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Secondary Prevention of
Atherothrombotic Events
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Examining the Burden
of the High-risk Patient
Philippe Gabriel Steg, MD, FESC, FACC
DHU-FIRE, Hôpital Bichat, Assistance Publique –
Hôpitaux de Paris
Université Paris – Diderot, INSERM U-1148
Paris, France
French Alliance for Cardiovascular Clinical Trials
& Imperial College, Royal Brompton Hospital
London, UK
Secondary Prevention of
Atherothrombotic Events
Examples of high-risk patients
• Post-myocardial infarction (MI) patients
Examining the Burden
of the High-risk Patient
Evolution of 30-day Mortality
After STEMI in France
13.7
8.7
6.9
4.4
11.3
7.66.4
4.4
0
4
8
12
16
1995 2000 2005 2010
Crude Standardized for2010 populationcharacteristics
USIK USIC-2000 FAST-MI FAST-MI-2
Puymirat E, et al. JAMA. 2012;308:998-1006.
18.9
8.2 8.7
11.3
6.4 6.3
10.8
4.5 4.7
8.7
2.13.2
0
4
8
12
16
20
No reperfusion Lysis PPCI
1995 2000 2005 2010
Adj. OR=0.47 0.32-0.70
Adj. OR=29 0.11-0.76
Adj. OR=0.29 0.15-0.58
Evolution of 30-day Mortality After STEMI
According to Use and Type of Reperfusion Therapy
Puymirat E, et al. JAMA. 2012;308:998-1006.
30
-da
y M
ort
ali
ty,
%
Secondary Prevention of
Atherothrombotic Events
Examples of high-risk patients
• Post-MI patients (but modern therapy does not
abolish risk)
Examining the Burden
of the High-risk Patient
Long-term Event Rates After ACSThe UK–Belgian GRACE Experience
Fox KAA, et al. Eur Heart J. 2010;31:2755–2764.
5-year Death Rates Proportion of Post-discharge Deaths
Recurrent EventsWorse Outcomes than the Index Event
Shotan J, et al. Am J Cardiol 2011;107:1730-1737.
First STEMIAdjusted Survival Curves
Recurrent STEMIAdjusted Survival Curves
Secondary Prevention of
Atherothrombotic Events
Examples of high-risk patients
• Post-MI patients
• Patients with diabetes
Examining the Burden
of the High-risk Patient
Causes of Death
in Patients with Diabetes
0
% o
f D
eath
s
Ischemic Other Strictly Cancer Stroke Infection Other heart heart diabetes-disease disease related
50
40
30
20
10
Geiss LS, et al. In: Diabetes in America. Second Edition. 1995;Chapter 11.
Diabetes as a Risk factor for CV Events:
Vascular Outcomes in Type 2 Diabetes
Sarwar N, et al. Lancet. 2010;375:2215-2222.
*Includes fatal and non-fatal events.
HRs for vascular outcomes in patients with vs without diabetes at baseline, analyses based on 530,083 participants.
Secondary Prevention of
Atherothrombotic Events
Type 2 Diabetes and Coronary
Heart Disease
7-year Incidence of Fatal/Non-fatal MI from the East West Study
Non-diabetic n=1373
Myo
card
ial I
nfa
rcti
on
3.5%
0
5
10
15
20
25
30
35
40
45
No DM, No MI
P<0.001 18.8% 20.2%
No DM, MI DM, No MI
P<0.001
45.0%
DM, MI
Diabetic n=1059
Haffner SM, et al. N Engl J Med 1998;339:229-2234.
Impact of Diabetes in Patients
with Atherothrombosis
0.5
1.1
2.0
3.2
0.7
1.8
3.0
4.6
0
1
2
3
4
5
≥ 3 risk factors EAD 1 site EAD 2 sites EAD 3 sites
Inci
den
ce o
f C
ard
iova
scu
lar
Dea
th (
%)
Nondiabetic subjects
Diabetic patients
*
*
*
• After adjustment for age, sex, hypertension, smoking, and cholesterol, patients with
diabetes in the REACH Registry had an increased risk of CV events at 1 year,
compared with non-diabetic patients
• Rates of CV death increase with the number of vascular beds with established
atherothrombotic disease
• Diabetes increases the risk of new CV events but does not carry the same risk as
previous atherothrombotic eventsKrempf M, et al. Am J Cardiol. 2010;105:667-673.
In Diabetic Patients, the Risk of CV Events Increases with
the Presence of Arterial Disease and History of Prior Events
Cumulative Incidence of CV Events (CV Death, MI, or Stroke)
Among Diabetic Patients from the REACH Registry
Ad
juste
d C
um
ula
tiv
e In
cid
en
ce o
f
Ca
rdio
vasc
ula
r D
eath
, M
I o
r S
tro
ke
(%
)
Months
Diabetes (Overall)
Diabetes (Known Atherothrombosis,
No Prior Ischemic Event)
Diabetes (Known Atherothrombosis, Prior Ischemic Event)
Diabetes
(Risk Factors Only)
Diabetes (Known Atherothrombosis)
n=19,699 pts in REACH with DM at 4 Yr followup
Cavender MA, et al. Circulation. 2015;132:923-931.
Secondary Prevention of
Atherothrombotic Events
Examples of high-risk patients
• Post-MI patients
• Patients with diabetes
• Patients with peripheral arterial disease (PAD)
Examining the Burden
of the High-risk Patient
Patients with PAD Have
the Highest Risk
Event Rates at 1 and 3 Years According to Disease Bed
11.6
29.7
15.4
28.1
14.8
40.4
0
10
20
30
40
50
MI/ Stroke/ Vascular death MI/ Stroke/ Vascular death/
Rehospitalization
3-Y
ear
even
t ra
te,
%
Any CAD (n=28 472)
Any CVD (n=13 463)
Any PAD (n=6118)
4.5
15.2
6.5
14.5
5.4
21.1
0
10
20
30
40
50
MI/ Stroke/ Vascular death MI/ Stroke/ Vascular death/Rehospitalization
1-Y
ear
even
tra
te,
%
Any CAD (n=38 602)
Any CVD (n=18 013)
Any PAD (n=7911)
1 Year 3 Years
• At enrolment, 53.7% of CVD patients had stroke only, 27.7% had a history of TIA
only, 18.5% had experience both a stroke and TIA
• By the 3-year follow-up, 40% of PAD patients had experienced a CV/ ischemic
event or been rehospitalized for another event
Roether J et al. Cerebrovasc Dis. 2008;25:366; Alberts MJ et al. Eur Heart J. 2009;30:2318.
