Evolving Role of Antithrombotic Therapy in CAD and PAD:
The COMPASS Trial
DEEPAK L. BHATT, MD, MPH
Executive Director of Interventional Cardiovascular
Programs, BWH Heart and Vascular Center
Professor of Medicine, Harvard Medical School
Disclosures for Dr. Bhatt
Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado
Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care;
Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees:
Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic,
Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate
Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter),
Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute
(clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology),
Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health
Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology
Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME
steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering
Committee, VA CART Research and Publications Committee (Chair); Research Funding: Amarin,
Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood,
Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier
(Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator:
Biotronik, Boston Scientific, St. Jude Medical; Trustee: American College of Cardiology; Unfunded
Research: FlowCo, Merck, PLx Pharma, Takeda.
This presentation discusses off-label and/or investigational uses of various drugs and devices.
Bhatt DL, Hulot J-S, Moliterno, DJ, Harrington RA. Circ Res 2014; 114:1929-1943. In Fuster V, Kovacic J. Compendium on ACS.
Recent ACS: STEMI, NSTEMI, UAStabilized 1-7 Days Post-Index Event
Exclusions: increased bleeding risk, warfarin use, ICH, prior
stroke or TIA if on ASA + thienopyridine
PRIMARY ENDPOINTS:
EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin)
SAFETY: TIMI major bleeding not associated with CABG
Rivaroxaban
5.0 mg BID
Stratified by Thienopyridine Use at MD Discretion
ASA 75 to 100 mg/day
Placebo Rivaroxaban
2.5 mg BID
N=15,526
ATLAS ACS 2 TIMI 51 Trial
Months After Randomization
Primary Efficacy Endpoint:
CV Death / MI / Stroke
Rivaroxaban(both doses)
HR 0.84
(0.74-0.96)
ARR 1.8%
NNT = 56
10.7%
8.9%
Esti
mate
d C
um
ula
tive I
ncid
en
ce
(%)
Placebo
5113 4307 3470 2664 1831 1079 421
10229 8502 6753 5137 3554 2084 831
Placebo
Rivaroxaban
2 Yr KM Estimate
No. at Risk
Mega et al and Gibson CM. NEJM 2011.
Placebo
0 24
Rivaroxaban
2.5 mg BID
All Cause Death
0 24
Cardiovascular Death
Months
CV Death / MI / StrokeE
sti
ma
ted
Cu
mu
lati
ve
in
cid
en
ce (
%)
0 24Months Months
HR 0.85
mITT
p=0.04
ITT
p=0.01
HR 0.62
mITT
p<0.001
ITT
p<0.001
2.7%
4.5%
4.2%
2.5%
10.4%
9.0%
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
PlaceboPlacebo HR 0.64
mITT
p<0.001
ITT
p<0.001
NNT = 56NNT = 71 NNT = 5912 12 12
12%
5% 5%
Efficacy Endpoints:Very Low Dose 2.5 mg BID
Patients Treated with ASA + Thienopyridine
Mega et al and Gibson CM. NEJM 2011.
COMPASS Design
R
Rivaroxaban 2.5 mg bid
+ aspirin 100 mg od
Aspirin 100 mg od
Rivaroxaban 5 mg bid Expected follow up
3-4 years
Run-in
(aspirin)
Stable CAD or PAD
2,200 with a primary outcome event
Outcomes
Primary
• CV death, stroke or myocardial infarction
Secondary
• CHD death, ischemic stroke, myocardial infarction, or acute limb ischemia
• CV death, ischemic stroke, myocardial infarction, or acute limb ischemia
• Mortality
Safety and net benefit
• ISTH major bleeding (modified)
• Primary plus fatal or critical organ bleeding
33 Countries, 602 Sites, 27,395 Participants
Canada
N=2443
United States
N=1475
Brazil
N=1515
Argentina N=2789
Netherlands
N=2522
China
