Antithrombotic Therapy for Long-Term Secondary Prevention

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


Pro

bab

ilit

y o

f P

rim

ary

Ev

en

ts

PAD with and without Diabetes Stroke/TIA with and without Diabetes


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

Brigham and Women’s Hospital and Harvard Medical School

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



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…



No. Patients – 1560 No. Sites - 41

Average patients per site = 38

Patient Retention 99.94%

NLI: DR. TON OUDE OPHUIS

NETHERLANDS

But Actually…



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




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



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




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)



-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



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


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



~40% Reduction in Very

Large MI



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



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%


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



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 (

%)


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



CV

D/M

I/S

tro

ke (

%)


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



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



Coronary Events in Multivessel Disease


CV

Death

, M

I, S

tro

ke (

%)

Bansilal S, et al. ACC 2016



MACE with Ticagrelor in Diabetics


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.



-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



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


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 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



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



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 (

%)


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



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

(%

)


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



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



Peripheral Artery Disease and Risk in

Placebo Patients


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



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



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


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



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


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)



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


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


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)



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


1.3% ARR

PAD


57% RRR

HR 0.43

(0.19 – 0.99)

P=0.042



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


MACE or MALE

In Patients with PAD and no MI or StrokeM

AC

E o

r M

AL

E

PAD


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


GUSTO Severe:

p-trend<0.01


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

Documents

Antithrombotic Therapy for Long-Term Secondary Prevention