Risk (MI, Ischemic Stroke, or CV Death) During
and Beyond the First Year After the Index MI
Jernberg et al. Eur Heart J. 2015;36:1163-1170.
Swedish National Registries: 108,315 Patients with
a Primary MI Between July 2006 and June 2011
First 365 Days After 365 Days
Secondary Prevention of
Atherothrombotic Events
• Examples of high-risk patients
• Modern therapy does not abolish risk
• Risk stratification schemes allow some
stratification of risk
Examining the Burden
of the High-risk Patient
A Validated
Prediction Model
for All Forms
of ACS
Estimating the Risk of
6-month Post-discharge
Death
Eagle EA, et al. JAMA. 2004;291:2727-2733.
1- Medical History
1) Age in yrs Points
≤29 0
30-39 0
40-49 18
50-59 36
60-69 55
70-79 73
80-89 91
≥90 100
2) History of
congest.
heart failure
24
3) History of
MI
12
Medical History1- Medical History
4) Resting
heart rate
Points
≤49.9 0
50-69.9 3
70-89.9 9
90-109.9 14
110-149.9 23
150-199.9 35
≥200 43
5) Systolic BP
≤79.9 24
80-99.9 22
100-119.9 18
120-139.9 14
140-159.9 10
160-199.9 4
≥200 0
6) ST-
segment
depression
11
1- Medical History
7) Initial
serum Cr.
Points
0-0.39 1
0.4-0.79 3
0.8-1.19 5
1.2-1.59 7
1.6-1.99 9
2-3.99 15
≥4 20
8) Elevated
cardiac enz.
15
9) No in-
hospital
coronary int.
14
Findings During
Hospitalization
Findings at Initial
Hospital Presentation
Total Risk Score ___ (Sum of Points)
Mortality Risk _____ (From Plot)
Long-term Survival According to GRACE Score
(Score for In-hospital Death)
Low Risk
Intermediate Risk
High Risk
Fox KA, et al. Eur Heart J. 2010;31:2755-2764.
Secondary Prevention of
Atherothrombotic Events
Predicting the Risk of Events in Stable
Outpatients with Atherothrombosis
Risk score sheet
2 year CV death/MI/stroke
No Yes
0 -1
No Yes
0 -2
No Yes
0 3
No Yes
0 2
One Two Three
0 1 3
No Yes
0 3
No Yes
0 2
30-39 40-49 50-59 60-69 70-79 80-89
-4 -2 0 2 4 6
Status and Points Assigned
TOTAL POINTS9
Aspirin therapy8
Statin therapy7
Congestive heart
failure6
CV event in past
year5
Number of
vascular beds4
Diabetes
mellitus3
Smoking2
Age (years)1
PointsFactorStep
54.6%17
48.3%16
> 60%18+
42.4%15
36.9%14
31.9%13
27.5%12
23.5%11
20.1%10
17.1%9
14.5%8
12.3%7
10.3%6
8.7%5
7.3%4
6.2%3
5.2%2
4.3%1
3.6%0
3.1%-1
2.6%-2
2.1%-3
1.8%-4
1.5%-5
1.3%-6
1.1%-7
2 Year RiskTOTAL Pts
Wilson PF, et al. Am J Med. 2012;125:695-703.
The REACH RiskScore Calculator
REACH Score: Predicting Events in
Post-ACS Patients in the IMPROVE IT Trial
Pre-specified Preliminary Analysis, Including 18,144 Patients Stabilized
After ACS, Randomized to Ezetimibe/Simvastatin or Simvastatin Alone
May E et al. ACC 2015. Presentation 1125M-07.
Risk Score Distribution Hazard by Risk Score Quartile
• Examples of high-risk patients
• Modern therapy does not abolish risk
• Risk stratification schemes allow some
stratification of risk
• The extent of arterial disease (CAD and at other
locations) impacts risk
Examining the Burden
of the High-risk Patient
Secondary Prevention of
Atherothrombotic Events
Patient 1
Patient 1 Patient 2
Patient 2
SYNTAX SCORE 21 SYNTAX SCORE 52
LCx 70-90%
LAD 70-90%
RCA2 70-90%
RCA3 70-90%
LM 99%
LCx 100%
LAD 99%
RCA 100%
There is “3-vessel Disease” and “3-vessel Disease”
Non-obstructive CAD and Risk of MI
Maddox TM, et al. JAMA. 2014;312:1754-1763.
Time-to-Event Plots for 1-Year MI, Mortality, and Combined MI and Mortality, by CAD Extent
1-year Combined Myocardial Infarction and Mortality
Acute MIs Evolve Most Frequently from
Plaques with Mild to Moderate Obstruction
Num
ber
of M
I patients
E Falk, et al. Circulation. 1995;92:657-963.
Secondary Prevention of
Atherothrombotic Events
1-year CV Event Rates as Function of Number of
Symptomatic Disease Locations in Atherothrombosis
Steg PG, et al. JAMA. 2007;297:1197-1206.
0.6 0.7 0.81.51.4
1.21.5
3.4
2.4
1.5
2.9
5.7
3.8
1.9
3.7
7.1
0
2
4
6
8
CV death Non-fatal MI Non-fatal stroke CV death / MI /stroke
Perc
ent
0
1
2
3
Perc
ent
All P values <0.001
Patients with 3 risk factors but no symptoms are counted as 0, even in the presence of asymptomatic carotid plaque or reduced
ABI
4-year Event Rates According
to Single vs Polyvascular Disease
Single vascular diseasePolyvascular disease
10.3
5.82.9 3.8
11.5
31.1
15.4
9.4
4.56.7
17.7
45.0
0
10
20
30
40
50
All-causemortality
CV death Nonfatal MI Nonfatal stroke CV death, MI,stroke
CV death, MI,stroke,
rehospitalization
4-y
ear
Even
t R
ate
(%
)*
Polyvascular disease Single vascular disease
Stable Atherosclerotic Disease
Bhatt DL, et al. JAMA. 2010;304:1350-1357.
All event rates adjusted for age and gender.
• Examples of high-risk patients
• Modern therapy does not abolish risk
• Risk stratification schemes allow some
stratification of risk
• The extent of arterial disease (CAD and at other
locations) impacts risk
• We should be worrying about the patient (not the
stent)
Examining the Burden
of the High-risk Patient
Secondary Prevention of
Atherothrombotic Events
Half of Recurrent CV Events Post-ACS
are NOT Related to the Index Culprit Lesion
Major CV Events After Successful, Uncomplicated PCI in 697 Patients with ACS in the PROSPECT Study
Stone GW et al. N Engl J Med. 2011;364:226-235.
