Antiplatelet Therapy: Stents, Strokes, MIs, and Prevention ... · CV Death, MI, Stroke or Hosp for Atherothrombosis 54% 20% 6% 20% Steg et al. JAMA 2007; 297:1197-1206. 5.31 14.4

Antiplatelet Therapy: Stents, Strokes, MIs, and Prevention - 1, 2 or 3 Drugs - What is a

Clinician to do?

Marc P. Bonaca, MD, MPHVascular Section, Cardiovascular Division

Investigator TIMI Study GroupBrigham and Women’s Hospital

Assistant Professor, Harvard Medical School

ASPC 2016 Congress on Atherosclerotic Cardiovascular Disease Prevention

0

4

8

12

16

20

24

CADOnly

CVDOnly

PADOnly

>1 Bed

CV Death, MI, Strokeor Hosp for Atherothrombosis

54% 20% 6% 20%

Steg et al. JAMA 2007; 297:1197-1206.

5.31

14.4

0

4

8

12

16

20

24

Multiple RiskFactors

EstablishedDisease

CV Death, MI, Strokeor Hosp for Atherothrombosis

%

Outcomes in Patients with Atherosclerotic Disease

REACH Registry (1 Year Outcomes) 64,977 pts ≥ 45 YO

Marc P. Bonaca, and Mark A. Creager Circulation Research. 2015;116:1579-1598

Copyright © American Heart Association, Inc. All rights reserved.

Targets for Antithrombotic Therapy

Aspirin in Primary and Secondary Prevention

ATT Meta-analysis, Lancet 2009

Primary Prevention

Low dose aspirin

• Reduces serious vascular events by ~12% at a cost of bleeding

• Not just for prevention of ischemic events, cancer prevention

• Benefit based on life expectancy and 10-yr CVD risk

• Bleeding risk needs to be assessed (history of GI/intracranial bleeding, concomitant NSAIDs or AC, liver disease, renal disease, bleeding disorder) and modified (e.g. H. Pylori)

• Need to balance ischemic benefit against risk of bleeding and weighing outcomes is complex

• Differences in US and European Guidelines

Primary Prevention

Halvorsen et al. JACC 2014

CAPRIE Steering Committee. Lancet 1996

Thienopyridine Monotherapy

Clopidogrel versus ASA (325 mg) in 19,185 patients (6,452 with PAD)

No difference in Amputations52 with clopidogrel vs 47 with ASA

CURE: benefit of DAPT with aspirin and clopidogrel after ACS

Prop

ortio

n Ev

ent-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 Risk5981 5481 4742 4004 3180 24185954 5390 4639 3929 3159 2388

Clopidogrel 6259 6145 6070 6026 5990Placebo 6303 6159 6048 5993 5965

No. at Risk

Prop

ortio

n Ev

ent-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

Dea

th, M

I, or

Stro

ke (%

)

Clopidogrel

Ticagrelor

4.775.43

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

Dea

th, M

I, or

Stro

ke (%

)

Efficacy of ticagrelor vs clopidogrel over time

*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)

CHARISMA: DAPT with ASA and Clopidogrel in Secondary Prevention

*All patients received ASA 75-162 mg/day

Placebo + ASA*7.3%

Clopidogrel + ASA*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

Dea

th, M

I, or

Str

oke

(%)

Bhatt DL, Fox KA, Hacke W, NEJM 2006

ASA vs. ASA + Clopidogrel in 1º and 2º Atherothrombosis Prevention

N=15,603

12% Reduction in SymptomaticRR 0.88 (0.77 – 0.998, p=0.046)

23% reduction in prior MI

Dual Antiplatelet Therapy in Patients with Symptomatic PAD after Bypass

• 851 patients undergoing unilateral below-knee bypass grafting for atherosclerotic PAD

• ASA (75 mg – 100 mg) + clopigogrel vs. ASA alone

• Primary endpoint composite of index-graft occlusion, revascularization, amputation, or death

Belch et al. Journal of Vascular Sugery. 2010

Benefit in subgroup with prosthetic grafts?

