COMPASS PRESENTACION.pptx

COMPASS Rationale and Background
Rivaroxaban in Vascular Protection
G.MKT.GM.XA.05.2017.1497

Atherosclerosis Is a Chronic, Progressive Disease
Leading to Thrombosis and Ischaemia
Insull W Jr, Am J Med 2009;122(1 Suppl):S3–S14; Bradberry JC et al, J Am Pharm Assoc 2004;44:S37–S45
Plaque disruption –
thrombosis
MI
(coronary arteries)
Acute limb ischaemia
(peripheral arteries)
1. Normal
artery
Normal artery
‘Fatty streak’ Fibrous plaque Atherosclerotic
plaque
Stroke
(cerebral arteries)
PAD
CAD

The Clinical Consequences of Atherosclerosis
Ischaemic
stroke,
lacunar
stroke
Heart failure
Transient ischaemic
attack (TIA)
Coronary artery
disease (CAD)
 Stable angina
 Acute coronary
syndrome
Peripheral arterial disease (PAD):
 Intermittent claudication
Rest pain
Gangrene
Necrosis
1. Adapted from Drouet L, Cerebrovasc Dis 2002;13 (suppl 1):1-6;
2. Bhatt DL, et al. JAMA. 2006;295:180-189.
PAD
CAD

Overview of CAD
 Caused by atherosclerosis of
the coronary arteries that leads
to a restriction of blood flow to
the heart1
 Symptoms depend on degree of
stenosis (narrowing) and level of
myocardial ischaemia2–4
 Depending on degree of stenosis
and plaque characteristics,
patients may experience stable
angina (angina pectoris) or
remain asymptomatic until a
plaque ruptures and thrombosis
occurs, causing ACS5
Coronary artery disease6
1. Sanchis-Gomar F et al, Ann Transl Med 2016;4:256; 2. Kumar A, Cannon CP, Mayo Clin Proc 2009;84:917–938;
3. Amsterdam EA et al, J Am Coll Cardiol 2014;64:e139–e228; 4. Thygesen K et al, Circulation 2012;126:2020–2035;
5. Libby P et al, Circulation 2005;111:3481–3488; 6. Kahn MR et al, Nat Rev Cardiol 2013;10:261–273
CAD

Overview of PAD
 PAD is an atherosclerotic process that causes stenosis and occlusion
of non-cerebral and non-coronary arteries1–3
 PAD typically refers to atherosclerosis affecting the arteries of the
lower extremities – the resulting limb ischaemia can lead to
amputation1–3
 PAD may also affect visceral arteries and carotid arteries1
 PAD is often asymptomatic1–3
Toe gangrene
1. Tendera M et al – ESC PAD Guidelines, Eur Heart J 2011;32:2851–2906;
2. Gerhard-Herman MD et al – AHA/ACC lower extremity PAD Guidelines, J Am Coll Cardiol 2016;69:e71–e126 ;
3. Norgren L et al – Inter-Society Consensus for the Management of PAD (TASC II), J Vasc Surg 2007;45:S5–S67
PAD

Lower Extremity Peripheral Artery Occlusion Leads
to Limb Ischaemia
 Atherosclerotic plaques lead to occlusion of peripheral arteries with
consecutive hypoperfusion and ischaemia of tissues distal to the obstruction1
 The most severe manifestations are:
 Acute limb ischaemia – sudden (<2 weeks) decrease in limb perfusion1,2
 Critical limb ischaemia – chronic (≥2 weeks) hypoperfusion that is inadequate to
sustain viability in the distal tissue bed; typically associated with multisegment
occlusive arterial disease1–3
Asymptomatic
Atypical leg pain
Intermittent claudication
Critical limb ischaemia
Acute limb ischaemia
Rest pain
Exercise pain
Presentation
of
PAD
1. Norgren L et al – Inter-Society Consensus for the Management of PAD (TASC II), J Vasc Surg 2007;45:S5–S67;
2 Gerhard-Herman MD et al – AHA/ACC lower extremity PAD Guidelines, J Am Coll Cardiol 2016;69:e71–e126;
3. Hirsch AT et al, Circulation 2006;113:e463–e654
PAD

Diagnosis of Lower Extremity PAD
PAD can be diagnosed by measurement of resting ankle–brachial index (ABI)1
Interpretation of ABI
>1.30 Non-compressible
1.00–1.29 Normal
0.91–0.99 Borderline
(equivocal)
0.41–0.90 Mild-to-moderate
PAD
0–0.40 Severe PAD
Left-arm systolic
pressure
Right-arm systolic
pressure
Right-ankle
systolic
pressure
Left-ankle
systolic
pressure
ABI
Higher ankle pressure
Higher arm pressure  Resting ABI is the
standard diagnostic test
for lower extremity PAD2
 ABI can also be used for
prognosis and monitoring
interventions2
 Additional tests include
pulse-volume recording,
segmental pressures,
duplex ultrasound and
exercise test with ABI2
1. Hiatt WR, N Engl J Med 2001;344:1608–1621; 2. Hirsch AT et al – ACC/AHA PAD guidelines, Circulation 2006;113:e463–e654
PAD

Major Risk Factors Linked to Atherosclerosis May
Be Modifiable or Non-modifiable
 These risk factors apply to all clinical manifestations of atherosclerosis
Atherosclerotic
CV disease
Age
Gender
(male)
Heredity (including
ethnicity)
Hypertension
Physical
inactivity
Obesity/
overweight
Diabetes
mellitus
Stress
Smoking/
alcohol
Diet and nutrition
(lifestyle)
Inflammation
Family history of
CV disease
Hyperglycaemia
Atherogenic
dyslipidaemia
Microalbuminuria
Non-modifiable
Modifiable
Modifiable/
lifestyle
Mozaffarian D et al, Circulation 2008;117:3031–3038; O’Flaherty M et al, ESC Textbook of Preventive Cardiology.
http://oxfordmedicine.com/view/10.1093/med/9780199656653.001.0001/med-9780199656653-chapter-1#med-9780199656653-
chapter-1-div1-4 [accessed 16 May 2017]
PAD
CAD

