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XARELTO® (rivaroxaban)

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XARELTO - Comparison of the COMPASS and VOYAGER PAD Trials

Last Updated: 04/29/2024

Summary

  • 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) plus aspirin 100 mg once daily or XARELTO 5 mg BID alone is more effective than aspirin 100 mg once daily alone for the prevention of myocardial infarction (MI), stroke, or cardiovascular (CV) death in patients with a history of stable atherosclerotic vascular disease (coronary artery disease [CAD] or peripheral artery disease [PAD]).1
    • The mean follow-up duration of the COMPASS study was 23 months.
    • The primary outcome occurred in fewer patients in the XARELTO plus aspirin group than in the aspirin alone group (379 patients [4.1%] vs 496 patients [5.4%]; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66-0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the XARELTO plus aspirin group than in the aspirin alone group (288 patients [3.1%] vs 170 patients [1.9%]; HR, 1.70; 95% CI, 1.40-2.05; P<0.001).
    • The primary outcome did not occur in significantly fewer patients in the XARELTO alone group than in the aspirin alone group (448 patients [4.9%] vs 496 patients [5.4%]; HR, 0.90; 95% CI, 0.79-1.03; P=0.12; z=-1.575), but major bleeding events occurred in more patients in the XARELTO alone group than in the aspirin alone group (255 patients [2.8%] vs 170 patients [1.9%]; HR, 1.51; 95% CI, 1.251.84; P<0.001).
    • Net clinical benefit (composite of CV death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ) occurred in 4.7% of patients treated with XARELTO plus aspirin and in 5.9% of patients treated with aspirin alone (P<0.001).
  • 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 BID plus aspirin 100 mg once daily is more effective than aspirin 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.2
    • The median follow-up duration of the VOYAGER PAD study was 28 months.
    • 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%]; HR, 0.85; 95% CI, 0.76-0.96; P=0.009) based on Kaplan-Meier estimates of the cumulative incidence at 3 years.
    • The principal safety outcome occurred in more patients in the XARELTO plus aspirin group than in the aspirin alone group (62 patients [2.65%] vs 44 patients [1.87%]; HR, 1.43; 95% CI, 0.97-2.10; P=0.07) based on Kaplan-Meier estimates of the cumulative incidence at 3 years.

CLINICAL STUDIES

  • COMPASS was a phase 3, event-driven, double-blind, randomized study designed to evaluate whether treatment with XARELTO 2.5 mg BID plus aspirin 100 mg once daily or XARELTO 5 mg BID alone is more effective than aspirin 100 mg once daily alone for the prevention of MI, stroke, or CV death in patients with a history of stable atherosclerotic vascular disease (CAD or PAD).1
  • 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 lower-extremity revascularization.2