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

MATCHRR 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 clopidogrelTRITON-TIMI 38

P=0.02

Diener H. et al. Lancet 2004 Sacco RL. et al. NEJM 2008, Wiviott SD. et al. NEJM 2007

SPS3 – Lacunar Stroke0.28%

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)

Challenge to the Broad Application of Potent Antiplatelet Strategies for Secondary Prevention

MI PAD Stroke

• DAPT beneficial in ACS and more potent agents are superior

• Long-term DAPT may be helpful for secondary prevention of new spontaneous events

• Monotherapybeneficial in symptomatic but benefit unclear in asymptomatic

• Uncertain benefit of DAPT (short or long-term) – does not appear to modify limb ischemic risk

• Monotherapybeneficial

• Long-term DAPT harmful in broad stroke populations

Vorapaxar in Stable Patients with Prior MI, Prior Stroke, or PAD

CV Death, MI, or Stroke

9.3%

10.5%

Hazard Ratio 0.87p < 0.001

N = 26449Mean f/u: 2.5 years Placebo

Vorapaxar

BleedingGUSTO Mod/Sev at 3 yrs

4.2 v. 2.5%, HR 1.66, p<0.001

Morrow DA, Braunwald E, Bonaca MP, et al. N Engl J Med. 2012; 366: 1404-1413

Major Bleeding EndpointsOverall Population

3-yr KM rate (%)Prior Stroke

n = 5746No Hx of Stroke

n = 20699

Morrow et al. NEJM 2012; 366: 1404-1413

ARD 2.0% HR 1.87 P<0.001

ARD 1.5% HR 2.55 P<0.001

ARD 0.2% HR 1.48 P=0.46

ARD 0.2% HR 1.55 P=0.049

ARD 0.1% HR 1.44 P=0.30

ARD 0.7% HR 1.35 P=0.005

Efficacy of PAR-1 Inhibition Independent of P2Y12 Inhibition

Bohula et al. Circulation 2015

Limb Ischemic Events in PADHospitalization for Acute Limb IschemiaPre-specified, adjudicated

2.3%

3.9%

Hazard Ratio 0.5895% CI 0.39 to 0.86

p = 0.006

Placebo

Vorapaxar

N = 3767

Days from randomization

Peripheral RevascularizationPrespecified, Investigator

18.4%

22.2%

Hazard Ratio 0.84;95% CI 0.73 to 0.97

p = 0.017

Bonaca et al. Circulation 2012

Challenge to the Broad Application of Potent Antiplatelet Strategies for Secondary Prevention

MI PAD Stroke

• DAPT beneficial in ACS and more potent agents are superior

• Long-term DAPT may be helpful for secondary prevention of new spontaneous events

• Monotherapybeneficial in symptomatic but benefit unclear in asymptomatic

• Uncertain benefit of DAPT (short or long-term) – does not appear to modify limb ischemic risk

• Monotherapybeneficial

• Long-term DAPT harmful in broad stroke populations

PAR-1 antagonismMACE and limb ischemic

risk reduction

Randomized trials of dual antiplatelettreatment duration after drug-eluting stents

Randomized trials of dual antiplatelettreatment duration after drug-eluting stents

Trial Total DESRandomized

Treatment 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 1259

Continued 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 events1.08 (0.51-2.27)

27 events

20

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

DAPT: Prior MI and Efficacy for MACE

Yeh et al. JACC 2015

An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Months from Randomization

Ticagrelor 60 mgHR 0.84 (95% CI 0.74 – 0.95)

P=0.004

CV

Dea

th, M

I, or

Str

oke

(%)

3 6 9 120 15 18 21 24 27 30 33 36

Ticagrelor 90 mgHR 0.85 (95% CI 0.75 – 0.96)

P=0.008

Placebo (9.0%)

Ticagrelor 90 (7.8%)Ticagrelor 60 (7.8%)

21,162 Patients with Prior MI

6

5

4

3

10

9

8

7

2

1

0

N = 21,162Median follow-up 33 months

Bonaca MP et al. NEJM 2015;372:1791-800


Primary Endpoint – Landmark (ITT)

0%

1%

2%

3%

4%

5%

6%

7%

0 90 180 270 3600%

1%

2%

3%

4%

5%

6%

7%

366 456 546 636 726 816 906 996 1086

CVD

/MI/S

trok

e (%

)

Time from Index MI

3.2%2.8%2.7%

5.9%

5.2%5.1%

First Year of Treatment Subsequent Two Years of Treatment

Ticagrelor 60 mgHR 0.82

(95% CI 0.67 – 0.99)P=0.037


(95% CI 0.71 – 1.03)P=0.10


(95% CI 0.73 – 0.998)P=0.047


(95% CI 0.72 – 0.99)P=0.036

Median 1.7 yrs(1.2 – 2.3)

