1. Rivaroxaban in stable peripheral or carotid artery disease
August 27, 2017
Rivaroxaban in stable peripheral or carotid artery disease
Sonia Anand, on behalf of the COMPASS Steering Committee and Investigators
Independently conducted by PHRI, sponsored by Bayer AG

2. - Consu lting/Royalties/Owner/ Stockholder of a healthcare company (I receive speaking honoraria from Phrumaceutical comapnies)

3. COMPASS PAD rationale
PAD patients have widespread atherosclerosis and increased risk of CV & limb adverse outcomes
Vascular events are high despite effective interventions
Few therapies have clearly reduced both Major Adverse CV Events (MACE) and Major Adverse Limb Events (MALE)

4. Primary objectives To determine in PAD whether:
Rivaroxaban 2.5 mg bid + aspirin 100 mg od, or
Rivaroxaban 5 mg bid
reduce the risk of MACE and MALE as compared with aspirin 100 mg od

5. Eligibility: PAD Peripheral artery revascularization
Limb or foot amputation for arterial vascular disease
Intermittent claudication plus:
Low ABI (<0.90), or
Significant peripheral artery stenosis (≥50%)
Previous carotid revascularization, asymptomatic carotid artery stenosis ≥50%
CAD + low ABI (<0.90)

6. Key Efficacy Outcomes Primary Cardiovascular Outcome (MACE):
- CV death, stroke, or MI
Major Adverse Limb Events (MALE):
Severe limb ischemia leading to an intervention (angioplasty, bypass surgery, amputation, thrombolysis)
Major Amputation above forefoot due to vascular cause

7. Primary Safety Outcome
Major Bleeding: Modified ISTH
Net Clinical Benefit: MACE, MALE, major amputation, fatal bleeding, or symptomatic bleeding into a critical organ

8. PAD Patients in COMPASS
PAD Groups
Number of patients
All Patients
7,470
Symptomatic PAD Limbs
4,129
Carotid Disease
1,919
CAD + Low ABI (<0.90) only
1,422
Mean Follow-up: 21 months

9. Baseline Characteristics
Riva + aspirin N=2,492
Rivaroxaban N=2,474
Aspirin N=2,504
Age, years (mean) 68
Current Smoker
27%
28%
Former Smoker
46%
47%
Diabetes
44%
Hypertension
79%
78%
81%
Prior CAD or Stroke
69%
68%
Lipid Lowering
84%
83%
ACE-I/ARB
71%
70%

10. Primary outcome & components
R + A
N=2,492 R
N=2,474 A
N=2,504
Riva + aspirin vs.
aspirin
Riva vs. aspirin N
(%) HR
(95% CI) P
MACE
126
(5.1)
149
(6.0)
174
(6.9)
0.72
( )
0.005
0.86
( )
0.19 MI 51
(2.0) 56
(2.3) 67
(2.7)
0.76
( ) -
0.84
( )
Stroke 25
(1.0) 43
(1.7) 47
(1.9)
0.54
( )
0.93
( )
CV Death 64
(2.6) 66 78
(3.1)
0.82
( )
( )
August 11, 2017

11. Limb outcomes Outcome R + A N=2,492 R N=2,474 A N=2,504
Riva + aspirin vs.
aspirin
Riva vs. aspirin N
(%) HR
(95% CI) P
MALE 30
(1.2) 35
(1.4) 56
(2.2)
0.54
( )
0.005
0.63
( )
0.03
Major amputation 5
(0.2) 8
(0.3) 17
(0.7)
0.30
( )
0.01
0.46
( )
0.07
Aug 11, 2017

12. Key Composite Outcome Outcome R + A N=2,492 R N=2,474 A N=2,504
Riva + aspirin vs. aspirin
Riva vs. aspirin N
(%) HR
(95% CI) P
MACE, MALE
or Major amputation
157
(6.3)
188
(7.6)
225
(9.0)
0.69
( )
0.0003
0.84
( )
0.08
August 14, 2017

13. MACE or MALE or Major Amputation
0.15
Aspirin
Rivaroxaban Rivaroxaban + Aspirin
Cumulative Hazard Rate
0.10
0.05
Rivaroxaban + Aspirin vs. Aspirin HR: 0.69 ( ) P=0.0003
0.0
Rivaroxaban vs. Aspirin
HR: 0.84 ( ) P=0.08 1 2 3
No. at Risk
Year
Riva + ASA
2492
2069
893
124
Riva
2474
2023
864
147
ASA
2504
2034
911
113

14. Major bleeding Outcome R + A N=2,492 R N=2,474 A N=2,504
Riva + aspirin vs. aspirin
Riva vs. aspirin N
(%) HR
(95% CI) P
Major Bleeding 77
(3.1) 79
(3.2) 48
(1.9)
1.61
( )
0.009
1.68
( )
0.004
Fatal 4
(0.2) 5 3
(0.1) -
Non-Fatal ICH 8
(0.3)
Non-fatal other critical organ* 13
(0.5) 18
(0.7)
1.55
( )
0.33
2.15
( )
0.06
* symptomatic

15. Net clinical benefit in PAD
Outcome
R + A N=2,492
R N=2,474
A N=2,504
Riva + aspirin vs. aspirin
Riva vs. aspirin
N (%)
HR (95% CI) P
Net Clinical Benefit
169 (6.8)
207 (8.4)
234 (9.3)
0.72
( )
0.0008
0.89
( )
0.23
August 14, 2017

16. MACE, MALE or Major Amputation
Overall COMPASS
Overall PAD
Symptomatic PAD
PAD Lower Extremeties Carotid Artery Disease
0.5
Riva ASA
better
1.5
ASA only better
1.0

17. Conclusions Rivaroxaban 2.5 mg BID plus aspirin is:
Significantly superior to aspirin alone in reducing MACE or MALE or major amputation (31% RRR)
Increased major bleeding, but no significant increase in fatal or critical organ bleeding

18. We thank all participants for their selfless dedication
COMPASS PAD paper forthcoming in The Lancet
Acknowledgements
Steering Committee: S. Yusuf (Chair), K. Fox (Co-Chair), S. Connolly (Co-PI), JW. Eikelboom (Co-PI), J. Bosch (Study Director), V. Aboyans, M. Alings, S. Anand, A. Avezum, D. Bhatt, K. Branch, P. Commerford, N. Cook-Bruns, G. Dagenais, A. Dans, R. Diaz, G. Ertl, C. Felix, , T. Guzik, J. Ha, R. Hart, M. Hori, A. Kakkar, K. Keltai, M. Keltai, J. Kim, A. Lamy, F. Lanas, B. Lewis, Y. Liang, L. Liu, E. Lonn, P. Lopez-Jaramillo, A. Maggioni,
K. Metsarinne, P. Moayyedi, M. O'Donnell, A. Parkhomenko, L. Piegas, N. Pogosova, J. Probstfield, L. Ryden, M. Sharma, P.G. Steg, S. Stoerk, A. Tonkin, C. Torp-Pedersen, J. Varigos, P. Verhamme, D. Vinereanu, P. Widimsky, K. Yusoff, J. Zhu
We thank all the investigators and study coordinators for their efforts
We thank all participants for their selfless dedication