-‍1.23)
0.45
Major bleeding -ICH
0.49
0.92
0.54 (0.31-‍0.95)
0.49
0.65
0.77 (0.50-‍1.19)
0.33
Major bleeding - fatal
0.26
0.61
0.43 (0.20-‍0.89)
0.23
0.42
0.56 (0.31-‍1.02)
0.57
Hemorrhagic stroke
0.29
0.59
0.49 (0.24-‍1.01)
0.25
0.37
0.68 (0.38-‍1.24)
0.50
Abbreviations: ASA, aspirin; CI, confidence interval; HR, hazard ratio; ICH; intracranial hemorrhage; MI, myocardial infarction; NMCR, nonmajor clinically relevant bleeding; SE, systemic embolism.
aData presented as events per 100 patient-years.

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE

The EINSTEIN program consisted of 3 randomized trials:

  1. Acute DVT Study (EINSTEIN-DVT) - Phase 3, open-label, event-driven, noninferiority trial that compared oral XARELTO alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin (1.0 mg/kg twice daily) followed by doseadjusted oral VKA (warfarin or acenocoumarol) in patients with confirmed symptomatic DVT without symptomatic PE.4
  2. Acute PE Study (EINSTEIN-PE) - Phase 3, open-label, event-driven, noninferiority study evaluating the efficacy and safety of oral XARELTO (15 mg twice daily for 3 weeks followed by 20 mg once daily) vs subcutaneous enoxaparin (1.0 mg/kg twice daily) followed by dose-adjusted oral VKA in patients with acute symptomatic PE with or without DVT.5
  3. Continued Treatment Study (EINSTEIN-Extension) - Phase 3, double-blind, eventdriven superiority study comparing XARELTO 20 mg once daily to placebo in patients with confirmed symptomatic PE or DVT who have been treated for 6-12 months with XARELTO or VKA.4

In the EINSTEIN program, patients were allowed to take ASA (up to 100 mg per day), if indicated. Use of antiplatelet agents were discouraged in this trial.4, 5

Davidson et al (2014)6 conducted a subanalysis of the EINSTEIN-DVT and EINSTEIN-PE studies to determine the incidence of major and all clinically relevant bleeding in patients treated with XARELTO or enoxaparin-VKA and exposed to NSAIDs or ASA.


EINSTEIN-DVT and EINSTEIN-PE: Incidence of Clinically Relevant Bleedinga With or Without Concomitant Use of ASA6
 
XARELTO
Enoxaparin-VKA
Events
Pt-y
Event/100 Pt-y
Events
Pt-y
Events/100 Pt-y
ASA +
57
163.5
34.9
47
120.1
39.1
ASA -
331
2058.9
16.1
365
2050.2
17.8
 
HR, 1.81 (95% CI, 1.36-2.41)
HR, 1.59 (95% CI, 1.17-2.17)
Abbreviations: ASA, aspirin; CI, confidence interval; HR, hazard ratio; pt-y, patient-years; VKA, vitamin K antagonist.
aClinically relevant bleeding was defined as bleeding that was not major but associated with medical intervention, an unscheduled contact with a physician, temporary cessation of study treatment, or discomfort for the patient such as pain or impairment of activities of daily living.


EINSTEIN-DVT and EINSTEIN-PE: Incidence of Major Bleedinga With or Without Concomitant Use of ASA6
 
XARELTO
Enoxaparin-VKA
Events
Pt-y
Events/100 Pt-y
Events
Pt-y
Events/100 Pt-y
ASA +
6
179.9
3.3
9
129.6
6.9
ASA -
34
2181.0
1.6
63
2172.6
2.9
 
HR, 1.50 (95% CI, 0.63-3.61)
HR, 1.50 (95% CI, 0.74-3.05)
Abbreviations: ASA, aspirin; CI, confidence interval; HR, hazard ratio; pt-y, patient-years; VKA, vitamin K antagonist.
aMajor bleeding was defined as bleeding that was fatal, occurred at a critical site, or were associated with a decrease in hemoglobin of more than 2 g/dL and/or the need for transfusion of 2 or more units of red blood cells.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

RECORD Program

The RECORD clinical trial program consisted of 4 double-blind, double-dummy, multinational studies that compared efficacy and safety of oral XARELTO 10 mg once daily and subcutaneous enoxaparin 40 mg once daily (RECORD 1-3) or 30 mg twice daily (RECORD 4) for VTE prevention in patients undergoing total hip replacement or total knee replacement.14-17

Eriksson et al (2012)7 analyzed the pooled data from the RECORD 1-4 studies to evaluate the safety of concomitant use of NSAIDs and PFI, including ASA, in patients receiving either XARELTO or enoxaparin after total hip or knee arthroplasty.

