Antithrombotic Therapy for Long-Term
Secondary Prevention – Considerations for
Long-Term DAPT
Marc P. Bonaca, MD, MPH
Vascular Section, Cardiovascular Division
Investigator TIMI Study Group
Brigham and Women’s Hospital
Assistant Professor, Harvard Medical School
WCN Congress 2017
Disclosures:
PEGASUS-TIMI 54 funded by a research grant to
Brigham & Women’s Hospital from AstraZeneca
Consulting: Aralez, AstraZeneca, Merck, Bayer,
Roche
Antithrombotic therapy aftercoronary stenting
Leon et al. NEJM 1998
1653 patients (1772 lesions) with successful stent implantation
“Antithrombotic drugs are used after coronary-artery stenting to prevent stent
thrombosis…
After coronary stenting, aspirin and ticlopidine should be considered for the
prevention of the serious complication of stent thrombosis”
Bhatt et al. JAMA 2010; 304:1350-7.
CV Death, MI, Stroke
%
21.1
17.2
12.2
9.1
0
4
8
12
16
20
24
Prior Ischemic
Event <=1 Yr
Prior Ischemic
Event >1 y
Stable
Atherosclerotic
disease
Risk Factor only
REACH Registry (4-yr outcomes) 64,977 patients ≥ 45 years old
Patients with Prior MI Remain at High Risk for
Ischemic Events
Pro
bab
ilit
y o
f P
rim
ary
Ev
en
tsPAD with and without Diabetes Stroke/TIA with and without Diabetes
Time (year) post-randomization
Pro
bab
ilit
y o
f P
rim
ary
Ev
en
tsPAD with and without Diabetes Stroke/TIA with and without Diabetes
Time (year) post-randomization
Pro
bab
ilit
y o
f P
rim
ary
Ev
en
ts
PAD with and without Diabetes Stroke/TIA with and without Diabetes
Time (year) post-randomization
Gutierrez et al. ACC 2016
Risk after ACS with Diabetes, Polyvascular Disease
or Both
CURE: benefit of DAPT with aspirin and
clopidogrel after ACSP
rop
ort
ion
Even
t-F
ree
.90
.92
.94
.96
.98
1.00
Week 0 1 2 3 4
RRR: 21%
95% CI, 0.67–0.92
P=.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
po
rtio
n E
ven
t-F
ree
RRR: 18%
95% CI, 0.70–0.95
P=.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
Yusuf S, et al. Circulation. 2003;107:966-972.
12,562 Patients with NSTEACS (mostly conservatively managed)
8,688
8,763
0 10 20 30
8
6
4
2
0
CV
Death
, M
I, o
r S
troke (
%)
Clopidogrel
Ticagrelor
4.77
5.43
HR 0.88 (95% CI 0.77–1.00), p=0.045
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,875
8,942
8,763
8,827
Days after randomisation
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.28
6.60
8,688
8,673
8,286
8,397
6,379
6,480
Days after randomisation*
HR 0.80 (95% CI 0.70–0.91), p<0.001
8,437
8,543
6,945
7,028
4,751
4,822
CV
De
ath
, M
I, o
r S
tro
ke
(%
)
Potent P2Y12 Inhibitor After ACS Reduces Risk
Early and Late & Reduces Mortality
*Excludes patients with any primary
event during the first 30 days
18,624 Patients w/in 24 hrs of onset of ACS (64% underwent PCI)
Death from any cause 4.5% vs 5.9%
HR 0.78 (0.69 – 0.89), p<0.001
Randomized trials of dual antiplatelettreatment duration after drug-eluting stents
TrialTotal DES
RandomizedTreatment Duration
Bleeding HR (95% CI)
Stent ThrombosisHR (95% CI)
Myocardial Infarction
HR (95% CI)
REAL + ZEST LATE 2701 24 vs. ~12 2.96 (0.31-28.46) 1.23 (0.33-4.58) 1.41 (0.54-3.71)
PRODIGY 1357 24 vs 6 2.17 (1.44-3.22) 0.87 (0.41-1.81) 0.94 (0.61-1.45)
EXCELLENT 1443 12 vs 6 2.0 (0.37-11.11) 0.17 (0.02-1.39) 0.54 (0.21-1.35)
OPTIMIZE 3120 12 vs 3 1.41 (0.63-3.13) 0.95 (0.42-2.04) 0.85 (0.57-1.29)
ARCTIC-Interruption
1259Continued DAPT vs.
ASA6.94 (0.85-56.61) 0 vs 3 events* 1.04 (0.41-26.2)
ITALIC 1850 12 vs 6 3 vs. 0 events* 0 vs. 3 events* 0.67 (0.19-2.38)
ISAR-SAFE 4005 12 vs 6 1.25 (0.34-4.76)0.80 (0.21-3.03)
9 events
1.08 (0.51-2.27)
27 events
8
Park, et al. N Eng J Med 2010; 362:15.
Valgimigli, et al. Circulation 2012;125:2015.
Gwon, et al. Circulation 2012;125:505.
Feres, et al. JAMA 2013; 310:510.