Median 2.7 yrs(2.2 – 3.3)

Median 4.7 yrs(4.2 – 5.3)

3.1%

2.8%2.5%


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


(95% CI 0.45 – 0.86)P=0.00016


(95% CI 0.41 – 0.79)P=0.0008

Placebo

Ticagrelor 90Ticagrelor 60

Days from Randomization

STEM

I (%

)


Major Adverse Limb Events with TicagrelorAc

ute

Lim

b Is

chem

ia o

r Pe

riphe

ral R

evas

cula

rizat

ion

for I

sche

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 0.6595% CI (0.44 – 0.95)

P=0.026

Number at RiskPlacebo

Ticagrelor7067

140956988

139296912

137896701

134256077

1218645189154

21234296


0.0%

0.2%

0.4%

0.6%

0.8%

1.0%

1.2%

1.4%

0 180 360 540 720 900 1080

Thro

mbo

tic C

ompl

icat

ions

(%)


PlaceboN=105

Ticagrelor 60 mgHR 0.68 (0.47 – 0.99)

P=0.041 Ticagrelor 60 mg N=47

N=14,112 patientsMedian FUP of 33 months

VENOUS AND INTRACARDIAC THROMBOSIS WITH TICAGRELOR

Outcomes with Continued DAPT after MI

6.4

2.3

3.5

1.40.6

7.5

2.6

4.4

1.7 1.4

0123456789

10

MACE CV Death MI Stroke StentThrombosis(Def/Prob)

Even

t Rat

e (%

)

Extended DAPTAspirin Alone

RR 0.78P = 0.001

RR 0.85P = 0.03

RR 0.70P = 0.003

RR 0.81P = 0.02 RR 0.50

P = 0.02

Udell JA, Bonaca MP et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.


0.1 0.2 0.5 1 2 5 10

P<0.001

0.1 0.2 0.5 1 2 5 10

Stroke Reduction with Intensive AP Therapy

Stroke

Favors More Intensive AP Therapy

Favors Less Intensive AP Therapy

Ischemic Stroke

P<0.001

Trial N n Intervention Background RR 95% CICHARISMA 3,846 75 Clopidogrel ASA 0.75 0.48-1.81

TRA°2P-TIMI 50 16,897 164 Vorapaxar ASA±clopidogrel 0.62 0.45-0.85

DAPT 9,961 80 Clopidogrel ASA 0.80 0.51-1.25

PEGASUS-TIMI 54 14,112 213 Ticagrelor 60 ASA 0.75 0.57-0.98

Overall 44,816 532 28% 0.72 0.60-0.85

Trial N n Intervention Background RR P-valueCHARISMA 3,846 65 Clopidogrel ASA 0.76 0.47-1.25

TRA2°P-TIMI 50 16,897 136 Vorapaxar ASA±clopidogrel 0.51 0.36-0.72

DAPT 9,961 58 Clopidogrel ASA 0.68 0.40-1.16

PEGASUS-TIMI 54 14,112 181 Ticagrelor 60 ASA 0.76 0.56-1.03

Overall 442 34% 0.66 0.54-0.81

Favors More Intensive AP Therapy

Favors Less Intensive AP Therapy

Bonaca MP et al. Circulation 2016

All Cause Mortality with Prolonged Intensive Antiplatelet Therapy after MI

~11% rededication 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

1.9

0.4 0.1

1.7

4.0

1.10.3 0.2

1.6

4.2

0123456789

10

MajorBleeding

ICH FatalBleeding

Non-CVDeath

All-CauseDeath

Even

t Rat

e (%

)

Extended DAPTAspirin Alone

RR 1.73P = 0.004

P = NS

RR 1.03P = NS

RR 0.92P = NS

P = NS

Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

Safety of Continued DAPT after MI

Prolonged Antiplatelet Therapy and Bleeding

Mauri et al. NEJM 2014

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

Slide by Bonaca MP

P < 0.001 for all comparisons at full follow upGUSTO Moderate or Severe

Annualized Rates

Clopidogrel 75 mg daily vs Placebo

Vorapaxar 2.5 mg daily vs Placebo

+ 0.5% + 0.6%

+ 0.3% + 0.5%

Bohula et al. Circ 2015

Vorapaxar“Triple”