  • The safety endpoints evaluated in this study were the composite of major and NMCR bleeding occurring after the first postoperative oral study drug intake. Events were followed from the day of surgery until 2 days after the last intake of study drug, which was considered the at-risk period.
  • Over 9% of patients in both groups concomitantly used PFIs or ASA at least once.
  • For patients receiving PFIs or ASA, the ratios for any bleeding events over the total at-risk period were similar between groups (XARELTO 1.32, 95% CI, 0.85-2.05; enoxaparin 1.40, 95% CI, 0.87-2.25). The ratios of major and NMCR bleeding events in patients taking PFIs and ASA were also similar between XARELTO- and enoxaparintreated patients (XARELTO 1.11, 95% CI, 0.55-2.55; enoxaparin 1.13, 95% CI, 0.47-2.75) over the total at-risk period.

Coronary Artery Disease or Peripheral Artery Disease

COMPASS8, 9, 18

COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) was a phase 3, event-driven, double-blind, randomized, controlled study designed to evaluate whether treatment with XARELTO and ASA versus ASA alone or XARELTO alone versus ASA alone is more effective for prevention of MI, stroke, or CV death in patients with stable CAD or PAD.

  • Dosing interventions were as follows:
    • XARELTO 2.5 mg twice daily + ASA 100 mg once daily
    • XARELTO 5 mg twice daily + placebo once daily
    • Placebo twice daily + ASA 100 mg once daily
  • Patients in the COMPASS study received enteric-coated ASA at a dose of 100 mg daily.8
  • There are no specific recommendations on when ASA should be taken. The once daily dose was generally taken in the morning.8, 19
  • The primary objective of the COMPASS trial was to determine whether XARELTO 2.5 mg twice daily + ASA 100 mg once daily compared with ASA 100 mg once daily reduces the risk of the composite of MI, stroke, or CV death in patients with stable atherosclerotic vascular disease, and similarly for XARELTO 5 mg twice daily compared with ASA 100 mg once daily.
  • For primary efficacy and safety outcomes, see Tables: Primary Efficacy Outcome in the COMPASS Trial and Safety Outcomes in the COMPASS Trial.

Primary Efficacy Outcome in the COMPASS Trial8
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
CV death, stroke or MIa
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
Abbreviations: CI, confidence interval; CV, cardiovascular; MI, myocardial infarction.
aOnly P values for the primary outcome are confirmatory.


Safety Outcomes in the COMPASS Trial8
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
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
Fatal Bleedinga
15 (0.2)
14 (0.2)
10 (0.1)
1.49
(0.67-3.33)

0.32
1.40
(0.62-3.15)

0.41
Nonfatal symptomatic ICHa
21 (0.2)
32 (0.4)
19 (0.2)
1.10
(0.59-2.04)

0.77
1.69
(0.96-2.98)

0.07
Other major bleedinga
210 (2.3)
164 (1.8)
112 (1.2)
1.88
(1.49-2.29)

<0.001
1.47
(1.16-1.87)

0.001
Fatal bleeding or symptomatic ICH
36 (0.4)
46 (0.5)
29 (0.3)
1.23
(0.76-2.01)

0.40
1.59
(1.00-2.53)

0.05
Fatal bleeding or symptomatic bleeding into critical organ
78 (0.9)
91 (1.0)
58 (0.6)
1.34
(0.95-1.88)

0.09
1.58
(1.13-2.19)

0.006
Major bleeding according to ISTH criteria
206 (2.3)
175 (1.9)
116 (1.3)
1.78
(1.41-2.23)

<0.001
1.52
(1.20-1.92)

<0.001
Abbreviations: ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis.
a
If a participant had more than one event of major bleeding, only the most serious bleeding event was counted in these analyses.

