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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



Examples of high-risk patients

• Post-myocardial infarction (MI) patients



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,

%




• Post-MI patients (but modern therapy does not

abolish risk)



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




• Post-MI patients

• Patients with diabetes



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.



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.




• Post-MI patients

• Patients with diabetes

• Patients with peripheral arterial disease (PAD)



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



• Examples of high-risk patients

• Modern therapy does not abolish risk

• Risk stratification schemes allow some

stratification of risk



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.



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





• The extent of arterial disease (CAD and at other

locations) impacts risk





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.



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.







• We should be worrying about the patient (not the

stent)





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







• We should be worrying about the patient (not the

stent)



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



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



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



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



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

*



• 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?



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



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



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


>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.



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.

.



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?



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



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.


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.



TRA 2P-TIMI50 Trial: Incidence

of New Ischemic Stroke

0.88%


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


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


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



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.



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

(%

)


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

(%

)


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




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)



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

(%

)


HR 0.73

(95% CI 0.60 – 0.89)


HR 0.71

(95% CI 0.50 – 1.00) 10.2%

7.8%

9.1%

7.3%



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

(%

)


HR 0.73

(95% CI 0.60 – 0.89)


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


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


Extended DAPT ASA Alone



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


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%



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];


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


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


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




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

Documents

Activity presentations are considered intellectual …img.medscape.com › images › 853 › 754 › AHA_Symposium...Secondary Prevention of Atherothrombotic Events Activity presentations