Comparative Review of Study Designs and Baseline Characteristics


Summary of COMPASS and VOYAGER PAD Trials Study Design and Baseline
Characteristics1-4
Parameter
COMPASS
VOYAGER PAD
N
N=27,395
N=6564
Randomization
XARELTO 2.5 mg plus aspirin:XARELTO
5 mg:placebo plus aspirin (1:1:1)
XARELTO 2.5 mg plus aspirin:placebo plus aspirin (1:1)
Key inclusion criteria
  • CAD or PAD, or both
  • 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 factorsa
  • Age ≥50 years
  • Moderate to severe symptomatic lower extremity atherosclerotic PAD
  • ABI ≤0.80 or TBI ≤0.60 without prior history of limb revascularization
  • ABI ≤0.85 or TBI ≤0.65 with prior history of limb revascularization
  • Successful peripheral revascularization distal to the external iliac artery (surgical and/or endovascular) for symptomatic PAD within the last 10‍ days prior to randomization
Key exclusion criteria
  • High risk of bleeding
  • Stroke within 1 month or any history of hemorrhagic or lacunar stroke
  • Severe HF with known ejection fraction <30% of NYHA class III or IV symptoms
  • Need for DAPT, other nonaspirin antiplatelet therapy, or oral anticoagulant therapy
  • eGFR <15 mL/min; or systemic treatment with strong inhibitors of both CYP3A4 and P-glycoprotein or strong inducers of CYP3A4
  • 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
Primary outcomes
Composite of CV death, stroke, or MI
Composite of ALI, major amputation for vascular causes, MI, ischemic stroke, or CV death
Main safety outcomes
Major bleeding per modified ISTH criteria, including:
  • Composite of fatal bleeding
  • Symptomatic bleeding into a critical organ
  • Bleeding into a surgical site requiring reoperation
  • Bleeding that led to hospitalization (including presentation to an acute care facility without an overnight stay).
Major bleeding according to TIMI classification
Secondary efficacy outcomes
  • Composite of ischemic stroke, MI, ALI, or death from coronary heart disease
  • Composite of ischemic stroke, MI, ALI, or CV death
  • Death from any cause
  • ALI, major amputation of a vascular etiology, MI, ischemic stroke, or death from coronary heart disease
  • Unplanned index-limb revascularizations for recurrent limb ischemia
  • Vascular hospitalizations for a peripheral or coronary event of a thrombotic nature
  • ALI, major amputation of a vascular etiology, MI, ischemic stroke, or all-cause mortality
  • ALI, major amputation of a vascular etiology, MI, all stroke, or CV death
  • All-cause mortality
  • VTE
Baseline Characteristics
XARELTO Plus Aspirin
XARELTO
Alone
Aspirin
Alone
XARELTO
Plus Aspirin
Aspirin Alone
Age, years
68.3b
68.2b
68.2b
67.0c
67.0c
BMI, kg/m2
28.3b
28.3b
28.4b
26.0c
26.0c
Race, n (%)
   White
5673 (62.0)
5672 (62.2)
5682 (62.3)
2647 (80.6)
2656 (81.0)
   Asian
1451 (15.9)
1421 (15.6)
1397 (15.3)
484 (14.7)
482 (14.7)
   Black
76 (0.8)
94 (1.0)
92 (1.0)
84 (2.6)
71 (2.2)
   Other
1952 (21.3)
1930 (21.2)
1955 (21.4)
71 (2.2)
69 (2.1)
CAD, n (%)
8313 (90.8)
8250 (90.5)
8261 (90.5)
-
-
PAD, n (%)
2492 (27.2)
2474 (27.1)
2504 (27.4)
-
-
Previous stroke, n (%)
351 (3.8)
346 (3.8)
335 (3.7)
-
-
Previous MI, n (%)
5654 (61.8)
5653 (62.0)
5721 (62.7)
365 (11.1)
349 (10.6)
HF, n (%)
1963 (21.4)
1960 (21.5)
1979 (21.7)
-
-
Previous median ABI
-
-
-
0.56
0.56
Study completion
May 2016
January 2018
Follow-up, months
23b
28c
Abbreviations: ABI, ankle-brachial index; ALI, acute limb ischemia; BP, blood pressure; CABG, coronary artery bypass surgery; CAD, coronary artery disease; CV, cardiovascular; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; HF, heart failure; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction; NYHA, New York Heart Association; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; TBI, toe-brachial index; TIMI, thrombolysis in myocardial infarction; VTE, venous thromboembolism.
aRisk factors included current smoking, diabetes mellitus, an eGFR of <60 mL per minute, HF, or nonlacunar ischemic stroke ≥1 month earlier. bData are mean. cData are median.

Results of the COMPASS and VOYAGER PAD Trials


Primary Efficacy Outcomes in COMPASS1
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; HR, hazard ratio; MI, myocardial infarction.
aOnly P values for the primary outcome are confirmatory.

Secondary Efficacy Outcomes in COMPASS1,a
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
Ischemic stroke, MI, ALI, or death from CHD
329 (3.6)
397 (4.4)
450 (4.9)
0.72 (0.63-0.83)
<0.001
0.88 (0.77-1.01)
0.06
Ischemic stroke, MI, ALI, or CV death
389 (4.3)
453 (5.0)
516 (5.7)
0.74 (0.65-0.85)
<0.001
0.88 (0.77-0.99)
0.04
All-cause mortality
313 (3.4)
366 (4.0)
378 (4.1)
0.82 (0.71-0.96)
0.01
0.97 (0.84-1.12)
0.67
Abbreviations: ALI, acute limb ischemia; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
aThe threshold P value used for statistical significance of secondary efficacy outcomes was 0.0025 per the COMPASS study statistical analysis plan. For outcomes that
did not meet this threshold, statistical significance cannot be claimed.