High Residual Risk of Atherothrombotic Events Exists in
Patients with CAD Despite Optimized Antiplatelet Therapy
NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction
1. Montalescot G et al – Task Force on the management of stable CAD of the ESC, Eur Heart J 2013;34:2949–3003;
2. Windecker S et al, Eur Heart J 2014;35:2541–2619; 3. Roffi M et al, Eur Heart J 2015;37:267–315; 4. Levine GN et al, J Am Coll Card
2016;68:1082–1115
CAD
ASA  Cornerstone therapy for prevention of
thrombosis in CAD1
DAPT  Recommended for a limited period of time in:
 Patients with ACS (unstable angina, NSTEMI or
STEMI)2–4
 Patients who underwent coronary stent
implantation2–4
 Not recommended systematically in stable
CAD patients1
Summary

High Residual Risk of Atherothrombotic Events Exists in
Patients with PAD Despite Optimized Antiplatelet Therapy
1. Tendera M et al, – ESC PAD Guidelines, Eur Heart J 2011;32:2851–2906; 2. Gerhard-Herman MD et al – AHA/ACC lower extremity PAD
Guidelines, J Am Coll Cardiol 2016;69:e71–e126; 3. Antithrombotic Trialists’ Collaboration, BMJ 2002;324:71–86;
4. CAPRIE Steering Committee, Lancet 1996;348:1329–1339; 5. Cacoub PP et al, Eur Heart J 2009:30:192–201;
6. Bonaca MP et al, Circulation 2013;127:1522–1529
ASA or
P2Y12 inhibitor
DAPT or vorapaxar
plus antiplatelet
therapy
PAD
 Guidelines recommend antiplatelet agents
to reduce the risk of CV events in patients
with PAD1,2
 23% reduction in risk of CV events with
antiplatelet versus control (meta-analysis)3
 Clopidogrel more effective than ASA in reducing
the risk of CV events (CAPRIE trial)4
 Limited benefits of more intensive antiplatelet
therapy (ASA plus clopidogrel; vorapaxar) in
patients with stable, symptomatic PAD5,6
Summary

High Residual Risk of Atherothrombotic Events Exists in Patients
with CAD and PAD Despite Optimized Antiplatelet Therapy
Trial/regimen Residual risk of
atherothrombotic events (composite
endpoint of CV death/MI/stroke)
CAPRIE: clopidogrel 75 mg od1 5.32%/year
CHARISMA: ASA + clopidogrel 75 mg
od2
6.8% (incidence proportion over a median follow-
up of 28 months)
PEGASUS: ASA + ticagrelor (90 mg
bid or 60 mg bid)3
7.9% with ticagrelor 90 mg bid (3-year rate)
7.8% with ticagrelor 60 mg bid (3-year rate)
EUCLID4 10.6%/year with clopidogrel 75 mg od
10.8%/year with ticagrelor 90 mg bid
TRA2°P-TIMI 50: vorapaxar +
standard antiplatelet therapy (prior
MI)5
8.1% (3-year rate)
TRA2°P-TIMI 50: vorapaxar +
standard antiplatelet therapy (PAD)6
11.3% (3-year rate)
PAD
CAD
1. CAPRIE Steering Committee, Lancet 1996;348:1329–1339; 2. Bhatt DP et al, N Engl J Med 2006:354:1706–1717; 3 . Bonaca MP et al, N Engl J
Med 2015;372:1791–1800; 4. Hiatt WR et al, N Engl J Med 2017;376:32–40; 5. Scirica BM et al, Lancet 2012;380:1317–13246. Bonaca MP et al,
Circulation 2013;127:1522–1529
Summary

Angiolillo DJ et al, Eur Heart J 2010;31:17–28
Coagulation
factors
Thrombin
PAR-1
PAR-4
Quiescent
platelet
Activated platelet
Haemostasis
& thrombosis
Fibrin
formation
Platelet
activation
Factor Xa
inhibitors
Coagulation
Platelet
activation
PAD
CAD
Rivaroxaban impacts not only fibrin formation, but also platelet activation
Rivaroxaban Targets Essential Components of
Atherothrombosis to Provide Vascular Protection

Current Clinical Evidence for Rivaroxaban in CAD
 Rivaroxaban vascular dose has been shown to reduce the
risk of atherothrombotic events, including deaths, in patients
with ACS (ATLAS ACS2 TIMI 51)1
 Rivaroxaban vascular dose with single antiplatelet has an acceptable
safety profile in patients with CAD (ATLAS ACS 1 TIMI 48, ATLAS
ACS2 TIMI 51 and GEMINI ACS1) 1,2,3
CAD
1. Mega JL et al, N Engl J Med 2012;366:9–19; 2. Mega JL et al, Lancet 2009;374:29–38; 3. Ohman EM et al, Lancet 2017;389:1799–1808
Summary

A Randomized Controlled Trial of Rivaroxaban for the
Prevention of Major Cardiovascular Events in Patients
With Coronary or Peripheral Artery Disease
(Cardiovascular OutcoMes for People Using Anticoagulation StrategieS)
COMPASS Topline Results
Study number 15786
www.clinicaltrials.gov/show/NCT01776424
Co-PIs: John Eikelboom & Stuart Connolly
SC Chair: Salim Yusuf
SC Co-Chair: Keith Fox

A Dual Pathway Approach Targeting Chronic Patients with
CAD or PAD was Investigated in COMPASS
Objective: To determine the efficacy and safety of rivaroxaban, vascular dose of rivaroxaban plus
aspirin or aspirin alone for reducing the risk of MI, stroke and cardiovascular death in CAD or PAD
Rivaroxaban 5.0 mg bid
Aspirin 100 mg od
Rivaroxaban 2.5 mg bid + Aspirin 100 mg od
30-day
washout
period
30-day run-in,
aspirin 100 mg
Final
follow-up
visit
R
Final
washout
period visit
1:1:1
N=27,395
Population:
Chronic
CAD (91%)
PAD (27%)
*Patients who were not receiving a proton pump inhibitor (PPI) were randomized to pantoprazole or placebo (partial factorial design); the PPI
pantoprazole component of the study is continuing; data will be communicated once complete
1. Eikelboom JW et al. N Engl J Med 2017;377:1319–1330; 2. Bosch J et al. Can J Cardiol 2017;33(8):1027–1035
Average follow-up: 23 months at
early termination of study
Factorial design
± pantoprazole*
PAD
CAD
Run-in phase: to identify patients unwilling/unable to adhere to long-term study treatment or who were otherwise not
suitable for randomization

http://www.reuters.com/article/us-bayer-xarelto-idUSKBN15N2BH [accessed 16 May 2017]
PAD
CAD
COMPASS: Stopped 1 Year Early for Overwhelming
Efficacy of Rivaroxaban in CAD/PAD
Image source:
http://www.news.bayer.com/baynews/baynews.nsf/id/BAF21410A6C41901C12580C10052A834/$F
ile/2017-0041E.pdf?open&mod=08.02.2017_16:43:04 [accessed 16 May 2017]
February 8, 2017