Years
Cum
ula
tive R
ate
of
Majo
r
Advers
e C
V E
vents
(%
) All events
CL-related events
NCL-related events
Indeterminate events
• Examples of high-risk patients
• Modern therapy does not abolish risk
• Risk stratification schemes allow some
stratification of risk
• The extent of arterial disease (CAD and at other
locations) impacts risk
• We should be worrying about the patient (not the
stent)
Examining the Burden
of the High-risk Patient
A Call to Clinicians Managing
High-risk Patients:
Defining New Paradigms in
Antiplatelet Therapy
Kenneth W. Mahaffey, MD
Vice Chair of Clinical Research, Department of Medicine
Director, Stanford Center for Clinical Research (SCCR)
Professor of Medicine,
Stanford University School of Medicine
Stanford, CA
Secondary Prevention of
Atherothrombotic Events
The Cycle of Clinical Therapeutics
Concept
Patient Outcomes
Clinical
Trials
Guidelines
Performance
Indicators
Performance
Modified from Califf RM. JAMA. 2006;295:1579-1580.
Level of Evidence ACurrent Guidelines*
Tricoci P, et al. JAMA. 2009;301:831-841.
11.7%
26.4%
15.3%
13.5%
12.0%
22.9%
6.4%
6.1%
23.6%
0.3%
9.7%
11.0%
19.0%
4.9%
4.8%
0% 10% 20% 30%
AF
Heart failure
PAD
STEMI
Perioperative
Secondary prevention
Stable angina
SV arrhythmias
UA/NSTEMI
Valvular disease
VA/SCD
PCI
CABG
Pacemaker
Radionuclide imaging
*Guidelines expressing Level of Evidence
Efficacy vs SafetyParadigm for Antithrombotic Drug Development
• New drugs
• Old drugs with new doses
• Old drugs in new combinations
• Combination of drugs and devices
• New drugs and new devices
2
1
010 2
Risk of Thrombosis
He
mo
rrh
ag
ic R
isk
ASA
Increase
DecreaseGoal of New Rx
“First, do no harm.”
Hippocrates, c 460-370 BC
Secondary Prevention of
Atherothrombotic Events
Anticoagulation: Balancing Risks
Ris
k o
f A
ny E
ven
t
High risk of
Thrombotic events
Ris
k o
f A
ny E
ven
t
Potency of Antithrombotic Therapy
“Sweet spot”High risk of
bleeding events
– +Thrombotic risk Bleeding risk
Adapted from Ferreiro JL, et al. Thromb Haemost. 2010;103:1-8; Courtesy, Dr. Thomas Ruff.
History of the Development
of Oral Antiplatelet Therapy
Reduction
of Clinical
Events
ASA TicagrelorNo Tx Clopidogrel Vorapaxar
Courtesy, Dr. Christopher Granger.
• DAPT
• Ticagrelor – PEGASUS
• Vorapaxar – TRA 2P
Secondary Prevention of
Atherothrombotic Events
TBX A2
Platelet Inhibition
Chackalamannil S. J Med Chem. 2006;49:5389-5403.
Platelet
PAR-4
TBXA2-R
Thrombin
Anionic
phospholipid
surfaces
GP IIb/IIIa
ADP
P2Y12
PAR-1
ASA
Vorapaxar
Clopidogrel
Prasugrel
Ticagrelor
Trial Designs and Populations
RandQualifying
Event
12 mo
2 wk – 1 yr
1 -3 yr
Study End
Planned 30 mo f/u
Median 33 mo f/u
Median 30 mo f/u
N= 25,682
N= 21,162
N= 26,449
Twelve or 30 months of
dual antiplatelet therapy
after drug-eluting stents.
Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp
P, Cutlip DE, Steg PG, Normand SL, Braunwald E,
Wiviott SD, Cohen DJ, Holmes DR Jr, Krucoff
MW, Hermiller J, Dauerman HL, Simon DI,
Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver
Lee P, Rinaldi MJ, Massaro JM; DAPT Study
Investigators.
N Engl J Med. 2014;371:2155-2166.
• DAPT decreased stent thrombosis
• DAPT decreased death, MI, or stroke
• DAPT increased moderate or severe bleeding
Summary
Secondary Prevention of
Atherothrombotic Events
Long-term use of ticagrelor in
patients with prior myocardial
infarction.
Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey
RF, Jensen EC, Magnani G, Bansilal S, Fish MP,
Im K, Bengtsson O, Oude Ophuis T, Budaj A,
Theroux P, Ruda M, Hamm C, Goto S, Spinar J,
Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held
P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54
Steering Committee and Investigators.
N Engl J Med. 2015;372:1791-1800.
• Ticagrelor decreased CV death, MI, or stroke
• Ticagrelor increased major bleeding
• No difference in fatal bleeding or ICH
Summary
Vorapaxar in the secondary
prevention of atherothrombotic
events.
Morrow DA, Braunwald E, Bonaca MP, Ameriso
SF, Dalby AJ, Fish MP, Fox KA, Lipka LJ, Liu X,
Nicolau JC, Ophuis AJ, Paolasso E, Scirica BM,
Spinar J, Theroux P, Wiviott SD, Strony J, Murphy
SA; TRA 2P–TIMI 50 Steering Committee and
Investigators.
N Engl J Med. 2012;366:1404-1413.
• Vorapaxar reduced CV death, MI, or stroke
• Vorapaxar increased moderate or severe bleeding
• Trial stopped in patients with prior stroke due to increased ICH
Summary
Primary Efficacy and Safety Outcomes
0
2
4
6
8
10
12
DAPT PEGASUS TRA-2P
Efficacy - Active
Efficacy - Control
Column1
Safety - Active
Safety - Control
Perc
enta
ge
HR 0.71
HR 1.61 HR 1.66HR 2.32
HR 0.87
HR 0.84
NNT = 63NNH = 111
NNT = 79NNH = 81
NNT = 83NNH = 59
* 60 mg group, PEGASUS
*
Secondary Prevention of
Atherothrombotic Events
• Longer therapy reduces ischemic risk
• More potent therapy reduces ischemic risk
• More potent therapy increases bleeding risk
Risk Scores – ACS and SIHD
Risk score for predicting death, myocardial
infarction, and stroke in patients with stable
angina, based on a large randomised trial
cohort of patients.
Clayton TC, Lubsen J, Pocock SJ, Vokó Z, Kirwan BA,
Fox KA, Poole-Wilson PA.