Hori et al (2022)9 conducted a subgroup analysis to evaluate the risk of MI, stroke, or CV death and safety of XARELTO 2.5 mg twice daily + ASA 100 mg once daily compared to ASA 100 mg once daily between Asian and non-Asian patients with chronic CAD/PAD.

Results

Baseline characteristics

  • The trial consisted of 27,395 patients that included 4269 Asian and 23,126 non-Asian patients.
    • Patients were considered Asian if they identified as South Asian, Chinese, Japanese, Malay, or Other Asian. All other races were analyzed as non-Asian.
    • The average age in Asian and non-Asian patients was 67.1 and 68.4, respectively.
    • The female sex accounted for 21% and 22.1% in Asian and non-Asian patients, respectively.
    • Baseline CAD and PAD, respectively, were reported in 3,878 (90.8%) and 801 (18.8%) of patients in the Asian group and 20,946 (90.6%) and 6,669 (28.8%) in the non-Asian group.

Efficacy

  • The outcome of CV death, stroke or MI was less common in XARELTO + ASA vs ASA alone in the Asian (risk reduction, 36%; HR, 0.64; 95% CI: 0.45-0.90) and non-Asian groups (risk reduction, 22%; HR, 0.78; 95% CI: 0.67-0.90), respectively with a P-value for interaction of 0.29.
  • For primary efficacy outcomes, see Table: Primary Efficacy and Safety Outcomes in the COMPASS trial sub-analysis.

Safety

  • The outcome of modified ISTH major bleeding was more common with XARELTO + ASA vs ASA alone in the Asian (>2-fold; HR, 2.24; 95% CI: 1.40–3.58) and non-Asian (1.6-fold; HR: 1.60; 95% CI: 1.30–1.97) groups, respectively [P (heterogeneity)=0.20].
  • For primary safety outcomes, see Table: Primary Efficacy and Safety Outcomes in the COMPASS trial sub-analysis.

Primary Efficacy and Safety Outcomes in the COMPASS trial sub-analysis9

Asian
Non-Asian
XARELTO + ASA
n (%)
ASA
n (%)
ARD (95% CI)
HR (95% CI)
XARELTO +ASA
n (%)
ASA n (%)
ARD
(95% CI)
HR (95% CI)
P-value (het)
Primary Efficacy Outcomes
(Asian, n= 2,848; Non-Asian, n = 15,430)
MI, stroke, CV death
54
(3.72)
81 (5.80)
-2.08 (-3.64, -0.51)
0.64 (0.45, 0.90)
325
(4.22)
415 (5.37)
-1.15
(-1.82,
-0.48)
0.78 (0.67, 0.90)
0.29
Safety Outcomes
(Asian, n= 2,636; Non-Asian, n= 15,642)
Modified ISTH Major Bleeding
57 (3.93)
25 (1.79)
2.14 (0.92, 3.36)
2.24 (1.40, 3.58)
231 (3.00)
145 (1.88)
1.12 (0.64,1.61)
1.60 (1.30, 1.97)
0.20
Fatal bleeding
2 (0.14)
2 (0.14)
−0.01 (−0.28, 0.27)
0.96 (0.14, 6.82)
13 (0.17)
8 (0.10)
0.07 (−0.05,0.18)
1.63 (0.68, 3.94)
0.63
Symptomatic bleeding into a critical organ
21 (1.45)
10 (0.72)
0.73 (−0.03, 1.49)
2.03 (0.96, 4.31)
52 (0.68)
43 (0.56)
0.12 (−0.13, 0.37)
1.21 (0.81, 1.81)
0.23
Surgical site bleeding leading to reoperation
3 (0.21)
0
0.21 (−0.03, 0.44)
-
12 (0.16)
12 (0.16)
0.00 (−0.12, 0.12)
1.00 (0.45, 2.22)
0.99
Bleeding leading to hospitalization
49 (3.99)
18 (1.29)
2.09 (0.99, 3.19)
2.66 (1.55, 4.57)
210 (2.73)
129 (1.67)
1.06 (0.60, 1.52)
1.63 (1.31, 2.03)
0.10
GI bleeding
27 (1.86)
12 (0.86)
1.00 (0.15, 1.85)
2.19 (1.11, 4.32)
113 (1.47)
53 (0.69)
0.78 (0.46, 1.11)
2.14 (1.55, 2.97)
0.95
ICH
11 (0.76)
3 (0.21)
0.54 (0.04, 1.05)
3.50 (0.98, 12.56)
17 (0.22)
21 (0.27)
−0.05 (−0.21, 0.11)
0.81 (0.43, 1.53)
0.04
Minor Bleeding
227 (15.64)
153 (10.95)
4.69 (2.21, 7.18)
1.52 (1.24, 1.87)
611 (7.93)
350 (4.53)
3.41 (2.64, 4.17)
1.78 (1.56, 2.03)
0.17
Net clinical outcomea
71 (4.89)
89 (6.37)
-1.48
(-3.17, 0.22)
0.77 (0.56, 1.05)
360 (4.67)
445 (5.76)
-1.08
(-1.78,
-0.38)
0.81 (0.70, 0.93)
0.78
Abbreviations: ARD, absolute risk difference; ASA, aspirin; CI, confidence interval; CV, cardiovascular; GI, gastrointestinal; Het, heterogeneity; HR, hazard ratio; ICH, intracranial haemorrhage; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction.aComposite of MI, stroke, or CV death, fatal bleeding, or symptomatic bleeding into a critical organ.