Vorapaxar“Dual”

Clopidogrel“Dual”

Berger et al. Circ 2010

Selection of Post-MI Patients for Long-Term Potent Antiplatelet Therapy

High Bleeding Risk

High Ischemic Risk


CVD

/MI/S

trok

e (%

)


9.9%

8.0%

7.4%

Placebo

Ticagrelor 60 mg BID Ticagrelor 90 mg BIDHR 0.75

(95% CI 0.61 – 0.92)P=0.0064

HR 0.70(95% CI 0.57 – 0.87)

P=0.0009

MACE at 3 Years with Ticagrelor in Patients with P2Y12Inhibitor Withdrawal ≤ 30 Days from Randomization

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


Efficacy of ticagrelor by eGFR

HR 95% CI0.81 (0.68 – 0.96)

ARR = 2.70%NNT 37

HR 95% CI0.88 (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-yr

KM

%

0

2

0

6

12

10

8

16

14

4

Magnani G et al. and Bonaca MP EHJ 2015

4

12

8

16

Incid

ence

(%)

7.9%

6.8%

12 24Time (Months)

36

15.7%

12.6%

HR 0.77 p=0.004

ARD -3.1NNT=30 95% CI 19, 92

HR 0.83 p=0.005

ARD -1.1 NNT=76 95% CI 47, 247

Efficacy of Vorapaxar in Patients w/ Prior MI Based on Diabetes History

CV Death, MI, or stroke (%)

PlaceboVorapaxar DM

No DM

0

p-int 0.51

Cavender et al. Circulation 2015;131:1047-53

Net Clinical Outcome(All‐Cause‐Mortality/MI/CVA/

GUSTO Severe Bleeding)HR: 0.77 (0.65‐0.93)

p = 0.006


CV

Dea

th, M

I, or

Str

oke

(%)


0%

5%

10%

15%

20%

25%

0 90 180 270 360 450 540 630 720 810 900 990 1080

19.3%

15.2%

8.4%7.4%

PADHR 0.75

95% (CI 0.55 – 1.01) ARR 4.1%NNT 25

No PADHR 0.86

95% (CI 0.77 – 0.96)

P-interaction 0.41

Ticagrelor(pooled doses)

Placebo

ARR 1.0%NNT 100

MACE with Ticagrelor by PAD at Baseline

Bonaca et al. JACC 2016

Risk Scores – Common Themes

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

PAD ▲Ischemic Risk ▲Ischemic Risk

CHF or low EF ▲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

An Approach to Long-Term DAPT/TAPT after MI

Who

• Patients with prior MI at high risk:

• Diabetes mellitus• Multiple prior MIs• Renal dysfunction• MVD / prior CABG• PAD• Smoker• CHF / low EF

• Not at high risk for bleeding

• Prior/risk of ICH• Recent major

Bleeding• Bleeding diathesis• On anticoagulation• Low BMI / anemia

When

• Continue after started for MI and re-evaluate at each visit:

• Recent bleeding?

• Are they tolerating?

• Are they adherent?

• Contraindications (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

1, 2, 3 Drugs – which drugs and for how long?

Slide by Marc Bonaca

CAD PAD AtherothrmoboticStroke

AP Monotherapy No prior MI or recent stenting

Symptomatic PAD notat high-risk for

MACE/ALI, consider in asymptomatic

Prior stroke (excluding AF/embolic)

ASA+ clopidogrel

Limited duration after elective

stenting or ACS and needs anticoagulant

Limited duration after elective stenting

Selected patients with acute stroke for short

duration

Monotherapy+ vorapaxar

Prior MI with highischemic risk and low bleeding risk (e.g. DM, MVD)

Symptomatic PAD with MACE or ALI

risk (e.g. prior ALI or revascularization)

Contraindicated

ASA+ticagrelor

ASA+clopiodgrel+vorapaxar

Prior MI with highischemic risk and low bleeding risk

Net benefit in high risk (e.g. DM, MVD)

Caution with ASA + potent P2Y12

Vorapaxar contraindicated

Documents

Antiplatelet Therapy: Stents, Strokes, MIs, and Prevention ... · CV Death, MI, Stroke or Hosp for Atherothrombosis 54% 20% 6% 20% Steg et al. JAMA 2007; 297:1197-1206. 5.31 14.4