Other Efficacy Outcomes in COMPASS1,a
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
160 (1.7)
195 (2.1)
203 (2.2)
0.78 (0.64-0.96)
0.02
0.96 (0.79-1.17)
0.69
Non-CV death
153 (1.7)
171 (1.9)
175 (1.9)
0.87 (0.70-1.08)
0.20
0.98 (0.79-1.21)
0.84
Death from CHD
86 (0.9)
128 (1.4)
117 (1.3)
0.73 (0.55-0.96)
0.03
1.09 (0.85-1.41)
0.48
Strokeb
83 (0.9)
117 (1.3)
142 (1.6)
0.58 (0.44-0.76)
<0.001
0.82 (0.65-1.05)
0.12
   Ischemic or uncertain type
68 (0.7)
91 (1.0)
132 (1.4)
0.51 (0.38-0.68)
<0.001
0.69 (0.53-0.90)
0.006
   Hemorrhagic
15 (0.2)
27 (0.3)
10 (0.1)
1.49 (0.67-3.31)
0.33
2.70 (1.31-5.58)
0.005
MI
178 (1.9)
182 (2.0)
205 (2.2)
0.86 (0.70-1.05)
0.14
0.89 (0.73-1.08)
0.24
Heart failure
197 (2.2)
191 (2.1)
192 (2.1)
1.02 (0.84-1.24)
0.84
0.99 (0.81-1.21)
0.95
VTE
25 (0.3)
36 (0.4)
41 (0.4)
0.61 (0.37-1.00)
0.05
0.88 (0.56-1.38)
0.58
Hospitalization
   For CV causes
1303 (14.2)
1317 (14.4)
1394 (15.3)
0.92 (0.86-1.00)
0.04
0.94 (0.87-1.01)
0.11
   For non-CV causes
1701 (18.6)
1649 (18.1)
1624 (17.8)
1.05 (0.98-1.13)
0.14
1.02 (0.95-1.09)
0.54
Abbreviations: CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; VTE, venous thromboembolism.
aThere was no adjustment for the testing of these outcomes.
bOne participant in the XARELTO alone group had more than 1 type of stroke. A total of 26 of the 392 participants who were reported to have atrial fibrillation had a
stroke: 7 participants in the XARELTO plus aspirin group, 8 participants in the XARELTO alone group, and 11 participants in the aspirin alone group.
Disclaimer: As the statistical analysis plan for COMPASS did not specify modifications to the prespecified control of multiple testing of secondary efficacy outcomes in the case of early termination of the trial, any HRs, corresponding CIs, and P values reported for secondary efficacy outcomes cannot be interpreted as statistically significant.

Primary Efficacy Outcomes in VOYAGER PAD2,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.

Secondary Efficacy Outcomes in VOYAGER PAD2,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 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
VTE
25 (0.8)
0.8
41 (1.3)
1.7
0.61 (0.37-1.00)
-
Abbreviations: ALI, acute limb ischemia; CI, confidence interval; HR, hazard ratio; K-M, Kaplan-Meier; MI, myocardial infarction; VTE, Venous thromboembolism.
aAll efficacy outcomes were analyzed on an intention-to-treat basis.

Safety Outcomes in COMPASS1
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
Modified ISTH major bleedinga
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 bleedingb
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 ICHb
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 bleedingb
210 (2.3)
164 (1.8)
112 (1.2)
1.88 (1.49-2.36)
<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
Transfusion within 48 hours after bleeding
87 (1.0)
66 (0.7)
44 (0.5)
1.97 (1.37-2.83)
<0.001
1.50 (1.03-2.20)
0.03
Minor bleeding
838 (9.2)
741 (8.1)
503 (5.5)
1.70 (1.52-1.90)
<0.001
1.50 (1.34-1.68)
<0.001
Sites of major bleeding
   Gastrointestinal
140 (1.5)
91 (1.0)
65 (0.7)
2.15 (1.60-2.89)
<0.001
1.40 (1.02-1.93)
0.04
   Intracranial
28 (0.3)
43 (0.5)
24 (0.3)
1.16 (0.67-2.00)
0.60
1.80 (1.09-2.96)
0.02
   Skin or injection site
28 (0.3)
28 (0.3)
12 (0.1)
2.31 (1.18-4.54)
0.01
2.34 (1.19-4.60)
0.01
   Urinary
13 (0.1)
30 (0.3)
21 (0.2)
0.61 (0.31-1.23)
<0.16
1.43 (0.82-2.50)
0.20
Net clinical benefit outcomec
431 (4.7)
504 (5.5)
534 (5.9)
0.80 (0.70-0.91)
<0.001
0.94 (0.84-1.07)
0.36
Abbreviations: CI, confidence interval; CV, cardiovascular; HR, hazard ratio; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and
Haemostasis; MI, myocardial infarction.
aModified ISTH bleeding was defined as a composite of fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and
bleeding that led to hospitalization (including presentation to an acute care facility without an overnight stay).
bIf a participant had more than 1 event of major bleeding, only the most serious bleeding event was counted in these analyses.
cThe net clinical benefit outcome was the composite of CV death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ.

Safety Outcomes in VOYAGER PAD2,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; K-M, Kaplan-Meier; ISTH, International Society on Thrombosis and Haemostasis; TIMI, thrombolysis in myocardial infarction.
aSafety analyses included all patients who underwent randomization and had received at least 1 dose of trial medication (on-treatment).
bBARC major bleeding is defined as grade 3b or higher.

LITERATURE SEARCH

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 19 April 2024.

References

Show
1 Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330.  
2 Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020;382(21):1994-2004.  
3 Eikelboom JW, Connolly SJ, Bosch J, et al. Supplement to: Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330.  
4 Bonaca MP, Bauersachs RM, Anand SS, et al. Supplement to: Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020;382(21):1994-2004.