BMJ. 2005;331:869
Risk score to predict serious bleeding in stable
outpatients with or at risk of atherothrombosis..
Ducrocq G, Wallace JS, Baron G, Ravaud P, Alberts
MJ, Wilson PW, Ohman EM, Brennan DM, D'Agostino
RB, Bhatt DL, Steg PG; REACH Investigators.
Eur Heart J. 2010;31:1257-1265.
Euan Ashley MRCP, DPhil, FACC, FAHA
Associate Professor of Medicine
Co-Director, Clinical Genomics Service
Chair, Biomedical Data Science Initiative @euanashley
So what is
medicine, anyway?
Secondary Prevention of
Atherothrombotic Events
The Precision Health Difference
Precision Health Precision MedicinePrecisePersonalizedProactiveIncludes prediction and preventionFocused on keeping you healthyHealth care
PrecisePersonalizedReactiveRelies on diagnosis and treatmentFocused on treating you when sickSick care
Courtesy, Dr. Lloyd Minor.
The Megatrial of Aspirin Dosing:
PCORnet’s First Pragmatic Clinical Trial
PCORnet
The National Patient-centered Clinical Research Network
The Sweet Spot of Anticoagulation
2
Patient
Risks
Dose
Clinical
Context
Secondary Prevention of
Atherothrombotic Events
Using Antiplatelet Therapy
in Practice: The Right Patient
at the Right Time
Marc P. Bonaca, MD, MPH
Vascular Medicine Section, Cardiovascular Division
Investigator TIMI Study Group
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
Outcomes in Patients
with Atherosclerotic Disease
0
4
8
12
16
20
24
CAD
Only
CVD
Only
PAD
Only
>1 Bed
CV Death, MI, Stroke
or Hosp for Atherothrombosis
54% 20% 6% 20%
Steg GP, et al. JAMA 2007;297:1197-1206.
5.31
14.4
0
4
8
12
16
20
24
Multiple Risk
Factors
Established
Disease
CV Death, MI, Stroke
or Hosp for Atherothrombosis
Pe
rce
nta
ge
REACH Registry (1-Year Outcomes) 64,977 patients ≥45 years old
Targets for Antithrombotic Therapy
Modified from Bonaca MP, Creager MA. Circ Res. 2015;116:1579-1598.
Thrombin
ADP
TxA2
Atherothrombosis
Anticoagulants
Secondary Prevention of
Atherothrombotic Events
Effect of ASA Monotherapy on
Vascular Events Across 145 trials
Prior MI 11 1331/9877 1693/9914 -158.5 561.6 25% (4)
(13.5%) (17.1%)
Acute MI 9 992/9388 1348/9385 -177.9 510.3 29% (4)
(10.6%) (14.4%)
Prior stroke/TIA 18 1076/5837 1301/5870 -98.5 386.5 22% (4)
(18.4%) (22.2%)
Other high risk 104 784/11,434 1058/11,542 -134.0 352.5 32% (4)
(6.9%) (9.2%)
ALL HIGH RISK 142 4183/36,536 5400/36,711 -568.8 1810.9 27% (2)
(4 main categories) (11.4%)(14.7%)
ALL LOW RISK 3 652/14,608 708/14,504 -28.5 273.5 10% (6)
(primary prevention) (4.46%) (4.85%)
ALL TRIALS* 145 4835/51,144 6108/51,315 -597.3 2084.4 25% (2)
(high or low risk) (9.5%) (11.9%)
Category
of Trial
No of
trials
with data
MI, STROKE OR
VASCULAR DEATH
Anti
platelet
Adjusted
Controls*
STRATIFIED
STATISTICS
O–E
Variance
OR and CI
(Antiplatelet :
Control)
% Odds
Reduction
(SD)
Antiplatelet
therapy
better
Antiplatelet
therapy
worse
Treatment effect 2P <0.00001
0 0.5 1.0 1.5 2.0
Heterogeneity of odds reductions
between four high risk categories Х23 = 4.1:NS
between high risk and low risk Х21 = 10.5:P=0.001
*Crude, unadjusted control total = 5274/45,172
BMJ. 1994;308:81-106.
Effect of Clopidogrel Monotherapy in
Patients with Symptomatic Vascular Disease
• Mean follow up: 1.91 years
• 21% of PAD group had history of MI
• 6% of PAD group had history of stroke
Clopidogrel vs ASA (325 mg) in 19,185 Patients (6452 with PAD)
Overall 7% RRR with Clopidogrel (P=0.043)
CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
Subgroups
& treatment
group
Individual first-outcome events Other
vascular
death
Total Event
rate/year
Relative risk
reduction
(95% CI)
P
Stroke MI
Non-
fatal
Fatal Non-
fatal
Fatal
PAD
Clopidogrel
(nyrs=5795)
70 11 50 18 66 215 3.71% 23.8%
(8.9-36.2)
0.0028
Aspirin
(nyrs=5797)
74 8 81 27 87 277 4.86%
CURE Trial: Benefit of DAPT
with ASA and Clopidogrel After ACS
Pro
port
ion E
vent-
free
.90
.92
.94
.96
.98
1.00
Week 0 1 2 3 4
RRR: 21%
95% CI, 0.67-0.92
P=0.003
Clopidogrel
Placebo
CV Death, MI, or Stroke
First 30 Days
No. at Risk
5981 5481 4742 4004 3180 2418
5954 5390 4639 3929 3159 2388
Clopidogrel 6259 6145 6070 6026 5990
Placebo 6303 6159 6048 5993 5965
No. at Risk
Pro
port
ion E
vent-
free
RRR: 18%
95% CI, 0.70-0.95
P=0.009
Clopidogrel
Placebo
CV Death, MI, or Stroke
>30 Days-1 Year
Month 1 4 6 8 10 12
.90
.92
.94
.96
.98
1.00
12,562 Patients with NSTE-ACS (Mostly Conservatively Managed)
Yusuf S, et al. Circulation. 2003;107:966-972.
Secondary Prevention of
Atherothrombotic Events
PLATO Trial:
Time to First Primary Efficacy Event
CV and All Cause Mortality
Significantly Reduced
Composite of CV Death, MI, or Stroke
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
CHARISMA Trial: ASA vs ASA + Clopidogrel in Primary
and Secondary Atherothrombosis Prevention
*All patients received ASA 75 mg-162 mg/day
7.3%
6.8%
RRR: 7.1% (95% CI: -4.5-17.5)
P=0.22
Months Since Randomization
0
2
4
6
8
0 6 12 18 24 30
De
ath
, M
I, o
r S
tro
ke
(%
)
N=15,60312% reduction in symptomatic
RR 0.88 (0.77-0.998, P=0.046)
23% reduction in prior MI
Bhatt DL, et al. N Engl J Med 2006;354:1706-1717.