Collet, et al. Lancet 2014;384:1577.
Gillard, et al. J Am Coll Card Nov 2104.
Schultz-Schupke, et al. EHJ Jan 25, 2015.
Mauri et al. NEJM 2014
~ 46% with history of MI
Death, MI or stroke
DAPT: Withdrawal of Thienopyridine 12
Months after Coronary Stenting
Moderate/Severe Bleeding
2.5% vs.1.6%
All Cause Mortality
2.0% vs 1.5%
CHARISMA: Prior MIa post-hoc exploratory subgroup
10
8
6
4
2
00 6 12 18 24 30
HR=0.774 (95% CI [0.613–0.978])
P=0.031
N=3,846
CV
Dea
th,
MI,
or S
trok
e (%
)
Months Since Randomization
8.3%
6.6%
Placebo + ASA
Clopidogrel + ASA
Bhatt DL et al. J Am Coll Cardiol. 2007;49:1982-1988.
23% risk reduction if prior MI
10
DAPT: Prior MI and Efficacy for MACE
Yeh et al. JACC 2015
Patients with MI
HR 0.56, p<0.001
~3% ARR at 18 Months
Mortality lower (NS)
Patients without MI
HR 0.83, p=NS
0.9% ARR at 18 Months
Mortality higher
An Academic Research Organization of
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Stable pts with history of MI 1-3 yrs prior
+ 1 additional atherothrombosis risk factor*
Ticagrelor
90 mg bidPlacebo
RANDOMIZE
DOUBLE BLIND
Follow-up Visits
Q4 mos for 1st yr, then Q6 mos
Planned treatment with ASA 75 – 150 mg &
Standard background care
* Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD,
or chronic non-end stage renal dysfunction
Event-driven trial
PEP: CVD/MI/Stroke
Secondary: CV Death, Mortality
Exploratory: Coronary death
Safety: TIMI Major, ICH, Fatal
Ticagrelor
60 mg bid
Trial Design
Bonaca MP et al. NEJM 2015;372:1791-800
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
21,162 patients randomized at 1161 sites in 31 countries between 10/2010 – 5/2013
Poland: 1399Sweden: 507
Canada:
1306
United States
2601
U.K.: 647
Netherlands: 1560
Belgium: 431
Germany: 924
France: 333
Spain: 535
Czech Rep: 870
Italy: 392
South Africa:
473
Australia: 327
Japan: 903Hungary: 831
Bulgaria: 447China: 383
S Korea: 506
Philippines: 250
Colombia: 528
Chile: 322
Argentina: 499
Brazil: 864Peru: 245
Romania: 404
Slovakia: 475
Russia: 1061Ukraine: 623
Turkey: 180
13
Norway: 336
Global Enrollment
America First!
Netherlands Second…
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No. Patients – 1560 No. Sites - 41
Average patients per site = 38
Patient Retention 99.94%
NLI: DR. TON OUDE OPHUIS
NETHERLANDS
But Actually…
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Months from Randomization
Ticagrelor 60 mg
HR 0.84 (95% CI 0.74 – 0.95)
P=0.004
CV
Death
, 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%)
Primary Endpoint
6
5
4
3
10
9
8
7
2
1
0
N = 21,162
Median follow-up 33 months
Bonaca MP et al. NEJM 2015;372:1791-800
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Brigham and Women’s Hospital and Harvard Medical School
0%
1%
2%
3%
4%
731 821 911 10010%
1%
2%
3%
4%
366 456 546 636 7260%
1%
2%
3%
4%
0 90 180 270 360
3.3%3.0%
2.8%
3.0%
2.6%
HR 0.82
(95% CI 0.67 – 0.99)
HR 0.90
(95% CI 0.74 – 1.11)
HR 0.79
(95% CI 0.62 – 1.00)
Median 1.7 yrs
From Index MI
(1.2 – 2.3)
Median 2.7 yrs
From Index MI
(2.2 – 3.3)
Median 3.7 yrs
From Index MI
(3.2 – 4.3)
First year in Trial Second year in Trial Third year in Trial
Placebo
2.7%
Ticagrelor 60 mg Twice Daily
Efficacy over time
Bonaca MP et al. JACC in Press
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Brigham and Women’s Hospital and Harvard Medical School
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 value
10.80.60.4 1.25 1.67
Ticagrelor better 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
Myocardial Infarction(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. NEJM 2015;372:1791-800
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Bleeding
2,6
1,3
0,6 0,6
0,1
2,3
1,2
0,7 0,60,3
1,1
0,40,6 0,5
0,3
0
1
2
3
4
5
TIMI Major TIMI Minor Fatal bleeding orICH
ICH Fatal Bleeding
3-Y
ea
r K