N=1086 Japan N=1556
Czech RepublicN=1553
ItalyN=1018
Follow-up, Adherence
• On February 6, 2017 the Data and Safety Monitoring Board recommended discontinuation of rivaroxaban/aspirin arms for clear evidence of efficacy (combination: Z= -4.59, P<0.00001; rivaroxaban: Z= -2.44, P=0.01)
• Close-out between March and June 2017
• Mean follow up 23 months
• Follow-up 99.8% complete
Baseline Characteristics
CharacteristicRivaroxaban +
aspirin N=9,152
RivaroxabanN=9,117
AspirinN=9,126
Age, yr 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 90% 90% 89%
ACE-I or ARB 71% 72% 71%
Primary: CV Death, Stroke, MI
Outcome
R + A R ARivaroxaban +
aspirin vs. aspirin
Rivaroxaban vs. aspirin
N(%)
N(%)
N(%)
HR(95% CI)
pHR
(95% CI)
p
CV death, stroke, MI
379(4.1%)
448(4.9%)
496(5.4%)
0.76 <0.0001 0.90 0.12
Primary: CV Death, Stroke, MI
Primary Components
Outcome
R + A N=9,152
AN=9,126
Rivaroxaban + Aspirinvs. Aspirin
N(%)
N(%)
HR(95% CI)
p
CV death160
(1.7%)203
(2.2%)0.78
(0.64-0.96)0.02
Stroke83
(0.9%)142
(1.6%)0.58
(0.44-0.76)<0.0001
MI178
(1.9%)205
(2.2%)0.86
(0.70-1.05)0.14
Secondary Outcomes
Outcome
R + A N=9,152
AN=9,126
Rivaroxaban + Aspirinvs. Aspirin
N(%)
N(%)
HR(95% CI)
P*
CHD death, IS,
MI, ALI
329(3.6%)
450(4.9%)
0.72(0.63-0.83)
<0.0001
CV death, IS,
MI, ALI
389(4.3%)
516(5.7%)
0.74(0.65-0.85)
<0.0001
Mortality313
(3.4%)378
(4.1%)0.82
(0.71-0.96)0.01
* pre-specified threshold P=0.0025
CAD and PADSubgroups for Primary Outcome
17
Outcome
R + A N=9,152
AN=9,126
Rivaroxaban +Aspirin
vs. Aspirin
N(%)
N(%)
HR(95% CI)
CAD347
(4.2%)
460
(5.6%)
0.74
(0.65-0.86)
PAD126
(5.1%)174
(6.9%)0.72
(0.57-0.90)
Major Bleeding
OutcomeR + A R A
Rivaroxaban +Aspirin
vs. Aspirin
Rivaroxaban vs. Aspirin
N(%)
N(%)
N(%)
HR(95% CI)
PHR
(95% CI)P
Major bleeding
288(3.1%)
255(2.8%)
170(1.9%)
1.70(1.40-2.05)
<0.00011.51
(1.25-1.84)
<0.0001
Fatal15
(0.2%)14
(0.2%)10
(0.1%)1.49
(0.67-3.33)
0.321.40
(0.62-3.15)
0.41
Non fatal ICH*
21(0.2%)
32(0.4%)
19(0.2%)
1.10(0.59-2.04)
0.771.69
(0.96-2.98)
0.07
Non-fatalother
critical organ*
42(0.5%)
45(0.5%)
29(0.3%)
1.43(0.89-2.29)
0.141.57
(0.98-2.50)
0.06* symptomatic
Net Clinical Benefit
Outcome
R + A N=9,152
AN=9,126
Rivaroxaban + Aspirinvs. Aspirin
N(%)
N(%)
HR(95% CI)
P
Net clinical benefit (Primary + Severebleeding events)
431(4.7%)
534(5.9%)
0.80(0.70-0.91)
0.0005
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)
Anand et Lancet (in press)
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
Anand et Lancet (in press)
Primary Safety Outcome
•Major Bleeding: Modified ISTH
•Net Clinical Benefit: MACE, MALE, major amputation, fatal bleeding, or symptomatic bleeding into a critical organ
Anand et Lancet (in press)
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
Anand et Lancet (in press)
Mean Follow-up: 21 months
Primary Outcome & Components
Outcome
R + AN=2,492
R N=2,474
AN=2,504
Riva + aspirin vs. aspirin
Riva vs. aspirin
N(%)
N(%)
N(%)
HR(95% CI)
PHR
(95% CI)P
MACE126(5.1)
149(6.0)
174(6.9)
0.72 0.005 0.86 0.19
MI51
(2.0)56
(2.3)67
(2.7)0.76 - 0.84 -
Stroke25
(1.0)43
(1.7)47
(1.9)0.54 - 0.93 -
CV Death64
(2.6)66
(2.7)78
(3.1)0.82 - 0.86 -
Limb Outcomes
R + AN=2,492
R N=2,474
AN=2,504
Riva + aspirin vs. aspirin
Riva vs. aspirin
N(%)
N(%)
N(%)
HR(95%
CI)P
HR(95%
CI)P
MALE
30(1.2)
35(1.4)
56(2.2)
0.54(0.35-0.84)
0.0050.63
(0.41-0.96)
0.03
Major amp. 5
(0.2)8
(0.3)17
(0.7)
0.30(0.11-0.80)
0.010.46
(0.20-1.08)
0.07
Key Composite Outcome
Anand et Lancet (in press)
Outcome
R + AN=2,492
RN=2,474
AN=2,504
Riva + aspirin vs. aspirin
Riva vs. aspirin
N(%)
N(%)
N(%)
HR(95%
CI)P
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
Year
Cu
mu