Placebo + ASA*
Clopidogrel + ASA*
Benefit of Chronic Clopidogrel
by Patient Type in CHARISMA
0
5
10
15
20
25
Atherothrombosis orRisk Factors
CAD, CVA, or PAD Prior MI, Stroke or sxPAD
Prior MI
MA
CE
Ris
k R
edu
ction
(%
, 9
5%
CI)
with
Clo
pid
og
rel
vs P
lacebo
15,603 12,153 9478 3846
7%
(-5-17)
12%
(0.2-23)
17%
(4-28)
23%
(2-39)
Bhatt DL, et al. N Engl J Med 2006;354:1706-1717; Bhatt DL, et al. JACC. 2007;49:1982-1988.
.
Secondary Prevention of
Atherothrombotic Events
Intracranial Hemorrhage with Long-term Intensive
Antithrombotic Therapy in Stroke Patients
1.4%
1.0%
0.0%
0.5%
1.0%
1.5%
ASA+ERDP Clopidogrel
PROFESS
HR=1.42 (1.11-1.83)
1.0%
0.6%
0.0%
0.5%
1.0%
1.5%
ASA+Clopidogrel Clopidogrel
MATCH
RR 1.89 (1.05-3.40)
2.30%
0.30%0.00%
0.30%
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
History of Stroke Overall
prasugrel clopidogrel
TRITON-TIMI 38
P=.02
Diener H, et al. Lancet. 2004;364:331-337; Sacco RL, et al. N Engl J Med. 2008;359:1238-1251;
Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
SPS3 – Lacunar Stroke
0.28%
0.15%
0.00%
0.05%
0.10%
0.15%
0.20%
0.25%
0.30%
ASA+Clopidogrel ASA
HR=1.92 (0.82-4.54)
Ev
en
t R
ate
Ev
en
t R
ate
Ev
en
t R
ate
Ev
en
t R
ate
Outcomes in Patients
with Symptomatic PAD
Events in PAD Patients at 4 Years
REACH Registry
5 6
22
6
0
5
10
15
20
25
MI Stroke Any Perip.Revasc.
Amputation
6
3
22
4
0
5
10
15
20
25
MI Stroke Any
Perip.
Revasc
Acute
Limb
Ischemia
Stroke Any
Perip.
Revasc.
Acute
Limb
Ischemia
Eve
nts
Eve
nts
Kumbhani DJ, et al. Eur Heart J. 2014;35:2864-2872; Bonaca MP, et al. Circulation. 2013;127:1522-1529.
Events in PAD Patients at 3 Years
TRA 2P-TIMI 50 Trial
DAPT in Patients with Symptomatic
PAD after Bypass
• 851 patients undergoing unilateral below-knee bypass grafting for
atherosclerotic PAD
• ASA (75 mg-100 mg) + clopidogrel vs ASA alone
• Primary endpoint composite of index-graft occlusion, revascularization,
amputation, or death
• Overall population: primary endpoint occurred in 149/425 pts in the
clopidogrel group vs 151/426 patients in the pbo (+ ASA) group (HR,
0.98; 95% CI 0.78-1.23)
• Prespecified subgroup analysis: primary endpoint was significantly
reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI,
0.45-0.95; P=0.025) but not in venous graft patients (HR, 1.25; 95%
CI, 0.94-1.67, NS)
• Significant statistical interaction between treatment effect and graft
type observed (Pint =0 .008)Belch JJ, et al. J Vasc Surg. 2010;52:825-833.
Benefit in subgroup with prosthetic grafts?
Secondary Prevention of
Atherothrombotic Events
Oral Anticoagulation for PAD
• 2161 patients with PAD (included LE and carotids) followed for 35 months
• Active run-in
• Warfarin (INR 2-3) + antiplatelet therapy vs antiplatelet therapy only (92% ASA)
MACE: 12.2% vs 13.3%
(HR=0.92; 95% CI, 0.73-1.16; P=0.48)
LE ischemia not reduced (3.9% vs 4.1%)
(HR=0.96; 95% CI 0.63-1.47; P=0.86)
The WAVE Trial Investigators. N Engl J Med. 2007;357:217-227.
Life-threatening bleeding: 4.0% vs 1.2%
(HR=3.41; 95% CI, 1.84-6.35; P<0.001)
CAD with ACS Aspirin indefinitely
P2Y12 inhibitor at least 12 months
Symptomatic PAD Monotherapy with aspirin or clopidogrel
Ischemic Stroke (non-AF) Aspirin (+/- dipyridamole) or clopidogrel
Current Antiplatelet Therapy Recommendations
for Long-term Secondary Prevention
2014 ACCF/AHA UA/NSTEMI; 2013 ACCF/AHA STEMI; 2011 ESC NSTEACS; 2012 ESC STEMI;
2014 CHEST Antithrombotic Guidelines, 2011 ACCF/AHA PAD Guidelines, 2014 AHA/ASA Guidelines.
TRA 2P-TIMI50 Trial: Study Design
Prior MI, CVA, or PAD 26,449
Vorapaxar 2.5 mg/d
Placebo
RANDOMIZED 1:1 DOUBLE BLIND
Follow up Visits
Day 30, Mo 4, Mo 8, Mo 12
Q6 months
Standard care including oral antiplt rx
Final Visit
Median F/U 30 Months
Qualifying Conditions
1) Type 1 MI (17,779; 67%)
2) Symptomatic PAD (3,787; 14%)
3) Ischemic CVA (4,883; 18%)
Stratified by:
1) Qualifying athero
2) Use of thienopyridine
Morrow et al. N Engl J Med 2012
ClinicalTrials.gov NCT00526474c
Efficacy EPs:
• CVD/MI/Stroke/RIUR
• CVD/MI/Stroke
Principal Safety EP:
• GUSTO Mod/Severe
Bleeding
Morrow DA, et al. N Engl J Med.
2012;3661404-1413
ClinicalTrials.gov/NTC00526474c
Secondary Prevention of
Atherothrombotic Events
TRA 2P-TIMI50 Trial: Efficacy at 3 Years in Patients with MI or PAD (No Stroke/TIA)
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
0 90 180 270 360 450 540 630 720 810 900 990 1080
V Death, MI, or Stroke
7.9%
9.5%
NNT 63
Eve
nt
Ra
te(%
)
Bonaca MP TCT 2014
N=20,170
Median f/u: 2.5 years
Placebo
Vorapaxar
HR=0.80
(0.73-0.89)
P <0.001
NNT 63
Eve
nt
Ra
te a
t 3
Ye
ars
Days from Randomization Bonaca, MP. Presented at: TCT 2014;
September 13-17; Washington DC.