M E
ve
nt
Ra
te (
%)
Ticagrelor 90 mg
Ticagrelor 60 mg
PlaceboP<0.001
P<0.001
P=NS P=NS P=NS
Ticag 60: HR 2.32 (1.68-3.21)
Ticag 90: HR 2.69 (1.96-3.70)
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-18
-5
-8
-4
0
9
-20
-15
-10
-5
0
5
10
15
CV Death, MI, orStroke
CV Death MI Stroke IntracranialHemorrhage orFatal Bleeding
Major bleed
To
tal #
of
Eve
nts
Pre
ve
nte
d o
ve
r 3
Ye
ars
pe
r 1
00
0 P
ati
en
ts In
itia
ted
on
Tre
atm
en
t
Ticagrelor 60
Events Prevented and Caused for 1000 Patients Initiated on
Ticagrelor 60 mg Twice Daily and Followed for 3 Years
Bonaca MP et al. JACC in Press
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Brigham and Women’s Hospital and Harvard Medical School
MACE in Patients with
& without Prior PCI/Stent
Prior PCI/Stent
N = 16,891
CVD / MI / Stroke
Ticagrelor Better Placebo Better1.0
3 Year KM Rates
Ticagrelor Placebo P-value
0.016
0.042
0.0092
0.14
0.0495
0.044
0.86 (0.75 – 0.99)
0.84 (0.73 – 0.97)
0.85 (0.75 – 0.96)
6.8
7.1
7.0 7.8
HR (95% CI)
0.80 (0.64 – 1.00)
0.85 (0.68 – 1.06)
0.82 (0.68 – 0.99)
11.7
10.5
11.1 13.2
Ticagrelor 60 mg
Ticagrelor 90 mg
Pooled
CVD / MI / Stroke
No Prior PCI/Stent
N = 4,271
All p-interaction NS
Any MI
Ticagrelor Better Placebo Better1.0
3 Year KM Rate (%)
Ticagrelor Placebo P–value
0.0055
0.81 (0.69 – 0.95)
0.84 (0.72 – 0.98)
0.83 (0.72 – 0.95)
4.53
4.40
4.47 5.25
HR (95% CI)
Ticagrelor 60 mg
Ticagrelor 90 mg
Pooled
Benefit of Ticagrelor By Size of MI
1.25 2.000.750.50
MI with Tn
≥ 25 x ULN
MI with Tn
≥ 50 x ULN
MI with Tn
≥ 100 x ULN
MI with Tn
≥ 200 x ULN
0.0052
0.77 (0.60 – 0.98)
0.71 (0.55 – 0.92)
0.74 (0.60 – 0.91)
1.68
1.74
1.71 2.18
0.0044
0.71 (0.53 – 0.94)
0.70 (0.53 – 0.93)
0.71 (0.55 – 0.90)
1.34
1.29
1.31 1.75
0.0096
0.76 (0.55 – 1.04)
0.64 (0.45 – 0.89)
0.70 (0.53 – 0.92)
0.93
1.05
0.99 1.30
0.022
0.71 (0.47 – 1.07)
0.62 (0.40 – 0.95)
0.66 (0.47 – 0.94)
0.52
0.61
0.56 0.83
ULN = upper limit of normal
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~40% Reduction in Very
Large MI
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Brigham and Women’s Hospital and Harvard Medical School
0.0%
0.5%
1.0%
1.5%
2.0%
0 90 180 270 360 450 540 630 720 810 900 990 1080
Effect of Ticagrelor on STEMI
Ticagrelor 60 mg
HR 0.62
(95% CI 0.45 – 0.86)
P=0.00016
Ticagrelor 90 mg
HR 0.57
(95% CI 0.41 – 0.79)
P=0.0008Placebo
Ticagrelor 90Ticagrelor 60
Days from Randomization
ST
EM
I (%
)
~40% Reduction in New
STEMI during Follow up
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0,0%
0,5%
1,0%
1,5%
2,0%
2,5%
0 180 360 540 720 900 1080
An
y S
tro
ke a
t 3 Y
ears
(%
)
1.94%
Days from Randomization
1.47%
Placebo
Ticagrelor 60 mg BID Any Stroke
HR 0.75
(0.57 – 0.98)
P=0.034
Effect of Ticagrelor on Stroke
22 19
28
18
14
15
8
5
6
5
6
3
15
7
0
20
40
60
80
100
120
Placebo Ticagrelor 60 mg
Rankin 0 Rankin 1 Rankin 2 Rankin 3 Rankin 4 Rankin 5 Rankin 6
Nu
mb
er
(N)
99
72
Asymptomatic No Significant
DisabilitySlight
Disability
Moderate
DisabilityModerately
Severe DisabilitySevere
DisabilityDead
HR 0.57
(0.33 – 0.99)
P=0.045
Modified Rankin Score at 30 Days
43% Reduction in
Moderate-Severely
Disabling or Fatal Stroke
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0,0%
0,2%
0,4%
0,6%
0,8%
1,0%
1,2%
1,4%
0 180 360 540 720 900 1080
Th
rom
bo
tic
Co
mp
lic
ati
on
s (
%)
Days from Randomization
PlaceboN=105
Ticagrelor 60 mg
HR 0.68 (0.47 – 0.99)
P=0.041Ticagrelor 60 mg
N=47
N=14,112 patients
Median FUP of 33 months
Venous Thromboembolism Reduced with Ticagrelor
Cavellari I, Bonaca MP et al. Circulation 2017
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)
Eve
nt
Ra
te (
%)
Extended DAPT
Aspirin Alone
RR 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, Bonaca MP et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.