Inclusion and Exclusion Criteria Ensure That Patients
Are Chronic CAD and PAD Patients
Key inclusion criteria*
 PAD
 CAD with ≥1 of:
 Age ≥65 years
 Age <65 years plus atherosclerosis
in ≥2 vascular beds or ≥2 additional
risk factors
– Current smoker
– Diabetes mellitus
– Renal dysfunction
(eGFR<60 ml/min)
– Heart failure
– Non-lacunar ischemic stroke
≥1 month ago
Key exclusion criteria‡
 Stroke ≤1 month or any
haemorrhagic or lacunar stroke
 Severe HF with known ejection
fraction <30% or NYHA class III or
IV symptoms
 Need for dual antiplatelet
therapy, other non-aspirin
antiplatelet therapy, or oral
anticoagulant therapy
 eGFR <15 ml/min
#Including but not limited to; ‡any other exclusion criteria in conjunction with the local Product Information and
any other contraindication listed in the local labelling for rivaroxaban or the comparator have to be considered
www.clinicaltrials.gov/ct2/show/NCT01776424 [accessed 21 Mar 2017];
Bosch J et al, Can J Cardiol 2017;33:1027–1035
PAD
CAD

Main Study Outcomes
Primary efficacy outcome
 Composite of MI, stroke or CV death
(MACE)
Primary safety outcome
 Modified ISTH major bleeding
 Fatal bleeding, and/or
 Symptomatic bleeding in a
critical area or organ, such as
intracranial, or
 Bleeding into the surgical site
requiring re-operation, and/or
 Bleeding leading to
hospitalization
Secondary efficacy outcomes
 Composite of major thrombotic events
 Coronary heart disease death, MI,
ischaemic stroke, acute limb ischaemia
 Cardiovascular death, MI, ischaemic
stroke, acute limb ischaemia
 Mortality (all cause)
PAD
CAD
Eikelboom JW et al. N Engl J Med 2017;377:1319–1330

Modified ISTH Major Bleeding Definition Applied at Regulators’ Request
with the Intent of Capturing all Bleeding that Required Medical Attention
Modified ISTH major bleeding
(COMPASS)2,3
 Fatal bleeding, and/or
 Symptomatic bleeding in a
critical area or organ (such as
intracranial), or
 Bleeding into the surgical
site requiring re-operation,
and/or
 Bleeding leading to
hospitalization
1. Schulman S et al, J Thromb Haemost 2005;3:692–694; 2. Eikelboom JW et al. N Engl J Med 2017;377:1319–1330;
3. Bosch J et al, Can J Cardiol 2017;33(8):1027–1035
ISTH major bleeding1
 Fatal bleeding, and/or
 Symptomatic bleeding in a
critical area or organ (such as
intracranial), and/or
 Bleeding causing a drop in
haemoglobin level of
≥20 g/l, or leading to
transfusion of ≥2 units of
whole blood or red cells
PAD
CAD
Unlike the standard ISTH criteria, all bleeding that led to presentation
to an acute care facility or hospitalization were considered as major
compared with the standard ISTH major bleeding definition

Key Baseline Characteristics Are in Line With Those
Usually Seen in Patients With Chronic CAD or PAD
Characteristic Rivaroxaban 2.5 mg
bid + aspirin 100 mg
N=9152
Rivaroxaban 5 mg bid
N=9117
Aspirin 100 mg
N=9126
Age, years 68 68 68
Blood pressure, mmHg 136/77 136/78 136/78
Total cholesterol, mmol/L 4.2 4.2 4.2
CAD, % 91 90 90
PAD, % 27 27 27
Diabetes, % 38 38 38
Lipid-lowering drugs, % 90 90 89
ACE inhibitors/ARB, % 71 72 71
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker
PAD
CAD

Patients in COMPASS Were Receiving
High Standard of Care
Baseline medication Total
N=27,395
n (%)
ACE inhibitor/angiotensin receptor blocker 19,518 (71.2)
Calcium channel blocker 7269 (26.5)
Diuretic 8139 (29.7)
Beta-blocker 19,184 (70.0)
Lipid-lowering agent 24,601 (89.8)
NSAID 1470 (5.4)
Non-study PPI 9798 (35.8)
PAD
CAD

Dual Pathway Inhibition with Rivaroxaban Vascular Dose
2.5 mg bid + Aspirin Reduced CV Death, Stroke and MI
PAD
CAD
*Rates as at mean follow up of 23 months
MACE* % HR (95% CI) p-value
Aspirin 100mg OD 5.4 - -
Rivaroxaban 5mg BID 4.9 0.90 (0.79-1.03) 0.12
Rivaroxaban 2.5mg BID +
Aspirin 100 mg OD
4.1 0.76 (0.66-0.86) <0.001
Cumulative
incidence
(%)
0
2
4
6
8
10
0 1 2 3
Rivaroxaban 2.5mg bid + Aspirin 100mg od
Rivaroxaban 5mg bid
Aspirin 100mg od
Number at risk
Aspirin 100mg od 9126 7808 3860 669
Riva 5mg bid 9117 7824 3862 670
Riva 2.5mg bid +
Aspirin 100mg od
9152 7904 3912 658
Year

