Rivaroxaban

1. Evolving Role of RIVAROXABAN

2. 25.7 million
Increase in CVD
prevalence in India 54.5 million
1990
2016
Burden of cardiovascular diseases and ischemic heart disease in India, 2016
CVD: cardiovascular disease; IHD: ischemic heart disease
India State-Level Disease Burden Initiative CVD Collaborators. The changing patterns of cardiovascular diseases and their risk
factors in the states of India: the Global Burden of Disease Study 1990-2016. Lancet Glob Health. 2018;6(12):e1339-e1351
 23·8 million prevalent cases of IHD
 6·5 million prevalent cases of stroke

3. Dietary risks
56.4%
High systolic
blood
pressure
54.6%
Air pollution
31.1%
High total
cholesterol
29.4%
Tobacco use
18.9%
High fasting
plasma
glucose
16.7%
High body
mass index
14.7%
Leading risk factors of CVD in India
India State-Level Disease Burden Initiative CVD Collaborators. The changing patterns of cardiovascular diseases and their risk factors in the
states of India: the Global Burden of Disease Study 1990-2016. Lancet Glob Health. 2018;6(12):e1339-e1351

4. Diabetes
Hypertension
Diabetes with multi-
vessel CAD
Obesity
Smoking
Tobacco consumption
Endothelial
dysfunction
Vascular inflammation
Pro-thrombotic state
Hemostatic imbalance
Increased platelet
activation and
aggregation
Increased
thrombogenesis
Increased
atherogenesis
Cardiovascular complications
• Coronary thrombosis
• Myocardial infarction
• Ischemic stroke
Overview of mechanism of major CV risk factors relevant to India
1. Kwagyan J, Retta TM, Ketete M, et al. Obesity and Cardiovascular Diseases in a High-Risk Population: Evidence-Based Approach to CHD Risk Reduction. Ethn Dis. 2015 Spring;25(2):208-13
2. Pechlivani N, Ajjan RA. Thrombosis and Vascular Inflammation in Diabetes: Mechanisms and Potential Therapeutic Targets. Front Cardiovasc Med. 2018 Jan 19;5:1
3. Koliaki C, Liatis S, Kokkinos A. Obesity and cardiovascular disease: revisiting an old relationship. Metabolism. 2019 Mar;92:98-107
4. Barua RS, Ambrose JA. Mechanisms of coronary thrombosis in cigarette smoke exposure. Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1460-7
There is need to target both platelet as well as thrombin generation to prevent thrombus formation

5. Biological rationale for testing dual pathway approach
Eikelboom JW. Res Pract Thromb Haemost 2019;3:431-497.

6. Prevalence of ischemic events remains high despite using effective single or dual antiplatelets1
Suitable therapeutic option for reduction of thrombosis in CAD patients
Antiplatelet
agent
Anticoagulant
Reduction of
thrombus
formation2
Inhibits platelet activation and
aggregation
Inhibits thrombin
generation
Dual pathway
inhibition
strategy2
Potential reduction in
the risk of recurrent
ischemic events
1. Cho SW, Franchi F, Angiolillo DJ. Role of oral anticoagulant therapy for secondary prevention in patients with stable atherothrombotic disease manifestations. Ther Adv
Hematol. 2019 Jul 12;10:2040620719861475
2. Coppens M, Weitz JI, Eikelboom JWA. Synergy of Dual Pathway Inhibition in Chronic Cardiovascular Disease. Circ Res. 2019 Feb;124(3):416-425
CAD: coronary artery disease

9. The genesis of COMPASS trial based on outcomes of 2 landmark trials
ATLAS VOYAGER
Patients
with ACS
Patients
with PAD

10. ATLAS: patients with a recent acute coronary syndrome
(n=15,526)
Mega J, et al. N Engl J Med 2012;366:9-19.

11. VOYAGER: patients with PAD & recent revascularization
(n=6,564)
Bonaca MP, et al. N Engl J Med 2020;382:1994-2004.

12. COMPASS Study Design
R
Rivaroxaban 2.5 mg bid
+ Aspirin 100 mg od
Aspirin 100 mg od
Rivaroxaban 5 mg bid
Expected mean follow up: 3-4 years
Run-in*
(aspirin plus
rivaroxaban placebo)
n=27,395 Chronic CAD or PAD
2,200 participants with a primary outcome event
*excluding patients enrolled 4-14 days post CABG
Bosch JJ, et al. Can J Cardiol 2017; 33: 1027-1035.

13. COMPASS: a well-treated population
R + A
N=9,152
Rivaroxaban
N=9,117
Aspirin
N=9,126
Lipid-lowering 90% 90% 89%
ACE-I/ARB 71% 72% 71%
Beta blocker 70% 70% 70%
Aspirin* 87% 87% 87%
Eikelboom JW, et al. N Engl J Med 2017; 377: 1319-1330.
*Excluding patients randomized 4-14 days post CABG

14. COMPASS: patients with chronic CAD or PAD
(n=27,395)
Eikelboom JW, et al. N Engl J Med 2017; 377: 1319-30.

15. Components of primary outcome of COMPASS Trial
Eikelboom JW, et al. N Engl J Med 2017; 377: 1319-30.

16. Net benefit: Absolute risk differences over time
Eikelboom JW, et al. J Am Coll Cardiol 2019 In Press

17. Rivaroxaban + Aspirin: net clinical benefit
Steffel J, et al. Circulation 2020 (available on line)
The benefits accumulate
over the time

18. Reduction in Mortality by 18%
Riva + aspirin
N=9,152
Aspirin
N=9,126
Rivaroxaban + Aspirin
vs. Aspirin
N
(%)
N
(%)
HR
(95% CI)
P
Death
313
(3.4)
378
(4.1)
0.82
(0.71-0.96)
0.01
Eikelboom JW, et al. N Engl J Med 2017; 377: 1319-30.