~15% Reduction in
Cardiovascular Mortality
All Cause Mortality with Prolonged
Intensive Antiplatelet Therapy after MI
~11% reduction in all cause mortality
– ~17% reduction in CV Mortality (about 60% of deaths)
– No excess in non-CV Mortality (about 40% of deaths)
Bonaca MP and Sabatine MS. JAMA Cardiology 2016
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
CV
D/M
I/S
tro
ke (
%)
Days from Randomization
9.9%
8.0%
7.4%
Placebo
Ticagrelor 60 mg BID Ticagrelor 90 mg BID
HR 0.75
(95% CI 0.61 – 0.92)
P=0.0064
HR 0.70
(95% CI 0.57 – 0.87)
P=0.0009
Greater Benefit in Patients Continuing
on P2Y12 Inhibition
NNT=40
NNT=53
0%
2%
4%
6%
8%
10%
12%
0 90 180 270 360 450 540 630 720 810 900 990 1080
Bonaca et al. EHJ 2015
~13 Events
Prevented per 1000
vs 9 Bleeds
~20 Events
Prevented per 1000
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Efficacy of ticagrelor by eGFR
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 = 1,649)
eGFR < 60 Ticagrelor Pooled (N = 3,200)
eGFR ≥ 60 Placebo (N = 5,336)
eGFR ≥ 60 Ticagrelor Pooled (N = 10,713)
13.99%
11.29%
7.43%
6.80%
3-y
r K
M %
0
2
0
6
12
10
8
16
14
4
Magnani G et al. and Bonaca MP EHJ 2015
An Academic Research Organization of
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Coronary Events in Multivessel Disease
Days from Randomization
CV
Death
, M
I, S
tro
ke (
%)
Bansilal S, et al. ACC 2016
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Brigham and Women’s Hospital and Harvard Medical School
MACE with Ticagrelor in Diabetics
Days from Randomization
CV
Death
, M
I, S
tro
ke (
%) 11.6%
10.1%
7.8%
6.7%
Benefit in Diabetic vs. Non-Diabetic Patients:
Interaction P=0.99
Ticagrelor in Non-Diabetic Patients
HR 0.84 (95% CI 0.74 – 0.96)
ARR 1.1%; P=0.01
Ticagrelor in Diabetic Patients
HR 0.84 (95% CI 0.72 – 0.99)
ARR 1.5%; P=0.03
Ticagrelor (doses pooled)
Placebo
Bhatt DL, Bonaca MP, Bansilal S, et al. Steg PG. JACC. 2016.
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Brigham and Women’s Hospital and Harvard Medical School
-16
-6
2
23
-20
-15
-10
-5
0
5
10
15
20
25
GDF-15 < 1200 GDF-15 >= 1200
Events Prevented or Caused for 1000 Initiated on
Ticagrelor 60 for 3 Years
Eve
nts
pre
ve
nte
d o
r c
au
se
d
for
10
00
Pa
tie
nts
In
itia
ted
on
Tre
atm
en
t fo
r 3
Ye
ars
GDF-15 Concentration at Baseline
No excess in ICH or Fatal Bleeding
CV Death, MI, Stroke
CV Death, MI, Stroke
Major Bleeds
Major Bleeds
Bonaca et al. ESC 2017
PEGASUS-TIMI 54 and COMPASS – Trial Comparison
*Doses pooled
Similarities
• Long-term secondary prevention
• Antithrombotic (safety concerns)
• Placebo controlled
• MACE primary outcome
Differences
• Post-MI vs. enriched polyvascular
(PAD, Carotid, CAD)
• PEGASUS-TIMI 54 – PAD ~5%
• COMPASS – PAD 27%
• Run-in phase to select patients who
for adherence
• COMPASS - 16-17% no difference
between groups
• PEGASUS-TIMI 54 - 21% vs 28%
vs 32%
• PPI factorial
• Mechanism of action
• Bleeding definitions
• Net benefit definitions
• Recent CABG included in COMPASS /
excluded in PEGASUS-TIMI 54
PEGASUS-TIMI 54 and COMPASS - Outcome Comparison
Outcome Ticagrelor 60 vs
Placebo
P-value Rivaroxaban 2.5
mg vs Placebo
P-value
CVD/MI/Stroke 0.84 (0.76 – 0.94) 0.001 0.76 (0.66 – 0.86) <0.001
CV Death 0.83 (0.68 – 1.01) 0.07 0.78 (0.64 – 0.96) 0.02
MI 0.84 (0.72 – 0.98) 0.03 0.86 (0.70 – 1.05) 0.14
Stroke 0.75 (0.57 – 0.98) 0.03 0.58 (0.44 – 0.76) <0.001
VTE 0.68 (0.47 – 0.99) 0.041 0.61 (0.37 – 1.00) 0.05
MALE (PAD)* 0.65 (0.44 – 0.95) 0.026 0.54 (0.35 – 0.84) 0.005
Mortality 0.89 (0.76 – 1.04) 0.14 0.82 (0.71 – 0.96) 0.01
Bleeding leading to
transfusion
1.52 (0.99 – 2.33) 0.058 1.97 (1.37 – 2.83) <0.001
GUSTO Severe vs.