VOYAGER PAD10

VOYAGER PAD (Vascular Outcomes StudY of ASA alonG with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate whether XARELTO 2.5 mg twice daily plus ASA 100 mg once daily is more effective than ASA 100 mg once daily alone for risk reduction of major atherothrombotic vascular outcomes consisting of both CV and limb events in patients with symptomatic PAD undergoing lower-extremity revascularization.

  • Dosing interventions were as follows:
    • XARELTO 2.5 mg twice daily and ASA 100 mg once daily
    • Placebo twice daily and ASA 100 mg once daily
  • The primary efficacy outcome of the VOYAGER PAD trial was to determine whether XARELTO 2.5 mg twice daily plus ASA 100 mg once daily compared with ASA 100 mg once daily reduces the risk of the composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or CV death.
  • The primary safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification.
  • For primary efficacy and safety outcomes, see Tables: Primary Efficacy Outcome in the VOYAGER PAD Trial and Safety Outcomes in the VOYAGER PAD Trial.

Primary Efficacy Outcomes in the VOYAGER PAD Trial10,a
Outcome
XARELTO Plus Aspirin
(n=3286)

Aspirin Alone
(n=3278)

HR
(95% CI)

P Value
Patients With Event,
n (%)
K-M Estimate at 3 Years (%)
Patients With Event,
n (%)
K-M Estimate at 3 Years (%)
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)

-
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 Outcomes in the VOYAGER PAD Trial10,a
Outcome
XARELTO Plus Aspirin
(n=3256)

Aspirin Alone
(n=3248)

HR
(95% CI)
P Value
Patients With Event, n (%)
K-M Estimate at 3 Years (%)
Patients With Event, n (%)
K-M Estimate at 3 Years (%)
Principal safety outcomes
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 1 dose of the trial medication (on-treatment).
bBARC major bleeding is defined as grade 3b or higher.

Pharmacokinetic and Pharmacodynamic Study

Kubitza et al (2006)11 conducted a randomized, nonblinded, 2-way crossover study to examine whether ASA influences the safety, tolerability, pharmacodynamics, and pharmacokinetics of XARELTO.

  • A total of 14 healthy male subjects aged between 18 and 55 years underwent 3 sequential treatment phases:
    • Treatment A: ASA 500 mg on the first day, followed by ASA 100 mg on the second day. Subjects were discharged on the third day.
    • Treatment B: XARELTO 15 mg orally on the first day. Subjects were discharged on the third day.
    • Treatment C: ASA 500 mg on the first day, ASA 100 mg and XARELTO 15 mg on the second day. Subjects were discharged on the fifth day.
  • Subjects that received treatment B first were crossed over to receive treatment C, and vice versa. There were 14-day washout periods between the treatments to allow for complete recovery of platelet function. All study medications were given with water to fasted subjects.

Safety and Tolerability

  • Sixteen treatment-emergent adverse events were reported (1 subject after ASA alone, 7 subjects after XARELTO alone, and 5 subjects after the combination of XARELTO and ASA). Of these events, 14 were mild in intensity, 2 were moderate in intensity, and all were resolved by the end of the trial.