Dual Pathway Inhibition with Rivaroxaban 2.5 mg bid + Aspirin:
Significantly Reduced CV Events by 24% Versus Aspirin
Outcomes, n (%) Rivaroxaban
2.5 mg bid +
aspirin 100 mg
N=9152
Aspirin
100 mg
N=9126
Rivaroxaban 2.5 mg bid +
aspirin 100 mg vs aspirin 100 mg
HR (95% CI) p-value
CV death, stroke,
or MI
379 (4.1) 496 (5.4) 0.76 (0.66–0.86) <0.001
CV death 160 (1.7) 203 (2.2) 0.78 (0.64–0.96) 0.02
Stroke 83 (0.9) 142 (1.6) 0.58 (0.44–0.76) <0.001
MI 178 (1.9) 205 (2.2) 0.86 (0.70–1.05) 0.14
PAD
CAD
Outcomes, n (%) Rivaroxaban
5 mg bid
N=9117
Rivaroxaban 5 mg bid vs
aspirin 100 mg
HR (95% CI) p-value
CV death, stroke,
or MI
448 (4.9) 0.90 (0.79–1.03) 0.12
CV death 195 (2.1) 0.96 (0.79–1.17) 0.69
Stroke 117 (1.3) 0.82 (0.65–1.05) 0.12
MI 182 (2.0) 0.89 (0.73–1.08) 0.24

Bleeding Rates Increased but Low with Rivaroxaban 2.5 mg bid + Aspirin Versus
Aspirin Alone, with No Differences Seen in Fatal and Intracranial Bleeding
PAD
CAD
Rates at mean follow-up of
23 months
Rivaroxaban
2.5 mg bid +
aspirin 100 mg
N=9152
Rivaroxaban
5 mg bid
N=9117
Aspirin 100 mg
N=9126
Modified major ISTH bleeding 288 (3.1%) 255 (2.8%) 170 (1.9%)
Fatal 15 (0.2%) 14 (0.2%) 10 (0.1%)
Non-fatal ICH* 21 (0.2%) 32 (0.4%) 19 (0.2%)
Non-fatal other critical organ* 42 (0.5%) 45 (0.5%) 29 (0.3%)
Rates at mean follow-up of
23 months
aspirin 100 mg
vs aspirin 100 mg
Rivaroxaban 5 mg bid vs
aspirin 100 mg
HR (95% CI) p-value HR (95% CI) p-value
Modified ISTH major bleeding 1.70 (1.40–2.05) <0.001 1.51 (1.25–1.84) <0.001
Fatal 1.49 (0.67–3.33) 0.32 1.40 (0.62–3.15) 0.41
Non-fatal ICH* 1.10 (0.59–2.04) 0.77 1.69 (0.96–2.98) 0.07
Non-fatal other critical organ* 1.43 (0.89–2.29) 0.14 1.57 (0.98–2.50) 0.06
The use of the standard ISTH major bleeding definition
would have led to approximately one third fewer major bleeding events
than with the use of the modified ISTH definition

Net Clinical Benefit: 20% RRR in Risk of the Composite Outcome
with Rivaroxaban 2.5 mg bid + Aspirin Versus Aspirin
 Definition: composite of CV death, stroke, MI, fatal bleeding or
symptomatic bleeding into a critical organ
 In other words, net clinical benefit represented the composite of fatal
and non-fatal events of irreversible harm
PAD
CAD
Rates at
mean follow-
up of
23 months
Rivaroxaban
2.5 mg bid +
aspirin
100 mg
N=9152
Aspirin
100 mg
N=9126
aspirin 100 mg
vs aspirin 100 mg
HR (95% CI) p-value
Composite
net clinical
benefit
outcome
431 (4.7%) 534 (5.9%) 0.80 (0.70–0.91) <0.001

Consistent Benefit Of Rivaroxaban 2.5 mg bid + Aspirin Supported
by Secondary Outcomes, Including All-Cause Mortality
PAD
CAD
Outcome
Rivaroxaban
2.5 mg bid +
aspirin 100 mg
N=9152
Aspirin 100 mg
N=9126
aspirin 100 mg
vs aspirin 100 mg
HR (95% CI) p-value
CHD death,
ischaemic stroke, MI,
ALI
329 (3.6%) 450 (4.9%) 0.72 (0.63–0.83) <0.001
CV death, ischaemic
stroke, MI, ALI
389 (4.3%) 516 (5.7%) 0.74 (0.65–0.85) <0.001
Mortality (all-cause) 313 (3.4%) 378 (4.1%) 0.82 (0.71–0.96) 0.01
CHD coronary heart disease death: death due to acute MI, sudden death, or CV procedure

Rivaroxaban Has Shown Improved Outcomes for Patients
with High Need for Increased Vascular Protection
In patients with chronic CAD or PAD, dual pathway inhibition with rivaroxaban
vascular dose 2.5 mg bid plus aspirin, versus aspirin alone:
 Significantly reduced the combined risk of stroke, CV death and MI
by 24%
 Demonstrated 42% reduction in stroke, 22% reduction in CV death, and 18%
reduction in all-cause mortality
 As expected, resulted in increased major bleeding, however bleeding rates
were low and notably, there was no significant increase in intracranial, critical
organ or fatal bleeding
 Showed a substantial improvement in net clinical benefit of 20%
PAD
CAD

COMPASS CAD Analysis
http://de.connolly-tl2017-els-96829.elsevierreprint.com/

Current recommendations and unmet needs
Current Management of CAD

Current Vascular Protection Strategies Aim to Reduce
Risk of CV Events in Patients with Chronic CAD
Vascular protection
Control of cardiovascular risk factors to limit
atherosclerosis progression and stabilize existing plaques
Lifestyle changes
 Smoking cessation
 Regular exercise
 Healthy diet
 Weight management
 Psychosocial support
Medical therapies
 Lipid control – statins
 Hypertension control –
ACE inhibitors/ARBs
 Diabetes control –
insulin/anti-glycaemic
drugs
Prevention of blood clot
formation over any
ruptured/eroded
atherosclerotic plaques
Antithrombotic therapy
 Single antiplatelet
therapy with aspirin
or clopidogrel
CAD
1. Montalescot G et al, Eur Heart J 2013;34:2949–3003; 2. Cortés-Beringola A et al, Eur J Prevent Cardiol 2017;24:22–28