lative
Ha
za
rd R
ate
0.0
0.0
50
.10
0.1
5
0 1 2 3
Rivaroxaban + Aspirin
Rivaroxaban
Aspirin
2492 2069 893 124
2474 2023 864 147
2504 2034 911 113
No. at Risk
Riva + ASA
Riva
ASA
Rivaroxaban + Aspirin vs. Aspirin HR: 0.69 (0.56-0.85) P=0.0003
Rivaroxaban vs. Aspirin HR: 0.84 (0.69-1.02) P=0.08
MACE or MALE or Major Amputation
Anand et Lancet (in press)
Major Bleeding
Anand et Lancet (in press)
Outcome
R + AN=2,492
R N=2,474
AN=2,504
Riva + aspirin vs. aspirin Riva vs. aspirin
N(%)
N(%)
N(%)
HR(95% CI)
PHR
(95% CI)P
Major Bleeding77
(3.1)79
(3.2)48
(1.9)1.61
(1.12-2.31)0.009
1.68(1.17-2.40)
0.004
Fatal4
(0.2)5
(0.2)3
(0.1)- - - -
Non-Fatal ICH4
(0.2)3
(0.1)8
(0.3)- - - -
Non-fatal othercritical site*
13(0.5)
18(0.7)
8(0.3)
1.55(0.64-3.74)
0.332.15
(0.94-4.96)0.06
* symptomatic
Net Clinical Benefit in PAD
Anand et Lancet (in press)
Outcome
R + AN=2,492
R N=2,474
AN=2,504
Riva + aspirin vs. aspirin
Riva vs. aspirin
N(%)
N(%)
N(%)
HR(95%
CI)P
HR(95%
CI)P
Net Clinical Benefit
169 (6.8)207 (8.4)
234 (9.3)
0.72 (0.59-0.87)
0.00080.89
(0.74-1.07)
0.23
Overall COMPASS
Overall PAD
Symptomatic PAD
PAD Lower Extremeties
Carotid Artery Disease
0 0.5 1.0 1.5
Riva 2.5 + ASA
better
ASA only
better
MACE, MALE, or Major Amputation
Anand et Lancet (in press)
Prevalence of atherothrombosis at baseline
Atherothrombotic status of REACH
Registry patients at baseline:
– 18.2% RFO (n=12 389)
– 59.3% CAD (n=40 258)
– 27.8% CVD (n=18 843)
– 12.2% PAD (n=8273)
(single bed disease and overlap in patients with
polyvascular disease shown to left)
Cardiovascular risk-factor profiles
were consistent across patient types
and across all participating regions.
Bhatt DL, et al. JAMA 2006;296:180.
CAD
PAD
8.4%
1.6%
44.6%
4.7%
4.7%
16.6%
CVD
1.2%
CAD, coronary artery disease; CVD, cerebrovascular disease;
PAD, peripheral artery disease; RFO, Risk Factors Only.
*All event rates adjusted for age and sex.
Impact of diabetes on CV events at 4 years
9.19.9
7.1
12.2
17.7
11.5
15.5
10.2
Stable atherosclerotic disease
18.3
25.0
15.7
22.5
15.9
Prior ischemic event Risk factor only
All
+ Polyvascular disease
- Polyvascular disease
+ Diabetes
- Diabetes
CV
de
ath
, M
I, o
r s
tro
ke
at
4 y
ea
rs (
%)*
0
5
10
15
20
25
30
Bhatt DL, Eagle KA, Ohman EM, et al. JAMA 2010; 304:1350-1357.
Eligibility for the COMPASS Trial Among 31,873 Evaluable REACH Registry Patients
Excluded29.9%
Non-included
17.2%
Eligible52.9%
51.8
44.8
25.9
12.4
2.2
0
10
20
30
40
50
60High bleeding risk
Oral anticoagulant treatment
DAPT for ACS/PCI <12 months
Ischaemic stroke <1 year
Severe renal failure
Darmon A, Bhatt DL,…Steg PG (EHJ in press)
4.2[4.0–4.3]
3.2[3.1–3.4]
1.9[1.8–2.1]
1.2[1.1–1.3]
2.9[2.6–3.2]
2.2[1.9–2.4]
1.2[1.0–1.3] 1.0
[0.9–1.2]
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
3.5%
4.0%
4.5%
CV death, MI or stroke All-cause mortality CV death Non-CV death
COMPASS-eligible COMPASS participants
p<0.001
p<0.0001
p<0.0001
p=0.711
Comparison of Main CV Event Rate per 100 Patient/Years for the COMPASS-Eligible Patients from REACH, and COMPASS
Participants from the Aspirin Treatment Arm (%)
Darmon A, Bhatt DL,…Steg PG (EHJ in press)
48.7%
68.4%
60.4%
0%
20%
40%
60%
80%
100%
CAD alone PAD alone CAD & PAD
Non-eligible
Eligible
n=22,969 n=8825 n=5079
Eligibility for the COMPASS Trial among REACH Participants According to the Presence of CAD, PAD, or Both
Darmon A, Bhatt DL,…Steg PG (EHJ in press)
www.brighamandwomens.org/heart
Deepak L. Bhatt, MD, MPHExecutive Director of Interventional Cardiovascular Programs, BWH Heart & Vascular CenterProfessor of Medicine, Harvard Medical School1 (857) [email protected]
Thank You!