CV Death, MI, or Stroke
TRA 2P-TIMI50 Trial: Bleeding at 3 Yearsin Patients with MI or PAD (No Stroke/TIA)
2.4%
1.0%
0.4% 0.2%
3.7%
1.3%
0.6%0.2%
0%
1%
2%
3%
4%
5%
6%
7%
8%
GUSTOmod/severe
GUSTO severe ICH Fatal Bleed
Placebo
Vorapaxar
Ev
en
t R
ate
at
3 Y
ears
N=20,170
Median f/u: 2.5 years
HR=1.55
(1.30-1.86)
P <0.001
NNH 77HR=1.24
(1.92-1.66)
P=0.16
NNH 333
HR=1.46
(0.92-2.31)
P=0.10
HR=1.15
(0.56-2.36)
P=0.70
30319910082
4531 1614
Magnani G, et al. J Am Heart Assoc. 2015;4:e001505.
TRA 2P-TIMI50 Trial: CV Death, MI, or Stroke
Landmark – MI or PAD (No Stroke/TIA)
Ev
en
t R
ate
0%
1%
2%
3%
4%
5%
6%
7%
0 90 180 270 360
0%
1%
2%
3%
4%
5%
6%
7%
361 451 541 631 721 811 901 991 1081
Placebo
Vorapaxar
2.9%
3.7%
5.5%
6.4%
First Year
HR=0.78
95% CI, 0.68-0.92
P=0.003
After 1 Year
HR=0.82
95% CI, 0.72-0.93
P=0.002
Days from Randomization
Placebo
Vorapaxar
Bonaca, MP. Presented at: TCT 2014;
September 13-17; Washington DC.
Secondary Prevention of
Atherothrombotic Events
TRA 2P-TIMI50 Trial: Incidence
of New Ischemic Stroke
0.88%
Days from Randomization
Eve
nt
Ra
te
Ischemic stroke HR 0.57, p<0.001
Hemorr stroke HR 2.78, p=0.049
Overall stroke HR 0.68, p=0.005
Patients with prior MI or PAD with no History of Stroke/TIA
1.47%
P <0.001
Placebo
Vorapaxar
Ischemic stroke HR=0.57, P<0.001
Hemorr. stroke HR=2.78, P=0.049
Overall stroke HR=0.68, P=0.005
Bonaca MP, et al. J Am Coll Cardiol.
2014;64:2318-2326.
N=20,170
TRA 2P-TIMI50 Trial: Stent Thrombosis
by Randomized Treatment
Days from Randomization
Eve
nt
Ra
te
Placebo
Vorapaxar
HR=0.71 (0.52-0.98)
P=0.04
1.4%
1.1%
Bonaca MP, et al. J Am Coll Cardiol. 2014;64:2318-2326.
No Thienopyridine
HR=0.72 (0.51-1.02)
Thienopyridine
HR=0.67 (0.29-1.54)
ARC Definite Stent Thrombosis
TRA 2P-TIMI50 Trial: Vorapaxar
and Limb Vascular Efficacy in PAD
N=3767
Days from Randomization
Eve
nt
Ra
te
Hospitalization for
Acute Limb IschemiaPre-specified, Adjudicated
Peripheral
RevascularizationPre-specified, Investigator
Placebo
22.2%
Vorapaxar
18.4%
3.9%
2.3%
Placebo
Vorapaxar
HR=0.58
(0.39-0.86)
P=0.006
HR=0.84
(0.73-0.97)
P=0.017
Bonaca MP, et al. Circulation. 2012;125:577-583.
Eve
nt
Ra
te
Secondary Prevention of
Atherothrombotic Events
DAPT Trial: Withdrawal of Thienopyridine
12 Months After Coronary Stenting
~ 46% patients with history of MI
Death, MI, or Stroke
Withdrawal of
P2Y12
Inhibition
Withdrawal of
P2Y12
Inhibition
Primary Analysis Period:
12-30 Months
HR=0.71 (0.59-0.85)
4.3% vs 5.9%
P<0.001
Mauri L, et al. N Engl J Med. 2014;371:2155-2166.
DAPT Trial: MI Subgroup
3.9%
0.5% 0.6%
2.2%1.9%
0.6%
6.8%
1.9%
0.9%
5.2%
0.8% 0.5%
0%
1%
2%
3%
4%
5%
6%
7%
8%
MACE ST CardiacDeath
MI GUSTOMod/SevBleeding
Non-CVDeath
Continued Thienopyridine Placebo
HR=0.56
(0.42-0.76)
P <0.001
HR=0.27
(0.13-0.57)
P <0.001
Yeh R, et al. J Am Coll Cardiol. 2015;65:2211-2221.
HR=2.38
(1.27-4.43)
P=0.005Even
t R
ate
PEGASUS-TIMI54 Trial:
Primary Endpoint
Months from Randomization
Ticagrelor 60 mg
HR=0.84 (95% CI, 0.74-0.95)
P=0.004
CV
De
ath
, M
I, o
r S
tro
ke
(%
)
3 6 9 120 15 18 21 24 27 30 33 36
Ticagrelor 90 mg
HR=0.85 (95% CI, 0.75-0.96)
P=0.008
Placebo (9.0%)
Ticagrelor 90 (7.8%)Ticagrelor 60 (7.8%)
6
5
4
3
10
9
8
7
2
1
0
N=21,162
Median follow-up: 33 months
Bonaca MP, et al. N Engl J Med. 2015;372:1791-1800.
Secondary Prevention of
Atherothrombotic Events
PEGASUS-TIMI54 Trial:
Components of Primary Endpoint
0.85 (0.75-0.96) 0.008
0.84 (0.74-0.95) 0.004
0.84 (0.76-0.94) 0.001
CV Death, MI, or Stroke(1558 events)
HR (95% CI) P
10.80.60.4 1.25 1.67
Placebo better
Endpoint
Ticagrelor 60 mg
Ticagrelor 90 mg
Pooled
CV Death(566 events)
0.87 (0.71-1.06) 0.15
0.83 (0.68-1.01) 0.07
0.85 (0.71-1.00) 0.06
MI(898 events)
0.81 (0.69-0.95) 0.01
0.84 (0.72-0.98) 0.03
0.83 (0.72-0.95) 0.005
Stroke(313 events)
0.82 (0.63-1.07) 0.14
0.75 (0.57-0.98) 0.03
0.78 (0.62-0.98) 0.03
Bonaca MP et al. N Engl J Med. 2015;372:1791-1800.