19. Major bleeding: modified ISTH and conventional ISTH
Eikelboom JW, et al. J Am Coll Cardiol 2019;74:1519-28.

20. Benefits of the COMPASS regimen in the context of routine therapies
*Not significant.
1. Eikelboom JW, et al. N Engl J Med 2017; 377:1319–30; 2. CTT Collaboration. Lancet 2015; 385:1397–405;
3. Collins R, et al. Lancet 2016; 388:2532–61; 4. Ettehad D, et al. Lancet 2016; 387:957–67; 5. Dagenais GR, et al. Lancet 2006; 368:581–8;
6. Zinman B, et al. N Engl J Med 2015; 373:2117–28; 7. Schwartz GG, et al. N Engl J Med 2018; 379:2097–107.
Newer approaches tested on top of
routine therapies
Routine therapies
Rivaroxaban
+ Aspirin1
SGLT2 inhibitor
(Empagliflozin)6
PCSK9 inhibitor
(Alirocumab)7
Lipid-lowering
(1mmol/l)2,3
BP-
lowering
(10mmHg)4
ACE5
MACE –24% –14% –14% –21% –20% –18%
Death –18% –32% –15% –9% –13% –14%
Stroke –42% +18%* –27% –15% –27% –23%

21. COMPASS regimen is the first long-term antithrombotic since ASA to reduce
mortality
*Not significant. †Major coronary event. ‡Gastrointestinal bleeding. §Non-fatal. ¶severe and moderate GUSTO bleeding, respectively
1. Antithrombotic Trialists’ Collaboration. Lancet 2009; 2: 172–183. 2. CAPRIE Investigators. Lancet 1996; 348: 1329-39.
3. Bhatt DL, et al. N Engl J Med 2006 Apr 20;354(16):1706-17. 4. Bonaca MP, et al. N Engl J Med 2015; 372: 1791-800.
5. Eikelboom JW, et al. N Engl J Med 2017; 377:1319–30.
Rivaroxaban
+ aspirin1 ASA1 Clopidogrel2 ASA +
clopidogrel3
ASA +
ticagrelor4
MACE –24% –19% –9% –7%* –16%
Death –18% –10% –2%* –1%* –11%*

22. • In patients with chronic CAD, the addition of rivaroxaban to aspirin:
• Reduces CV death, stroke, or MI by about one-quarter
• Reduces ischemic stroke by half
• Reduces mortality by about one-fifth
• Net benefits continue to accrue during long term treatment
• Those who derive greatest benefits are patients with polyvascular disease, HF, CKD, DM
• Dual pathway therapy provides a highly attractive option for long term management of
patients with chronic CAD
Outcomes of COMPASS Trial

23. Chronic cardiovascular disease: who derives the greatest benefit from
the COMPASS regimen?
1. Dumaine RL et al. Am Heart J 2009;158:141–148.e1; 2. Bhatt DL et al. JAMA 2010;304:1350–1357. 3. Eikelboom JW et al.
N Engl J Med 2017;377(14):1319–1330. 4. Connolly SJ et al. Lancet 2018;391:205–218; 5. Anand SS et al. JACC 2019;nn:xx–yy.

26. Rivaroxaban in VTE, AF and Atherothrombosis
Venous
thromboembolism
Cardiac
thromboembolism
Atherothrombosis
Events
(%)
0
80% RRR 40% RRR
100
90% RRR

27. Rivaroxaban is the single most extensively evaluated DOAC for
thromboembolism prevention and treatment
• Venous thromboembolism prevention in surgical patients
• Venous thromboembolism prevention in medical patients
• Venous thromboembolism treatment
• Atrial fibrillation (includes cardioversion, ablation, post
stenting)
• Pediatric indications
• Acute coronary syndromes
• Chronic arterial vascular disease

28. Under-use of anticoagulants
• Misconceptions about the benefits of anticoagulation
• Over estimates of a patient’s bleeding risk and underestimates
of stroke risk
• Fear of bleeding
Sen S, et al. Am J Med Sci 2014;348:513-21.

29. Contraindications and unresolved issues
Contraindications
• Mechanical heart valves
• APA syndrome
• ESRD
• Advanced liver disease
• Drug-drug interactions
Unresolved issues
• Chronic kidney disease
• Chronic liver disease
• Obesity
• LV thrombus

30. Summary
• Rivaroxaban is the most widely studied and most widely approved DOAC
• Safety benefits of DOACs including Rivaroxaban appear to be amplified
in Asian populations
• Challenge for clinicians is to treat a higher proportion of eligible patients