Pharmacodynamics

  • Factor Xa (FXa) activity was inhibited after administration of XARELTO alone and in combination with ASA; ASA alone had no effect on FXa activity. Inhibition of FXa activity returned to almost baseline after 24 hours.
  • Prothrombin time (PT), activated partial thromboplastin time (aPTT), and HepTest were prolonged by XARELTO alone and in combination with ASA. Administration of ASA alone had no relevant effect on these clotting tests.
  • ASA alone and in combination with XARELTO inhibited collagen-stimulated platelet aggregation, whereas XARELTO alone did not.
  • XARELTO alone did not affect bleeding time. In contrast, mean bleeding time was prolonged by 1.46 times baseline and 1.96 times baseline with ASA and the combination of XARELTO and ASA, respectively.

Pharmacokinetics

Pharmacokinetic parameters for XARELTO, including the plasma concentration profile, were not substantially altered by coadministration of ASA.

Real-World Evidence

Schaefer et al12: conducted a registry-based cohort study of adult patients with NVAF or VTE who were started on a direct oral anticoagulant therapy [DOAC; apixaban, dabigatran, edoxaban or XARELTO] at 4 medical centers in Michigan between 2015-2019. The objective was to evaluate the frequency and outcomes of concomitant ASA use with DOAC therapy.

  • Patients with less than 3 months of follow-up data, a myocardial infarction (MI) within 6 months prior to DOAC initiation, and history of heart valve replacement were excluded from the study.  
  • Primary outcome: rate of bleeding events (any bleeding event, regardless of severity).
  • Secondary outcomes:
    • Bleeding events consisting of major bleeding, non-major bleeding, emergency department (ED) visits for bleeding, and hospitalizations related to bleeding.
    • Thrombotic events consisting of ischemic strokes, transient ischemic attack, VTE, ACS/MI, ED visits for thrombosis and hospitalizations for thrombosis.
  • A total of 3280 patients (1107 treated with DOAC + ASA and 2173 treated with DOAC monotherapy) without a clear indication for ASA were included in the study cohort. The cohort consisted of 1673 (51%) males, and the mean age was 68.2 years. In the DOAC + ASA group, 90.1% (n=997) of patients used low dose (≤100 mg) ASA. Two propensity score matched cohorts of 1047 patients in each group were analyzed.
  • After propensity score matching, a total of 29.3% and 31% of patients were taking XARELTO in the DOAC monotherapy and DOAC + ASA groups respectively. Median (Interquartile range) follow up was 12 (6,30) months.
  • Outcomes for both the DOAC monotherapy and DOAC + ASA groups are shown in the Table: Outcomes for DOAC Monotherapy and DOAC + ASA in Propensity Score Matched Cohorts

Outcomes for DOAC Monotherapy and DOAC + ASA in Propensity Score Matched Cohorts
DOAC
Monotherapy
(n=1047)
DOAC + ASA
(n=1047)
P value
Number per 100 patient-years (95% CI)
Any bleeding event
26.00 (25.05-27.06)
31.60 (30.54-32.75)
0.009
Major bleeding
3.59 (3.23-3.98)
4.95 (4.52-5.41)
0.09
Non-major bleeding
21.70 (20.77-22.60)
26.10 (25.14-27.15)
0.02
Thrombotic events
2.30 (1.98-2.59)
2.50 (2.20-2.83)
0.80
Hospitalization
6.50 (6.03-7.04)
9.10 (8.51-9.70)
0.02
For bleeding
10.40 (9.77-11.04)
13.00 (12.31-1374)
0.08
For clotting
1.30 (1.06-1.51)
0.90 (0.75-1.14)
0.31
Emergency room visits
11.50 (10.84-12.18)
13.80 (13.05-14.52)
0.14
For bleeding
10.40 (9.77-11.04)
13.00 (12.31-13.74)
.08
Mortality
3.40 (3.02-3.75)
3.80 (3.39-4.16)
0.76
Abbreviations: ASA, aspirin; CI, confidence interval; DOAC, direct oral anticoagulant

LITERATURE SEARCH

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 18 May 2023.

References

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