Major Bleeding
1.83 (1.22 – 2.74) 0.004 1.70 (1.40 – 2.05) <0.001
Fatal Bleeding or ICH 1.22 (0.74 – 2.01) 0.43 1.23 (0.76 – 2.01) 0.40
NET Outcome
(CVD/MI/Stroke/ICH/F
atal bleeding)
0.86 (0.77 – 0.97) 0.016 0.80 (0.70 – 0.91) <0.001
*Doses pooled
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
366 456 546 636 726 816 906 996 10860%
2%
4%
6%
8%
10%
12%
14%
16%
18%
0 90 180 270 360
First Year Years 2 + 3
Drug discontinuation for AE by TreatmentK
M R
ate
Days from Randomization
Ticagarelor 90 mg twice daily Ticagrelor 60 mg twice daily Placebo
16%
13%
6%
6.0%
4.5%
6.5%
P-value for each
dose vs.
placebo < 0.01
P<0.01 for each dose
vs. placebo
Treatment Arm Annualized Rate
Ticagrelor 90 3.3%
Ticagrelor 60 3.0%
Placebo 2.3%
0
50
100
150
200
250
300
350
400
450
500
0 90 180 270 360 450 540 630 720 810 900 990
Discontinuation over time for Dyspnea by
Randomization GroupN
um
ber
of
Pati
en
ts D
isco
nti
nu
ed
fo
r D
ysp
nea
Days From Randomization
Ticagrelor 90 mg twice dailyTicagrelor 60 mg twice dailyPlacebo
8
11
53
P<0.01 for each
dose vs. placebo
Median Days to
Discontinuation
Efficacy of Ticagrelor – On Treatment*
CVD / MI / Stroke
Ticagrelor Better Placebo Better1.0
Ticagrelor Placebo
3 Year KM Rate (%)
P-value
<0.001
*N=20,942 patients who received at least one dose of study drug including events through 7 days
from the last dose of study drug. Results consistent after propensity score adjustment
CV Death
Coronary Heart Disease Death
<0.001
<0.001
0.031
0.076
0.019
0.052
0.087
0.029
0.79 (0.68 – 0.91)
0.78 (0.68 – 0.90)
0.78 (0.70 – 0.88)
6.8
6.6
6.7
8.4
HR (95% CI)
0.78 (0.60 – 1.03)
0.74 (0.57 – 0.97)
0.76 (0.61 – 0.96)
1.8
1.9
1.9
2.4
0.75 (0.54 – 1.04)
0.72 (0.52 – 1.00)
0.74 (0.56 – 0.97)
1.2
1.3
1.3
1.6
Ticagrelor 60 mg
Ticagrelor 90 mg
Pooled
Myocardial Infarction
Stroke
0.0236
0.0080
0.0036
0.048
0.094
0.029
0.78 (0.65 – 0.94)
0.81 (0.68 – 0.97)
0.80 (0.68 – 0.93)
4.1
3.8
4.0
4.9
0.77 (0.56 – 1.05)
0.73 (0.53 – 1.00)
0.75 (0.58 – 0.97)
1.4
1.4
1.4
1.8
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Patients ≤ 2 Yrs from MI or 1 Yr from ADP
Receptor Blocker Treatment
5391 5246 5138 4914 4380 3177 1485
5388 5280 5187 4999 4436 3253 1507T60 EU
Placebo EUNumber at risk:
7.85%
9.56%
0 180 360 540 720 900 1080Days after randomization
0%
2%
4%
6%
8%
10%
T60 EUPlacebo EU
Prim
ary
endpoin
t(%
)
OutcomeTicagrelor 60
(N=5388)
Placebo
(N=5391)
Hazard ratio
(95% CI) P value
n 3-yr n 3-yr
PEP 373 7.9 463 9.6 0.80 (0.70, 0.91) 0.001
CV death 119 2.6 167 3.6 0.71 (0.56, 0.90) 0.0041
MI 230 4.8 274 5.6 0.83 (0.70, 0.99) 0.041
Stroke 71 1.5 95 2.0 0.74 (0.55, 1.01) 0.058
All-cause mortality 206 4.4 256 5.4 0.80 (0.67, 0.96) 0.018
TIMI major bleeding 94 2.5 43 1.1 2.36 (1.65, 3.39) <0.0001
Fatal or intracranial bleeding27 0.8 25 0.7 1.17 (0.68, 2.01) 0.58
Dellborg et al. ESC 2017
PAD+CAD Higher Risk Than PAD or CAD Alone
Franzone et al. JAHA 2016
8,4%
6,0%4,6%
19,3%
22,3%
11,7%
0%
5%
10%
15%
20%
25%
PEGASUS-TIMI 54 PRODIGY DAPT
No PAD PAD
Secemsky et al. AHA 2016Bonaca et al. JACC 2016
CV
D / M
I /
Str
oke
60% increased risk of MACE after
adjusting for risk factors