ESC Guidelines Recommend a Comprehensive
Pharmacological Strategy to Manage Stable CAD
Indication Class* Level#
Event prevention
Low-dose aspirin daily is recommended in all SCAD patients I A
Clopidogrel is indicated as an alternative in case of aspirin intolerance I B
Statins are recommended in all SCAD patients I A
It is recommended to use ACE inhibitors (or ARBs) if presence of
other conditions (e.g. heart failure, hypertension or diabetes)
I A
CAD
*Class of recommendation; #Level of evidence
Montalescot G et al, Eur Heart J 2013;34:2949–3003

Aspirin Is Still the Cornerstone of Long-term
Antithrombotic Therapy for Chronic CAD
Aspirin  Lifelong single antiplatelet therapy with aspirin
is recommended for chronic CAD1
DAPT
(Aspirin + P2Y12 inhibitor)
 Recommended for a limited period of time in:
 Patients with ACS (unstable angina, NSTEMI or
STEMI)2–4
 Patients who underwent coronary stent
implantation2–4
 Not recommended systematically in chronic
CAD patients1
CAD
1. Montalescot G et al, Eur Heart J 2013;34:2949–3003; 2. Windecker S et al, Eur Heart J 2014;35:2541–2619;
3. Roffi M et al, Eur Heart J 2015;37:267–315; 4. Levine GN et al, J Am Coll Card 2016;68:1082–1115

Dual Pathway Inhibition with Rivaroxaban Vascular Dose 2.5 mg bid
+ Aspirin Significantly Reduced MACE by 26% Versus Aspirin
Outcome Rivaroxaban
2.5 mg bid
+ aspirin
N=8313
Rivaroxaban
5 mg bid
N=8250
Aspirin
N=8261
Rivaroxaban
2.5 mg bid + aspirin
vs aspirin
Rivaroxaban
5 mg bid
vs aspirin
N (%) N (%) N (%) HR
(95% CI)
p-value HR
(95% CI)
p-value
MACE 347 (4) 411 (5) 460 (6)
0.74
(0.65–0.86)
<0.0001
0.89
(0.78–1.02)
0.094
CV death 139 (2) 175 (2) 184 (2)
0.75
(0.60–0.93)
0.010
0.95
(0.77–1.17)
0.63
Stroke 74 (1) 105 (1) 130 (2)
0.56
(0.42–0.75)
<0.0001
0.81
(0.62–1.05)
0.10
Ischaemic/
unspecified
60 (1) 79 (1) 120 (2)
0.50
(0.36–0.67)
<0.0001
0.66
(0.50–0.87)
0.0037
Haemorrhagic 14 (<1) 27 (<1) 10 (<1)
1.39
(0.62–3.32)
0.43
2.70
(1.31–5.59)
0.0051
MI 169 (2) 176 (2) 195 (2)
0.86
(0.70–1.05)
0.15
0.90
(0.74–1.11)
0.33
CAD
Connolly SJ et al, Lancet 2017; doi:10.1016/S0140-6736(17)32458-3

Dual Pathway Inhibition with Rivaroxaban 2.5 mg bid + Aspirin
Significantly Reduced MACE by 26% Versus Aspirin
Stroke/MI/cardiovascular death
Cumulative
incidence
risk
(%)
0
2
4
6
8
10
0 1 2 3
Year
CAD
Aspirin 100 mg od

Cumulative
incidence
risk
(%)
0
2
4
6
8
10
0 1 2 3
Year
CAD
Rivaroxaban 2.5 mg bid + aspirin 100 mg od
Aspirin 100 mg od
Rivaroxaban 2.5 mg bid + aspirin vs aspirin HR=0.74 (95% CI 0.65–0.86) p<0.0001

Cumulative
incidence
risk
(%)
0
2
4
6
8
10
0 1 2 3
Year
CAD
Aspirin 100 mg od
Rivaroxaban 2.5 mg bid + aspirin vs aspirin
Rivaroxaban 5 mg bid vs aspirin
HR=0.74 (95% CI 0.65–0.86) p<0.0001
HR=0.89 (95% CI 0.78–1.02) p=0.094

Bleeding Rates Increased but Low with Rivaroxaban
Vascular Dose 2.5 mg bid + Aspirin Versus Aspirin Alone
Outcome
Rivaroxaban
2.5 mg bid
+ aspirin
N=8313
Rivaroxaban
5 mg bid
N=8250
Aspirin
N=8261
Rivaroxaban
vs aspirin
Rivaroxaban
5 mg bid
vs aspirin
N (%) N (%) N (%)
HR
(95% CI)
p-value
HR
(95% CI)
p-value
Major bleeding 263 (3) 236 (3) 158 (2)
1.66
(1.37–2.03)
<0.0001
1.51
(1.23–1.84)
<0.0001
Fatal 14 (<1) 12 (<1) 9 (<1)
1.55
(0.67–3.58)
0.30
1.33
(0.56–3.16)
0.51
ICH 19 (<1) 32 (<1) 19 (<1)
0.99
(0.52–1.87)
0.98
1.69
(0.96–2.99)
0.065
Critical organ 36 (<1) 42 (1) 25 (<1)
1.42
(0.85–2.36)
0.18
1.70
(1.04–2.79)
0.033
Other 194 (2) 150 (2) 105 (1)
1.85
(1.46–2.34)
<0.0001
1.44
(1.12–1.84)
0.0041
CAD
No significant increase in critical organ bleeding
including intracranial or fatal bleeding

2.5 mg bid + Aspirin Versus Aspirin Alone
Major bleeding
CAD
Year
Cumulative
incidence
risk
(%)
0
2
4
6
8
10
0 1 2 3
Aspirin 100 mg od

Major bleeding
CAD
Year
Cumulative
incidence
risk
(%)
0
2
4
6
8
10
0 1 2 3
Aspirin 100 mg od
Rivaroxaban 2.5 mg bid + aspirin vs aspirin HR=1.66 (95% CI 1.37–2.03) p<0.0001

