NSTEMI-ACS:

Management of Patients with Non-ST-

Elevation Acute Coronary Syndromes

Eugene Braunwald, M.D.

47th Annual New York Cardiovascular Symposium

December 12, 2014

Plaque Rupture and Healing

Bentzon J F et al. Circulation Research. 2014;114:1852-1866

A Brief History of NSTE-ACS

NSTEMI UA - 1975

Pre-CKMB

1975-98

CK-MB

1998-2009

Tn

2009 -

hsTn

UA NSTEMI

UA NSTEMI

NSTEMI UA

Described in 1937, separately, by Sampson and Feil

Circulation 2013;127:2452

Benefit of INV vs CONS Strategy

O’Donoghue M, et al. JAMA 2008;300:71-80

TACTICS-TIMI 18

0 1 2 3 4 5 6 Time (months)

0

4

8

12

16

20

% P

atie

nts

CONS

INV

O.R 0.78

95% CI (0.62, 0.97)

p=0.025

19.4%

15.9%

Death, MI, Rehosp for ACS at 6 Months

Cannon CP, N Engl J Med 2001; 344:1879-87

14.8

24.2

16.714.8

0

5

10

15

20

25

30

TnT - TnT +

(%

)

CONS INV

TnT cut point = 0.01 ng/ml (54% of Pts TnT +)

Death, MI, Rehosp ACS at 6 Months

OR=0.55 *p<0.001

Interaction

P=0.013

p=NS

*

N=426 414 480 506

Morrow DA, JAMA 2001; 286:2405-12

TACTICS-TIMI 18

2014 ACC/AHA NSTEACS Guidelines

Immediate

(w/in 2 h)

Early Invasive

(w/in 24 h)

Delayed Invasive

(w/in 25-72 h)

Ischemia-Guided

• Signs or

symptoms of HF

or new or

worsening MR

• Recurrent angina

or ischemia at

rest or with low-

level activity

despite intensive

med Rx

• GRACE score

>140

• Temporal change

in Tn

• New or

presumably new

ST depression

• TIMI Risk Score

≥2

• GRACE score

>109-140

• Diabetes

• GFR <60

mL/min/1.73m2

• EF <0.40

• Early

postinfarction

angina

• PCI w/in 6 mo

• Prior CABG

• TIMI Risk Score

0-1

• GRACE score

<109

• Low-risk Tn-neg

female patient

• Patient or

clinician

preference in

absence of high-

risk features

Circulation 2014;epub ahead of print

Desai NR, Bhatt DL. JACC Cardiovasc Intervention. 2010;3:571-83.

Antiplatelet Agents

CONCLUSION

In NSTE-ACS, early (routine) eptifibatide was not superior to delayed

(provisional) admin, but was associated with excess bleeding

Early (Routine) vs Delayed (Provisional)

Eptifibatide in ACS (9492 pts)

12%

4%

0%

8%

OR 0.92, p=.23 0.89, p=.08 1.75, p <0.001

Giugliano RP et al. NEJM 2009;360:2176

Death/MI/Ri-Revasc

96 hrs

Death/MI

30 d.

Bleeding

TIMI major/minor

120 hrs

2014 ACC/AHA NSTEACS Guidelines:

GP IIb/IIIa Inhibitors

Timing Recommendation CO

R

LO

E Initially If treated w/ early invasive strategy and DAPT with

intermediate/high-risk features (eg, troponin),

GPI MAY BE CONSIDERED as part of initial antiplatelet

Rx. Preferred options are eptifibatide or tirofiban.

IIb B

At PCI If high-risk features and not adequately preRx’d w/

clopidogrel or ticagrelor, IT IS USEFUL to administer

GPI at the time of PCI

I A

Desai NR, Bhatt DL. JACC Cardiovasc Intervention. 2010;3:571-83.