Longer DAPT in PAD With CAD/ACS
Franzone et al. JAMA Cardiology 2016
27%
16%
7%
ARR
PAD with prior ACS
HR 0.46 (0.25 – 0.87)
P=0.016
P-interaction 0.011
9%
7%
All Cause Mortality
21.1% vs 10.2%
HR 0.45 (0.23 – 0.88)
P=0.02
TIMI Major Bleeding
1.8% vs 3.5%
HR 0.50 (0.09 – 2.74)
P=0.43
GUSTO Mod/Severe
2.6% vs 2.6%
HR 1.02 (0.21 – 5.04)
P=0.51
Large reduction in MACE
Lower mortality
Modest bleeding excess
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
CVD / MI / Stroke
Ticagrelor Better Placebo Better 1.0
Absolute Risk
Difference at
3 Years
P=0.045
CV Death
Mortality
P=0.014
P=0.0074
0.69
(0.47 – 0.99)
HR
(95% CI)
0.47
(0.25 – 0.86)
0.52
(0.32 – 0.84)
10 0.1
TIMI Major Bleeding
– 5.2
– 5.4
– 5.7
P=0.82
1.18
(0.29 – 4.70) 0.02
0%
5%
10%
15%
20%
25%
CV
Death
, M
I, o
r S
tro
ke (
%)
Days from Randomization
P-interaction NS
Ticagrelor 60 mg BID
Placebo
ASA+Ticagrelor in PAD with Prior MI
Bonaca MP et al. JACC 2016
PAD
No PAD
19.3%
14.1%
ARR 5.2%
NNT 20
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Major Adverse Limb Events with TicagrelorA
cu
te L
imb
Is
ch
em
ia o
r
Pe
rip
he
ral R
eva
sc
ula
riza
tio
n f
or
Isc
he
mia
(%
)
Days from Randomization
0.0%
0.2%
0.4%
0.6%
0.8%
1.0%
0 180 360 540 720 900 1080
0.71%
0.46%
HR 0.65
95% CI (0.44 – 0.95)
P=0.026
Number at Risk
PlaceboTicagrelor
7067
14095
6988
13929
6912
13789
6701
13425
6077
12186
4518
9154
2123
4296
Bonaca MP et al. JACC 2016
Vorapaxar and Limb Vascular Efficacy
Hospitalization for
Acute Limb IschemiaPre-specified, adjudicated
2.3%
3.9%
Hazard Ratio 0.58
95% CI 0.39 to 0.86
p = 0.006
Placebo
Vorapaxar
N = 3767
Days from randomization
Peripheral
Revascularization
Prespecified,
Investigator
18.4%
22.2%
Hazard Ratio 0.84;
95% CI 0.73 to 0.97
p = 0.017
Bonaca et al. Circulation 2012
More Intensive Antithrombotic Therapy
Reduces MACE in PAD + CAD
• Not “CAD Patients” – risk exceeds PAD or CAD alone
– PEGASUS-TIMI 54, PRODIGY, DAPT
• Concomitant CAD may an “effect modifier” and it
remains unclear more potent strategies reduce MACE
risk in PAD without CAD– EUCLID – ticagrelor monotherapy benefit if CAD
– COMPASS – MACE benefit in PAD with/without CAD?
• More potent regimens reduce limb events (vorapaxar,
ticagrelor, rivaroxaban)
• Robust benefit of more potent antithrombotic therapy
with significantly reduced mortality in multiple trials
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Summary of Effects of
PCSK9i Evolocumab• LDL-C by 59% to a median of 30 mg/dL
• CV outcomes in patients on statin
• Safe and well-tolerated
14,6
9,9
12,6
7,9
0
5
10
15
KM
Ra
te (
%)
at
3 Y
ea
rs
HR 0.85 (0.79-0.92)
P<0.0001
HR 0.80 (0.73-0.88)
P<0.0001
CVD, MI, stroke
UA, cor revasc
CVD, MI, stroke
Sabatine MS et al. NEJM 2017;376:1713-22
Evolocumab
(median 30 mg/dl, IQR 19-46 mg/dl)
Placebo
59% reduction
P<0.00001
Absolute 56 mg/dl
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Peripheral Artery Disease and Risk in
Placebo Patients
Days from Randomization
CV
D /
MI / S
tro
ke
adjusted age, sex, race, BMI, diabetes, hypertension, smoking, eGFR, CHF, prior MI,
CABG/PCI, and history of stroke or TIA.