Major bleeding
CAD
Year
Cumulative
incidence
risk
(%)
0
2
4
6
8
10
0 1 2 3
Aspirin 100 mg od
Rivaroxaban 2.5 mg bid + aspirin vs aspirin
Rivaroxaban 5 mg bid vs aspirin
HR=1.66 (95% CI 1.37–2.03)
HR=1.51 (95% CI 1.23–1.84)
p<0.0001
p<0.0001

22% Reduction in Risk of the Composite Net Clinical Benefit Outcome
with Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin vs Aspirin
 For every 1000 patients with CAD treated with rivaroxaban plus aspirin,
13 MACE events would be prevented and 2 fatal or critical organ bleeds
would be caused over a mean 23-month period
Rates at mean
follow-up of
23 months
Rivaroxaban
2.5 mg bid
+ aspirin
N=8313
Rivaroxaban
5 mg bid
N=8250
Aspirin
N=8261
Rivaroxaban
vs aspirin
Rivaroxaban
5 mg bid
vs aspirin
N (%) N (%) N (%) HR
(95% CI)
p-value HR
(95% CI)
p-value
Net clinical benefit
(CV death, stroke,
MI, fatal or critical
organ bleeding)
392 (5) 462 (6) 494 (6)
0.78
(0.69–0.90)
0.0003
0.94
(0.82–1.06)
0.31
All-cause mortality 262 (3) 316 (4) 339 (4)
0.77
(0.65–0.90)
0.0012
0.93
(0.80–1.09)
0.37
CV death 139 (2) 175 (2) 184 (2)
0.75
(0.60–0.93)
0.010
0.95
(0.77–1.17)
0.63
Non-CV death 123 (2) 141 (2) 155 (2)
0.79
(0.62–1.00)
0.048
0.91
(0.73–1.15)
0.43
CAD

Rivaroxaban Was Associated with Improved Outcomes
in a Broad Population of Patients with CAD
 Dual pathway inhibition with rivaroxaban vascular dose 2.5 mg bid plus
aspirin significantly reduced the risk of MACE by 26%
 Stroke 44% (significant)
 MI 14% (non-significant)
 CV death 25% (significant)
 Overall bleeding rates were low, with an expected increase in major
bleeding with the dual pathway inhibition versus aspirin alone. Notably
there was no significant increase in critical organ bleeding including
intracranial or fatal bleeding
 There was a significant reduction in all three secondary outcomes
including a reduction in all-cause mortality by 23%
CAD

COMPASS PAD Analysis
http://de.anand-tl2017-els-96831.elsevierreprint.com/

Progressive Atherosclerosis Underlying Lower Extremity
PAD Results in a Spectrum of Limb Symptoms
Fontaine stage1–3 Rutherford category1–3 Proportion of
patients3
I Asymptomatic 0 Asymptomatic
II IIa Non-disabling
intermittent
claudication*
1 Mild claudication*
2 Moderate claudication*
IIb Disabling
intermittent
claudication*
3 Severe claudication*
III Ischaemic rest pain 4 Rest pain
IV Ulceration or gangrene 5 Minor tissue loss
6 Major tissue loss
PAD
CLI
 ALI is caused by either native atherosclerotic plaque disruption and thrombus
formation, or in situ stent or graft thrombosis in revascularized patients4
*Or atypical leg pain
1. Aboyans V et al, Eur Heart J 2017: doi:10.1093/eurheartj/ehx095; 2. Aboyans V et al, Eur J Vasc Endovasc Surg 2017:
doi:10.1016/j.ejvs.2017.07.018; 3. Norgren L et al, J Vasc Surg 2007;45:S5–S67; 4. Hirsch AT et al, Vasc Med 2016;21:535–538

Current recommendations and unmet needs
Current Management of PAD

Current Vascular Protection Strategies Aim to Reduce Risk of
Atherothrombotic CV and Limb Events in Patients with PAD
Vascular protection1–4
Control of cardiovascular risk factors to limit
atherosclerosis progression and stabilize existing plaques
Lifestyle changes
 Smoking cessation
 Regular exercise
 Healthy diet
 Weight management
 Psychosocial support
Medical therapies
 Lipid control – statins
 Hypertension control –
ACE inhibitors/ARBs
 Diabetes control –
insulin/anti-glycaemic
drugs
Prevention of blood clot
formation over any
ruptured/eroded
atherosclerotic plaques
Antithrombotic therapy
 Single antiplatelet
therapy with aspirin or
clopidogrel
PAD
1. Aboyans V et al, Eur Heart J 2018;39:763–816; 2. Aboyans V et al, Eur J Vasc Endovasc Surg 2017: pii: S1078-5884(17)30454-9;
3. Gerhard-Herman MD et al, J Am Coll Card 2016: doi:10.1016/j.jacc.2016.11.007; 4. Cortés-Beringola A et al, Eur J Prevent Cardiol 2017;24:22–28

The Current ESC Guidelines for PAD Management
Recommend Treatment of Symptomatic PAD
PAD
Patients with… Recommendation Class
Symptomatic PAD Antiplatelet therapy is recommended Ic
Lower extremity PAD In patients requiring antiplatelet therapy, clopidogrel may be preferred
over aspirin
IIb
Anticoagulation with VKAs may be considered after autogenous vein
infrainguinal bypass
IIb
DAPT (aspirin plus clopidogrel) for ≥1 month should be considered
after infra-inguinal stent implantation
IIa
DAPT (aspirin plus clopidogrel) may be considered in the case of
below-knee bypass with a prosthetic graft
IIb
Long-term SAPT is recommended in all patients who have undergone
revascularization
Ic
SAPT is recommended after infrainguinal bypass surgery Ia
1. Aboyans V et al, Eur Heart J 2018;39:763–816; 2. Aboyans V et al, Eur J Vasc Endovasc Surg 2017: pii: S1078-5884(17)30454-9
 SAPT is recommended for all patients with symptomatic PAD
 DAPT is recommended only for a limited period of time after certain revascularization
procedures
2017 ESC guideline recommendations for antithrombotic therapies in
patients with PAD