Antiplatelet Agents

Hazard Ratio 1.53

(95% CI 1.07-2.19)

P=0.014

8.0

12.1

1064 1009 999 980 870 755 542

Number at Risk:

Days After Randomization

Non-Carrier

395 364 360 348 306 270 181Carrier

CV

De

ath

, M

I, o

r S

tro

ke

(%

)

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

0 30 90 180 270 360 450

Non-carriers

Carriers

CYP2C19 and CVD, MI, or Stroke: Clopidogrel

* Carriers ~30% of the population

CYP2C19 Reduced-Function Allele Carriers

N=1,459

Mega JL et al. N Eng J Med. 2009; 360:354-62.

Hazard Ratio 3.09

(95% CI 1.19-8.00)

P=0.015

0.8

2.6

1014 1004 1001 989 885 765 547

375 368 366 359 316 279 186

De

fin

ite

or

Pro

ba

ble

Ste

nt

Th

rom

bo

sis

(%

)

0

1

2

3

4

0 30 90 180 270 360 450

Number at Risk:

Days After Randomization

Non-Carrier

Carrier

Non-carriers

Carriers

* Carriers ~30% of the population

CYP2C19 Reduced-Function Allele Carriers

N=1,389

CYP2C19 and Stent Thrombosis: Clopidogrel

Mega JL et al. N Eng J Med. 2009; 360:354-62.

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81

(0.73-0.90)

P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32

(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel 1.8

2.4

138

events

35

events

Balance of

Efficacy and Safety

CV Death / MI / Stroke

TIMI Major

NonCABG Bleeds

NNT = 46

NNH = 167

Wiviott SD et al. NEJM 2007;357: 2001

Definite/Probable ST:

Any Stent (N=12844)

0

0.5

1

1.5

2

2.5

0 50 100 150 200 250 300 350 400 450

% o

f S

ubje

cts

HR 0.48 [0.36-0.64]

P<0.0001

1 year: 1.06 vs 2.15%

HR 0.48 [0.36-0.65], P<0.0001

2.35%

1.13%

52%

STENT ANALYSIS

DAYS

CLOPIDOGREL

PRASUGREL

Wiviott SD et al Lancet 2008;371:1353

Primary EP: D/MI/CVA

DM No DM

0

0.05

0.1

0.15

0.2

0 100 200 300 400 500

DM Clopidogrel

DM Prasugrel0

0.05

0.1

0.15

0.2

0 100 200 300 400 500

No DM Clopidogrel

No DMPrasugrel

17.0

12.2

HR 0.70 (0.58-0.85), <0.001 n=3146

10.6

9.2

HR 0.86(0.76-0.98), 0.02 n=10,462

P interaction = 0.09

%

0

5

10

15

20

0 100 200 300 400 500 0 100 200 300 400 500

Days Days

%

0

5

10

15

20

Wiviott SD et al. Circulation 2008;118:1626

Ticagrelor vs Clopidogrel in

18,624 Patients within 24 hrs of Onset of ACS

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,521

8,628

8,362

8,460

8,124

Days after randomisation

6,743

6,743

5,096

5,161

4,047

4,147

0 60 120 180 240 300 360

12

11

10

9

8

7

6

5

4

3

2

1

0

13

CV

Death

, M

I, S

tro

ke (

%)

9.8

11.7

8,219

HR 0.84

(95% CI 0.77–0.92)

P=0.0003

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Wallentin L, et al. NEJM 2009;361:1045-57

Primary Efficacy Endpoint

by Treatment Strategy

Planned Invasive Planned Non-Invasive

Number 13,408 5216

Treatments during Index Hospitalization

Angio 97% 42%

PCI 77% 20%

CABG 6% 4%

HR (95% CI) for Ticagrelor vs Clopidogrel

CV Death, MI, Stroke 0.84 (0.75-0.94) 0.85 (0.73-1.00)

Mortality 0.82 (0.69-0.98) 0.76 (0.61-0.96)

Bleeding 1.16 (0.97-1.38) 1.30 (0.95-1.77)