0%
2%
4%
6%
8%
10%
12%
14%
16%
0 180 360 540 720 900Days from Randomization
0%
2%
4%
6%
8%
10%
12%
14%
16%
0 180 360 540 720 900
P=0.0028
7.6%
10.3%
14.9%
P=0.0001
CV
D /
MI / S
tro
ke
7.6%
13.0%Adjusted HR
1.81(1.53 – 2.14)
P<0.001
PAD N=1784
MI or Stroke and no PAD N=11996 MI or Stroke and no PAD N=11996
PAD with MI/Stroke N=1036
PAD no MI/Stroke N=748
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
MI or Stroke
and no PAD
N=23,922
PAD
N=3,642
Age, median (IQR) 63 (56, 69) 64 (58, 69)
Female sex (%) 24 28
History Hypertension (%) 79 85
Current Smoker (%) 27 36
History of Diabetes (%) 36 43
History of Stroke (%) 20 15
History of Myocardial Infarction (%) 86 50
Statin, High/Moderate (%) 69 / 30 69 / 31
Antiplatelet therapy (%) 93 89
Anticoagulant therapy (%) 8 11
ACE-I or ARB use at baseline (%) 78 76
All p-values < 0.05 except statin use/intensity (p=0.57)
Statin dose at baseline missing in 10 (0.0%) without PAD and 3 (0.1%) with PAD
Baseline Characteristics
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
CV
De
ath
, M
I o
r S
tro
ke
Placebo
Evolocumab
13.0%
7.6%
9.5%
6.2%
PAD
3.5% ARR
NNT2.5y 29
No PAD
1.4% ARR
NNT2.5y 72
PADN=3,642
27% RRR
HR 0.73
(0.59 – 0.91)
P=0.0040
p-interaction = 0.41
No PAD
N=23,922
HR 0.81
95% CI (0.73 – 0.90)
P<0.001
Days from Randomization
CV Death, MI or Stroke in Patients with
and without Peripheral Artery Disease
0%
2%
4%
6%
8%
10%
12%
14%
0 90 180 270 360 450 540 630 720 810 900
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
10%
12%
0 90 180 270 360 450 540 630 720 810 900
CV
De
ath
, M
I o
r S
tro
ke
Days from Randomization
Placebo
Evolocumab
10.3%
5.5%
PAD
4.8% ARR
NNT2.5y 21
PAD
(no MI/stroke, N=1505)
43% RRR
HR 0.57
(0.38 – 0.88)
P=0.0095
CV Death, MI or Stroke in Patients with
PAD and no MI or Stroke
Outcome HR 95% CI
MACE 0.57 (0.38–0.88)
CV Death 0.78 (0.39–1.57)
MI 0.66 (0.38–1.14)
Stroke 0.30 (0.11–0.82)
Mortality 0.86 (0.51- 1.45)
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Ma
jor
Ad
ve
rse
Lim
b E
ve
nts
Placebo
0.45%
0,0%
0,1%
0,2%
0,3%
0,4%
0,5%
0 90 180 270 360 450 540 630 720 810 900
Days from Randomization
Major Adverse Limb Events
Placebo
Evolocumab
0.45%
0.27%
All PatientsN=27,564
42% RRR
HR 0.58
(0.38 – 0.88)
P=0.0093
0,0%
0,1%
0,2%
0,3%
0,4%
0,5%
0 90 180 270 360 450 540 630 720 810 900
Days from Randomization
Outcome HR 95% CI
MALE 0.58 (0.38–0.88)
ALI or major amputation 0.52 (0.31–0.89)
ALI 0.55 (0.31–0.97)
Major amputation 0.57 (0.17–1.95)
Urgent revascularization 0.69 (0.38–1.26)
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0,0%
0,5%
1,0%
1,5%
2,0%
2,5%
3,0%
0 90 180 270 360 450 540 630 720 810 900
Ma
jor
Ad
ve
rse
Lim
b E
ve
nts
Placebo
Evolocumab
2.6%
1.3%
Major Adverse Limb Events in Patients
with PAD and no MI or Stroke
Days from Randomization
1.3% ARR
PAD
(no MI/stroke, N=1505)
57% RRR
HR 0.43
(0.19 – 0.99)
P=0.042
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
10%
12%
14%
0 90 180 270 360 450 540 630 720 810 900
Placebo
Evolocumab
12.8%
6.5%
PAD
6.3% ARR
NNT2.5y 16
Days from Randomization
MACE or MALE
In Patients with PAD and no MI or StrokeM
AC
E o
r M
AL
E
PAD
(no MI/stroke, N=1505)
48% RRR
HR 0.52
(0.35 – 0.76)
P=0.0006
The DAPT Score
53
0%
5%
10%
15%
20%
25%
30%
-2 -1 0 1 2 3 4 5 6 7 8 9 10
Perc
en
tag
e o
f P
ati
en
ts
DAPT Score
Variable Points
Patient Characteristic
Age
≥ 75 -2
65 - <75 -1
< 65 0
Diabetes Mellitus 1
Current Cigarette Smoker 1
Prior PCI or Prior MI 1
CHF or LVEF < 30% 2
Index Procedure
Characteristic
MI at Presentation 1
Vein Graft PCI 2
Stent Diameter < 3mm 1
Distribution of DAPT Scores among all
randomized subjects in the DAPT Study
Yeh et al. JAMA 2016
54
Continued Thienopyridine vs. Placebo, by DAPT Score, Excluding PES
Ris
k D
iffe
ren
ce
(Co
nti
nu
ed T
hie
no
pyr
idin
e –
Pla
ceb
o),
12
-30
M
P values are for comparison of risk differences across DAPT Score category (interaction).