Inclusion and Exclusion Criteria Ensure That
Patients with Chronic PAD are Enrolled
Key inclusion criteria
 Previous peripheral artery
revascularization
 Previous limb or foot amputation for
arterial vascular disease
 Intermittent claudication plus:
 Low ABI (<0.90), or
 Significant peripheral artery
stenosis (≥50%)
 Previous carotid revascularization,
or asymptomatic carotid artery
stenosis ≥50%
 CAD + low ABI (<0.90)
Key exclusion criteria
 High risk of bleeding
 Stroke within 1 month
 History of haemorrhagic/lacunar
stroke
 Severe heart failure (ejection
fraction <30%)
 eGFR <15 ml/min
 A need for dual antiplatelet therapy
 A need for non-aspirin antiplatelet
therapy
 An indication for anticoagulation
therapy
Anand SS et al, Lancet 2017: doi:10.1016/S0140-6736(17)32757-5
PAD
CAD

PAD-Specific Limb Outcomes Were Added to
Main Study Outcomes for COMPASS
 Primary cardiovascular outcome was MACE, defined as:
 Composite of cardiovascular death, stroke or MI
 Key composite outcomes for PAD:
 Primary limb outcome was major adverse limb events (MALE),
defined as development of ALI or CLI and major amputations not included in
ALI or CLI
 The composite of MACE and MALE
 The composite of MACE, MALE and major amputations not included in
ALI or CLI
PAD

Major Adverse Limb Events and Major Amputation
Were Included in PAD-Specific Net Clinical Benefit
 Primary safety outcome: modified ISTH
 Major bleeding defined as:
– Fatal bleeding, or
– Bleeding into a critical organ, or
– Surgical site bleeding requiring reoperation, or
– Bleeding requiring hospitalization
 Net clinical benefit outcome defined as:
 MACE
 MALE including major amputation
 Fatal bleeding
 Bleeding into a critical organ
PAD

COMPASS Included over 7000 Patients with
Symptomatic PAD or Concomitant CAD and PAD
 PAD was defined according to patient presentation at enrolment
 In addition, a patient could be defined as a PAD patient based on
medical history and/or measurement of ABI at baseline visit
 The latter category added patients with CAD and asymptomatic PAD
patients into the overall PAD subgroup
 Median follow-up: 21 months
Number of patients
All patients with PAD 7470
Symptomatic lower-extremity PAD 4129
Carotid disease 1919
CAD + asymptomatic PAD (ABI <0.90) 1422
PAD
CAD

Baseline Characteristics Were Consistent across Treatment Arms
and in Line with Those Usually Seen in Patients with PAD
Characteristic
Rivaroxaban
N=2492
Rivaroxaban
5 mg bid
N=2474
Aspirin
N=2504
Age, years, mean ± SD 67.9±8.5 67.8±8.5 67.8±8.5
Current smoker, n (%) 682 (27.4) 685 (27.7) 685 (27.4)
Former smoker, n (%) 1147 (46.0) 1154 (46.6) 1143 (45.6)
Diabetes, n (%) 1100 (44.1) 1083 (43.8) 1104 (44.1)
Hypertension, n (%) 1966 (78.9) 1939 (78.4) 2017 (80.6)
Prior CAD, n (%) 1656 (66.5) 1609 (65.0) 1641 (65.5)
Prior stroke, n (%) 171 (6.9) 177 (7.2) 154 (6.2)
Lipid lowering, n (%) 2088 (83.8) 2074 (83.8) 2074 (82.8)
ACE inhibitor/ARB, n (%) 1715 (68.8) 1757 (71.0) 1765 (70.5)
PAD

Dual Pathway Inhibition with Rivaroxaban Vascular Dose 2.5 mg
bid + Aspirin Reduced MACE by 28% Versus Aspirin Alone
Outcome
Rivaroxaban
2.5 mg bid
+ aspirin
N=2492
Rivaroxaban
5 mg bid
N=2474
Aspirin
N=2504
Rivaroxaban
vs aspirin
Rivaroxaban
5 mg bid
vs aspirin
N (%) N (%) N (%)
HR
(95% CI)
p-
value
HR
(95% CI)
p-
value
MACE 126 (5) 149 (6) 174 (7)
0.72
(0.57–0.90)
0.0047
0.86
(0.69–1.08)
0.19
CV death 64 (3) 66 (3) 78 (3)
0.82
(0.59–1.14)
–
0.86
(0.62–1.19)
–
Stroke 25 (1) 43 (2) 47 (2)
0.54
(0.33–0.87)
–
0.93
(0.61–1.40)
–
MI 51 (2) 56 (2) 67 (3)
0.76
(0.53–1.09)
–
0.84
(0.59–1.20)
–
PAD

Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Significantly
Reduced Major Amputation by 70% Versus Aspirin Alone
Outcome
Rivaroxaban
2.5 mg bid
+ aspirin
N=2492
Rivaroxaban
5 mg bid
N=2474
Aspirin
N=2504
Rivaroxaban
vs aspirin
Rivaroxaban
5 mg bid
vs aspirin
N (%) N (%) N (%)
HR
(95% CI)
p-
value
HR
(95% CI)
p-
value
MALE 30 (1) 35 (1) 56 (2)
0.54
(0.35–0.84)
0.0054
0.63
(0.41–0.96)
0.032
Major
amputation
5 (<1) 8 (<1) 17 (<1)
0.30
(0.11–0.80)
0.011
0.46
(0.20–1.08)
0.068
MALE plus
major
amputation*
32 (1) 40 (2) 60 (2)
0.54
(0.35–0.82)
0.0037
0.67
(0.45–1.00)
0.046
PAD
*An additional 11 major amputations of a vascular cause were done that were unlinked to acute or chronic limb
ischaemia, two in the low-dose rivaroxaban plus aspirin group, five in the rivaroxaban alone group, and four in
the aspirin alone group

Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin
Significantly Reduced MACE and MALE Versus Aspirin Alone
Composite
outcome
Rivaroxaban
2.5 mg bid
+ aspirin
N=2492
Rivaroxaban
5 mg bid
N=2474
Aspirin
N=2504
Rivaroxaban
vs aspirin
Rivaroxaban
5 mg bid
vs aspirin
N (%) N (%) N (%)
HR
(95% CI)
p-
value
HR
(95% CI)
p-
value
MACE or
MALE
including
major
amputation
157 (6) 188 (8) 225 (9)
0.69
(0.56–0.85)
0.0003
0.83
(0.69–1.02)
0.077
PAD

Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Significantly Reduced
Acute Limb Ischaemia and Vascular Amputations Versus Aspirin Alone
Outcome
Rivaroxaban
2.5 mg bid
+ aspirin
N=2492
Rivaroxaban
5 mg bid
N=2474
Aspirin
N=2504
Rivaroxaban
vs aspirin
Rivaroxaban
5 mg bid
vs aspirin
N (%) N (%) N (%)
HR
(95% CI)
p-
value
HR
(95% CI)
p-
value
Acute limb
ischaemia
19 (1) 19 (1) 34 (1)
0.56
(0.32–0.99)
0.042
0.57
(0.32–1.00)
0.046
Chronic limb
ischaemia
16 (1) 18 (1) 24 (1)
0.67
(0.35–1.26)
0.21
0.76
(0.41–1.40)
0.37
All vascular
amputations
11 (<1) 17 (1) 28 (1)
0.40
(0.20–0.79)
0.0069
0.61
(0.33–1.11)
0.10
PAD

PAD
0 1 2 3
0.05
0.10
0.15
Cumulative
incidence
risk
Year
0
28% RRR in MACE with Rivaroxaban Vascular
Dose 2.5 mg bid + Aspirin Versus Aspirin Alone
Aspirin 100 mg od
Number at risk
Aspirin 2504 2065 930 119

PAD
0 1 2 3
0.05
0.10
0.15
Cumulative
incidence
risk
Year
0
Aspirin 100 mg od
Number at risk
Rivaroxaban + aspirin 2492 2086 907 127
Aspirin 2504 2065 930 119
Rivaroxaban 2.5 mg bid + aspirin vs aspirin: HR 0.72 (0.57–0.90), p=0.005

PAD
0 1 2 3
0.05
0.10
0.15
Cumulative
incidence
risk
Year
0
Aspirin 100 mg od
Number at risk
Rivaroxaban 2474 2044 870 147
Aspirin 2504 2065 930 119
Rivaroxaban 5 mg bid vs aspirin 100 mg: HR 0.86 (0.69–1.08), p=0.192

PAD
46% RRR in MALE Including Major Amputation with
Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Versus Aspirin Alone
MALE including major amputation
0
0.02
0.04
0.10
0.06
0.08
0 1 2 3
Cumulative
incidence
risk
Year
Number at risk
Aspirin 2504 2072 951 120
Aspirin 100 mg od

PAD
0
0.02
0.04
0.10
0.06
0.08
0 1 2 3
Cumulative
incidence
risk
Year
Number at risk
Aspirin 2504 2072 951 120
Aspirin 100 mg od

PAD
0
0.02
0.04
0.10
0.06
0.08
0 1 2 3
Cumulative
incidence
risk
Year
Number at risk
Rivaroxaban 2474 2071 902 151
Aspirin 2504 2072 951 120
Aspirin 100 mg od
Rivaroxaban 5 mg bid vs aspirin 100 mg: HR 0.67 (0.45–1.00), p=0.05

Bleeding Increased but Low with Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin
Versus Aspirin Alone, with No Differences Seen in Fatal and Intracranial Bleeding
Outcome
Rivaroxaban
2.5 mg bid
+ aspirin
N=2492
Rivaroxaban
5 mg bid
N=2474
Aspirin
N=2504
Rivaroxaban
vs aspirin
Rivaroxaban
5 mg bid
vs aspirin
N (%) N (%) N (%)
HR
(95% CI)
p-value
HR
(95% CI)
p-value
Major bleeding 77 (3) 79 (3) 48 (2)
1.61
(1.12–2.31)
0.0089
1.68
(1.17–2.40)
0.0043
Fatal 4 (<1) 5 (<1) 3 (<1) – – – –
Intracranial 5 (<1) 6 (<1) 9 (<1)
0.56
(0.19–1.66)
–
0.68
(0.24–1.91)
–
Fatal or
symptomatic
bleeding into
a critical
organ
21 (1) 26 (1) 19 (1)
1.10
(0.59–2.05)
-
1.39
(0.89–3.09)
-
PAD
Anand SS et al, Lancet 2017;doi:10.1016/S0140-6736(17)32757-5

28% Reduction in Risk of the Composite Outcome with Rivaroxaban
Vascular Dose 2.5 mg bid + Aspirin Versus Aspirin Alone
 For every 1000 patients with PAD treated with rivaroxaban plus aspirin,
27 MACE or MALE (including major amputation) events would be
prevented, and 1 fatal and 1 critical organ bleed would be caused over
a 21-month period
Rates at
median
follow-up of
21 months
Rivaroxaban
2.5 mg bid
+ aspirin
N=2492
Rivaroxaban
5 mg bid
N=2474
Aspirin
N=2504
Rivaroxaban
vs aspirin
Rivaroxaban
5 mg bid
vs aspirin
N (%) N (%) N (%)
HR
(95% CI)
p-
value
HR
(95% CI)
p-
value
Composite
net clinical
benefit
outcome*
169 (7) 207 (8) 234 (9)
0.72
(0.59–0.87)
0.0008
0.89
(0.74–1.07)
0.23
PAD
*Defined as CV death, MI, stroke, MALE, major amputation, fatal bleeding or critical organ bleeding

Vascular Dose Rivaroxaban Showed Improved Outcomes for
PAD Patients with a Need for Increased Vascular Protection
 Rivaroxaban vascular dose 2.5 mg bid plus aspirin reduced the
composite endpoint of stroke, MI or CV death by 28%
 MALE by 46%
 Major amputations by 70%
 Despite an expected increase in major bleeding events with
rivaroxaban 2.5 mg bid plus aspirin, no significant increase was
observed in fatal or critical organ bleeding
 This dual pathway inhibition of rivaroxaban vascular dose and aspirin
represents a major advance in the management of PAD and is the only
available therapeutic option to significantly reduce both MACE and
MALE
PAD

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