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
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