Myocardial Infarctionor Stent Thrombosis
GUSTO Moderate or Severe Bleed
Net AdverseEvents
P=0.06 P=0.07 P=0.17
Mortality
P=0.003
-0,52%
1,44%
1,03%0,79%
-1,90%
0,38%
-1,67%
-0,01%
-4,0%
-3,0%
-2,0%
-1,0%
0,0%
1,0%
2,0%
3,0%
4,0%
DAPT Score < 2
DAPT Score ≥ 2
Yeh et al. JAMA 2016
Variable HR (95% CI) p-value Points
CHF 2.03 (1.68, 2.46) <0.001 1
Prior Stroke 1.83 (1.39, 2.40) <0.001 1
Hypertension 1.61 (1.34, 1.93) <0.001 1
Diabetes mellitus 1.49 (1.27, 1.75) <0.001 1
Current Smoking 1.47 (1.23, 1.75) <0.001 1
Prior CABG 1.44 (1.20, 1.73) <0.001 1
Age≥75 1.40 (1.11, 1.75) 0.004 1
Peripheral arterial disease 1.36 (1.13, 1.64) 0.001 1
Renal dysfunction (eGFR< 60) 1.36 (1.12, 1.65) 0.002 1
Maximum Possible # Risk Indicators 9
Multivariable Model
Risk of CV death, MI or ischemic stroke in
placebo-treated cohort (N=8598)
Bohula et al. Circulation in Press
Efficacy & Safety By Risk Group
# Risk Indicators 0 1-2 ≥3
3217 (19) 9967 (61) 3214 (20)
3,6%
8,1%
17,7%
3,5%
6,0%
14,5%
0,1%1,0%
2,0%
0,7%1,1%
1,9%
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
20%
CV
de
ath
/ M
I / is
ch
em
ic s
tro
ke
at
3 Y
rs (
%)
Placebo (CV death, MI, or Ischemic Stroke)Vorapaxar (CV death, MI, or Ischemic Stroke)Placebo (GUSTO Severe Bleeding)Vorapxar (GUSTO Severe Bleeding)
ARR 2.1% (1.0, 3.4)
NNT 48
ARR 3.2% (0.4, 6.3)
NNT 31
CVD/MI/iCVA:
p-trend<0.001
p-interaction = 0.35
GUSTO Severe:
p-trend<0.01
p-interaction = 0.13
Prior MI without a history of stroke or TIA
Bohula et al. AHA 2015
CHF, prior stroke,
HTN, DM, age,
smoking, CABG,
PAD, renal
dysfunction
PARIS Risk Score
Baber et al. JACC 2016
PRECISE-DAPT – Bleeding Risk in ACS
http://precisedaptscore.com/webcalculator.php
Consideration for PEGASUS-TIMI 54 Population
Hemoglobin at Baseline marker of occult bleeding? part of bleeding definition?
Age Also associated with ischemic risk and greater benefit
WBC Unclear mechanism
Creatinine Clearance Also asociated with ischemic risk and greater benefit
Prior Bleeding Excluded from trial
Which Post-MI Have Greatest Benefit?
Baber et al. JACC 2016
DAPT PARIS TIMI PEGASUS-
TIMI 54
Diabetes Mellitus ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk
Prior MI/ACS ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk
Prior CABG / MVD ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk
Renal Dysfunction ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk
Current Smoking ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk
PAD ▲Ischemic Risk ▲Ischemic Risk
CHF or low EF ▲Ischemic Risk ▲Ischemic Risk ▲Ischemic Risk
Age ▲Bleeding Risk ▲Bleeding Risk ▲Ischemic Risk ▲Ischemic Risk
Prior stroke ▲Ischemic Risk
Hypertension ▲Ischemic Risk
Prior PCI ▲Ischemic Risk ▲Ischemic Risk
Stent Diameter ▲Ischemic Risk
Paclitaxel Stent ▲Ischemic Risk
Yeh et al. JAMA 2016 Bohula et al. Circ 2016Slide by Marc Bonaca
A Framework for Optimizing DAPT Duration
Who
• Patients with prior MI at
high risk:
• Diabetes mellitus
• Multiple prior MIs
• Renal dysfunction
• MVD / prior CABG
• PAD
• Recent MI/on P2Y12
• Not at high risk for
bleeding
• Prior/risk of ICH
• Recent major
Bleeding
• Bleeding diathesis
• On anticoagulation
• Low BMI / anemia
• < GDF-15
When
• Continue after started
for MI and re-evaluate
at each visit:
• Recent bleeding?
• Are they
tolerating?
• Are they
adherent?
• Contraindication
s (e.g. new dx of
AF requiring
anticoagulation)
Why
• To reduce long-term
ischemic risk
including:
• New spontaneous
MI including
STEMI
• Ischemic stroke
including
disabling events
• Limb ischemic
events in PAD
• CV mortality as
predominant
cause of death
Slide by Marc Bonaca