Cannon CP et al. Lancet 2010;375:283-93

James SK et al. BMJ 2011;342:d3527

2014 ACC/AHA NSTEACS Guidelines:

P2Y12 Inhibitors – PCI

Recommendation (to be given before the procedure) COR LOE

Clopidogrel 600 mg load dose 75 mg/d I B

Prasugrel 60 mg loading dose 10 mg/d I B

Ticagrelor 180 mg loading dose 90 mg/bid I B

Reasonable to use ticagrelor in preference to clopidogrel IIa B

Reasonable to use prasugrel in preference to clopidogrel IIa B

Antiplatelet and Anticoagulant Therapy:

Anticoagulant Therapy in Patients Undergoing PCI

Recommendations COR LOE

An ANTICOAGULANT SHOULD BE ADMINISTERED to patients

with NSTE-ACS undergoing PCI to reduce the risk of

intracoronary and catheter thrombus formation.

I C

INTRAVENOUS UFH IS USEFUL in patients with NSTE-ACS

undergoing PCI. I C

BIVALIRUDIN IS USEFUL as an anticoagulant with or without

prior treatment with UFH in patients with NSTE-ACS undergoing

PCI.

I B

In patients with NSTE-ACS, ANTICOAGULANT THERAPY SHOULD

BE DISCONTINUED after PCI unless there is a compelling

reason to continue such therapy. I C

Lancet 2014;384:599

Cavender MA, Sabatine MS

Lancet 2014;384:599

Bivalirudin & Bleeding

Cavender MA and Sabatine MS. Lancet 2014;384:599-606

heparin +

planned GPI

vs

bival +

prov GPI

RR 0.53

(0.47-0.61)

prov GPI in both

RR 0.78

(0.51-1.19)

planned GPI

in both

RR 1.07

(0.87-1.31)

Recommendations COR LOE

The duration of triple antithrombotic therapy with a vitamin K

antagonist, aspirin, and a P2Y12 receptor inhibitor in patients

with NSTE-ACS SHOULD BE MINIMIZED to the extent possible

to limit the risk of bleeding.

I C

Proton pump inhibitors SHOULD BE PRESCRIBED in patients

with NSTE-ACS with a history of gastrointestinal bleeding who

require triple antithrombotic therapy with a vitamin K

antagonist, aspirin, and a P2Y12 receptor inhibitor.

I C

Combined Oral Anticoagulant Therapy and Antiplatelet

Therapy in Patients With NSTE-ACS

Targeting oral anticoagulant therapy to a lower international

normalized ratio (e.g., 2.0 to 2.5) MAY BE REASONABLE in

patients with NSTE-ACS managed with aspirin and a P2Y12

inhibitor.

IIb C

Desai NR, Bhatt DL. JACC Cardiovasc Intervention. 2010;3:571-83.

Antiplatelet Agents

Dewilde WJM et al. Lancet 2013;381:1107

Chronic Therapy

WOEST: Incidence of the secondary endpoint

(death, MI, Stroke, TVR, ST)

_ OAC + clopi + ASA

OAC + clopi C

um

ula

tive

In

cid

en

ce

(%

)

Time (days)

17.6

11.1

HR 0.60 (95% CI 0.38-0.94) p<0.025

Chronic Therapy

WOEST: Incidence of the primary endpoint (any bleeding)

_ OAC + clopi + ASA

OAC + clopi

Cu

mu

lati

ve I

ncid

en

ce

(%

)

Time (days)

44.4

19.4

HR 0.36 (95% CI 0.26-0.50) p<0.0001

Dewilde WJM et al. Lancet 2013;381:1107

1) Ever-diminishing incidence of UA

2) Revasc in most pts: Timing recommendations

3) Use of more potent P2Y12 inhibitors (prasugrel, ticagrelor)

for PCI (IIa)

4) Routine pretreatment with GPIIb/IIIa inh. in pts receiving

DAPT not recommended (especially in pts receiving

prasugrel or ticagrelor)

5) Bivalirudin: ? ↑ MACE; ↓ bleeding only when compared to

UFH+GPI

6) Avoid or shorten period of triple therapy

7) Drop aspirin??

NSTE-ACS TAKE-HOME MESSAGES