Ticagrelor better
PEGASUS-TIMI54 Trial: MACE in Patients Randomized
to Placebo by Time from P2Y12 Inhibitor Withdrawal
0%
2%
4%
6%
8%
10%
12%
0 90 180 270 360 450 540 630 720 810 900 990 1080
0.0%
0.5%
1.0%
1.5%
2.0%
0 30 60 90
CV
D/M
I/S
tro
ke
(%
)
Days from Randomization
1.46%
0.60% 0.55%
9.9%
8.7%
6.9%
≤ 30 days
30 days – ≤1 Year >1 Year
Adj. HR 1.47 (95% CI
1.12 – 1.93)
Adj. HR 1.28 (95% CI
0.98 – 1.67)
Ref.
P-trend 0.0097
Adjusted for baseline characteristics that differed between groups including age, sex, race, region, time from qualifying
MI, diabetes, multivessel disease, hypertension,
hypercholesterolemia, and history of PCI/stent.
CV
De
ath
, M
I, o
r S
tro
ke
(%
)
Days from Randomization
Adj. HR=1.47
(95% CI, 1.12-1.93)
Adj. HR=1.28
(95% CI, 0.98-1.67)
Ref.
≤30 days
30 days - ≤1 year
>1 year
Bonaca MP, et al. Eur Heart J. 2015 Oct 21. pii: ehv531. [Epub ahead of print]
PEGASUS-TIMI54 Trial: Reduction in MACE with
Ticagrelor by Time from P2Y12 Inhibitor Withdrawal
Ticagrelor Better Placebo Better1.0
<0.001
0.11
0.96
0.70 (0.57-0.87)
0.75 (0.61-0.92)
0.73 (0.61-0.87)
HR (95% CI)
0.90 (0.72-1.12)
0.82 (0.65-1.02)
0.86 (0.71-1.04)
0.96 (0.73 – 1.26)
1.06 (0.81 – 1.38)
1.01 (0.80 – 1.27)
Ticagrelor 60 mg
Ticagrelor 90 mg
Pooled
≤30 days
N=7181
>30 days
to 1 year
N=6501
>1 year
N=5079
Time from
P2Y12 inhibitor
withdrawal to
randomization
P-interaction 0.0097
27% RRR
14% RRR
RRR
0.70 0.90 1.10
P
Bonaca MP, et al. Eur Heart J. 2015 Oct 21. pii: ehv531. [Epub ahead of print]
Secondary Prevention of
Atherothrombotic Events
PEGASUS-TIMI54 Trial: MACE at 3 Years
with Ticagrelor by Time from MI in Patients
with P2Y12 Inhibitor Withdrawal ≤30 Days
Days from Randomization Placebo
Ticagrelor Doses Pooled
0%
2%
4%
6%
8%
10%
12%
0 180 360 540 720 900 1080
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
0 180 360 540 720 900 1080
CV
D/M
I/S
tro
ke
(%
)
MI < 24 Months Prior
HR 0.73
(95% CI 0.60 – 0.89)
MI ≥ 24 Months Prior
HR 0.71
(95% CI 0.50 – 1.00) 10.2%
7.8%
9.1%
7.3%
Bonaca et al. EHJ 2015
HR=0.73
(95% CI, 0.60-0.89)
HR=0.71
(95% CI, 0.50-1.00)
Days from Randomization Placebo
Ticagrelor Doses Pooled
0%
2%
4%
6%
8%
10%
12%
0 180 360 540 720 900 1080
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
0 180 360 540 720 900 1080
CV
D/M
I/S
tro
ke
(%
)
MI < 24 Months Prior
HR 0.73
(95% CI 0.60 – 0.89)
MI ≥ 24 Months Prior
HR 0.71
(95% CI 0.50 – 1.00) 10.2%
7.8%
9.1%
7.3%
Days from Randomization Placebo
Ticagrelor Doses Pooled
0%
2%
4%
6%
8%
10%
12%
0 180 360 540 720 900 1080
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
0 180 360 540 720 900 1080
CV
D/M
I/S
tro
ke
(%
)
MI < 24 Months Prior
HR 0.73
(95% CI 0.60 – 0.89)
MI ≥ 24 Months Prior
HR 0.71
(95% CI 0.50 – 1.00) 10.2%
7.8%
9.1%
7.3%
Days of Randomization
MI <24 Months Prior MI ≥24 Months Prior
Bonaca MP, et al. Eur Heart J. 2015 Oct 21. pii: ehv531. [Epub ahead of print]
CV
Death
/MI/S
tro
ke (
%)
Bonaca MP, et al. Eur Heart J. 2015 Oct 21. pii: ehv531. [Epub ahead of print]Bonaca MP, et al. Eur Heart J. 2015 Oct 21. pii: ehv531. [Epub ahead of print]
CV Death with Continued DAPT After MI
CHARISMA 53 1903 65 1943
PRODIGY 31 732 31 733
ARCTIC-Int’n 0 156 1 167
DAPT 11 1805 16 1771
DES-LATE 21 1512 21 1551
PEGASUS 356 14,095 210 7067
TOTAL 472 20,203 344 13,232
2.3% 2.6%
P=0.03
0.82 (0.57-1.18)
1.00 (0.61-1.64)
0.36 (0.01-8.69)
0.67 (0.31 - 1.44)
1.00 (0.55-1.83)
0.85 (0.71-1.00)
Study Events Total Events Total
Extended ASA Risk Ratio
DAPT Alone (95% CI)
0.2 0.5 1 2Extended DAPT Better Aspirin Alone Better
0.85 (0.74-0.98)
Udell JA, et al. Eur Heart J. 2015 Aug 31. pii: ehv443. [Epub ahead of print]
Other Outcomes with Continued
DAPT After MI
6.4
2.3
3.5
1.4
0.6
7.5
2.6
4.4
1.71.4
0
1
2
3
4
5
6
7
8
9
10
MACE CV Death MI Stroke StentThrombosis(Def/Prob)
Even
t R
ate
(%
)
Extended DAPT Aspirin AloneRR 0.78
P=0.001
RR 0.85
P=0.03
RR 0.70
P=0.003
RR 0.81
P=0.02RR 0.50
P=0.02
Udell JA, et al. Eur Heart J. 2015 Aug 31. pii: ehv443. [Epub ahead of print]
Extended DAPT ASA Alone
Secondary Prevention of
Atherothrombotic Events
Major Bleeding Events and Safety
1.9
0.4 0.1
1.7
4.0
1.1
0.3 0.2
1.6
4.2
0
1
2
3
4
5
6
7
8
9
10
MajorBleeding
ICH FatalBleeding
Non-CVDeath
All-CauseDeath
Even
t R
ate
(%
)
Extended DAPT Aspirin Alone
RR 1.73
P=0.004
P=NS
RR 1.03
P=NS
RR 0.92
P=NS
P=NS
Extended DAPT ASA Alone
Udell JA, et al. Eur Heart J. 2015 Aug 31. pii: ehv443. [Epub ahead of print]
Ref
Trial=?
1.6%1.7%
1.1%
0.9%
1.1% 1.1%
0.8%
0.4%
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
CHARISMA DAPT TRA2P-TIMI 50 MIon DAPT
TRA2P-TIMI 50 MIon ASA
Treatment Placebo
P<0.001 for all comparisons at full follow-upGUSTO Moderate or Severe
Clopidogrel 75 mg
Daily vs Placebo
Vorapaxar 2.5 mg
Daily vs Placebo
+ 0.5% + 0.6%
+ 0.3% + 0.5%
Vorapaxar
“Triple”
Vorapaxar
“Dual”
Clopidogrel
“Dual”
Prolonged Antiplatelet Therapy and Bleeding
Mauri L, et al. N Engl J Med.
2014;371:2155-2166.
Berger PB, et al. Circulation.
2010;122:2575-2583.
Bohula EA, et al. Circulation. 2015 Sep 3.
pii: 114.015042. [Epub ahead of print]
An
nu
alized
Ev
en
t R
ate
0
5
10
15
20
25
30
35
40
45
50
TIMIMinimal
TIMI Minor TIMI Major Any TIMIbleeding
Doubletherapy group
Triple therapygroup
16.7%
11.2%
27.2%
3.3%5.8%
19.5%
P <0.001
6.5%
P <0.001
P=0.159
Double therapy group
Triple therapy group
Even
t R
ate
(%
)
Dewilde JM, et al. Lancet. 2013;381:1107-1115.
Annualized Rates
WOEST Trial – Primary Endpoint:
Bleeding Events TIMI Classification
P <0.001
44.9%
Secondary Prevention of
Atherothrombotic Events
HR (95% CI)
0.81 (0.68-0.96)
ARR=2.70%
NNT 37
HR (95% CI)
0.88 (0.77-1.00)
ARR=0.63%
Primary Endpoint: CV Death, MI, Stroke
Months Since Randomization12 24 36
eGFR <60 Placebo (N=1649)
eGFR <60 Ticagrelor Pooled (N=3200)
eGFR ≥60 Placebo (N=5336)
eGFR ≥60 Ticagrelor Pooled (N=10,713)
13.99%
11.29%
7.43%
6.80%
3-y
ea
r K
M %
0
2
0
6
12
10
8
16
14
4
PEGASUS-TIMI54 Trial: Efficacy of Ticagrelor by eGFR
Magnani G, et al. Eur Heart J. 2015 Oct 5. pii: ehv482. [Epub ahead of print];
Bonaca MP, et al. Eur Heart J. 2015 Oct 21. pii: ehv531. [Epub ahead of print]
TRA 2P-TIMI50 Trial: Efficacy of Vorapaxar in
Patients with Prior MI Based on Diabetes History
4
12
8
16
Inci
den
ce (
%)
7.9%
6.8%
15.7%
12.6%
HR=0.77
P=0.004
ARD -3.1
NNT=30 95% CI, 19-92
HR=0.83
P=0.005
ARD -1.1
NNT=76 95% CI, 47-247
CV Death, MI, or Stroke
Placebo
Vorapaxar DM
No DM
0
P-int=0.51
Cavender MA, et al. Circulation. 2015;131:1047-1053.
PlaceboVorapaxar
12 24 36
Time (Months)
Net Clinical Outcome
(All-cause mortality/MI/CVA/
GUSTO severe bleed)
HR=0.77 (0.65-0.93) – P=0.006
TRA 2P-TIMI50 Trial: Efficacy of Vorapaxar
in Patients with Prior CABG
0
2
4
6
8
10
12
14
16
18
0 180 360 540 720 900 1080
Even
tR
ate
( %)
Days Since Randomization
Placebo
Vorapaxar11.9%
15.6%
p<0.001
Hazard Ratio: 0.7195% CI: 0.58-0.88
CV Death, MI, or Stroke
N= 2,942
NNT 27 P(interaction) = 0.24
PlaceboN=2942
HR=0.71
95% CI,:0.58-0.88
P <0.001
NNT 27P (interaction)=0.24
Kosova E. et al. Presented at: ACC 2015, October 18-21; Boston, MA. Abstract 905-04.
Vorapaxar
CV Death, MI, or Stroke
Secondary Prevention of
Atherothrombotic Events
TRA 2P-TIMI50 Trial: Safety Endpoints
in the Prior CABG Population
HR=1.87 95% CI, 1.28-2.72
P <0.001
HR=1.12 95% CI, 0.59-2.12
P=0.72
HR=0.74 95% CI, 0.55-0.99
P=0.045
P(interaction)=.36
Placebo
VorapaxarNet Clinical Outcome
(All-cause mortality/MI/CVA/
GUSTO severe bleed)
HR=0.72 (0.60-0.88) – P <0.001
Kosova E. et al. Presented at: ACC 2015, October 18-21; Boston, MA. Abstract 905-04.
Clinical ApplicationMI Symptomatic
PAD
ASA + P2Y12
inhibitor for ACS
If ASA and/or
clopidogrel consider
vorapaxar particularly
if DM, CABG, or PAD
Withdrawal of therapy
associated with risk
even very late after MI
Is ASA needed?
Vascular Bed
Acute Setting/
Revascularization
Long-term
Secondary
Prevention
Other
Considerations
ASA + P2Y12
inhibitor common
Clopidogrel (or ASA)
+ vorapaxar for MACE
and LIMB benefit,
particularly if:
concomitant CAD, prior
revascularization, or
other high-risk
Long-term use of
warfarin is harmful
unless another
indication (eg, AF)
Unclear benefit of ASA
+ P2Y12 inhibitor
long-term
Risk scores could
provide guidance
Stroke
Short-term
ASA + P2Y12
inhibitor for
selected
Long-term
combination
therapy
associated
with increased
bleeding