Evaluation and

Management of Non-ST
Elevation ACS

James de Lemos, MD
The University of Texas
Southwestern Medical School
Non-ST Elevation ACS
Pathophysiology
Epidemiology
Pathophysiology of Acute Coronary Syndromes
and Potential Pharmacologic Interventions

4. Downstream from thrombus

myocardial ischemia/necrosis
(Beta-blockers, Nitrates etc)

Fibrin 3. Activation of clotting

Fibrinogen clot cascade - Thrombin
Thrombin (Heparin/LMWH/
IIb/IIIa Fondaparinux/Bivalirudin)
Receptor 2. Platelet adhesion/
activation/aggregation
(ASA, P2Y12 inhibitors,
GP IIb/IIIa inhibitors)
Platel
et 1. Plaque rupture,
(Statins)
 Acute Coronary Syndrome

Davies MJ
Heart 83:361,
2000
No ST Elevation ST Elevation
NSTEMI

Myocardial Infarction
Uns Angina NQMI Qw MI
Changing Epidemiology of ACS

Age-adjusted and sex-adjusted

incidence of acute MI in Kaiser
Permanente, Northern
California, USA, 1999-2008

Yeh RW, et al, N Engl J Med. 2010.

Non-ST Elevation ACS
Initial Management,
Risk Assessment, and
Risk Stratification
Initial Chest Pain Symptoms Suggestive of ACS
Evaluation
Possible ACS Definite ACS

(-) ECG, No ST  ST 
Normal biomarkers
ST-T ’s, Use MI
Observe; repeat ECG, chest pain,
markers at ~3 hrs  markers Guidelines

No recurrent pain; Recurrent pain;

(–) follow-up studies (+) follow-up studies

Noninvasive eval
(+) test
for ischemia
Admit, Use Acute
(–) test: outpt follow-up Ischemia Pathway
 ACC/AHA UA/NSTEMI Guideline
Risk Assessment Dependent on Contingent Probabilities
• Likelihood of obstructive CAD as • Risk of bad outcome
cause of symptoms – Dominated by acute
– Dominated by acute findings
findings • Older age very
• Examination important
• Symptoms • Hemodynamic
• Markers abnormalities critical
– Traditional risk factors are • ECG, markers
of limited utility • What is the likelihood of death,
• Does this patient have symptoms MI, heart failure?
due to acute ischemia from
obstructive CAD?
 Short-Term High Risk
of Death/MI in UA

• Accelerating tempo or prolonged ongoing pain

• Hemodynamic instability or evidence of CHF

• Dynamic ST changes (not T wave changes)

• Ventricular arrhythmias

• Elevated Cardiac markers (troponin, CKMB, BNP)

 TIMI Risk Score For UA/NSTEMI
• Age > 65 y
• > 3 CAD Risk Factors
• Prior Stenosis > 50 %
D/MI/Urg Revasc (%) 50 • ST deviation
• > 2 Anginal events < 24 40.9
40 h
• ASA in last 7 days
30 • Elev Cardiac Markers 26.2
19.9
20 13.2
8.3
10 4.7
0
0/1 2 3 4 5 6/7
Number of Risk Factors
% 4.3 17.3 32.0 29.3 13.0 3.4
Popl’n: Antman et al JAMA 284 : 835, 2000
 GRACE Prediction
Score for All-Cause
Mortality From
Discharge to
6 Months

NSTEMI 6-Month
Postdischarge Mortality
Risk GRACE Probability
Category Score of Death
Low 1-88
<3%
Medium 89-118
3-8%
High 119-263
>8%

http://www.outcomes-
umassmed.org/grace/grace_risk_
table.cfm.

Eagle KA, et al. JAMA. 2004;291(22):2727-2733.

 Cardiac Troponins
• Preferred biomarker for MI diagnosis
• Elevation in cTnT or cTnI is indicative of
myocyte injury
– NEVER normal to have detectable levels
– Not specific for ISCHEMIC injury
• Elevation 3-9 hours after sx’s
• Can remain  for 1-2 weeks
• Interpretation depends on the clinical context
– > 50% will be elevated from causes other than
ACS
Non-ACS  of Cardiac Troponins
in Hospitalized Patients

• Pulmonary embolism
• Congestive Heart Failure
• Sepsis
• Renal Failure
• Chronic CAD
• LVH
 Troponins: What is an MI in 2016?
Cardiac Injury?

Acute Chronic
Rise and/or fall in cTn Flat but elevated cTn

Ischemic Mechanism?
History, ECG, echo, etc Think structural heart
yes no disease, renal disease

Picture c/w Precipitant?

plaque rupture? Anemia, HTN urgency, Non ischemic acute injury
arrhythmia, etc PE, CHF

Type I MI Type II MI
 Differentiating Type 1 vs. Type 2

Thygesen et al. EHJ 2012; 33: 2551-2567.

GRACE Registry: Impact of In-hospital
Major Bleeding on Patient Mortality

0.36
0.32
Cumulative death rate
0.28
In-hospital bleeding: 293 deaths among 1140 patients
0.24
0.20
0.16
0.12
0.08
0.04 No bleeding: 3,605 deaths among 38,647 patients
0.00
0 20 40 60 80 100 120 140 160 180
Days since admission
40,087 patients, 53% STEMI, 47% NSTEMI.
Major in-hospital bleeding: life-threatening bleeding requiring a transfusion of ≥ 2 U of packed RBCs,
resulting in a decrease in hematocrit of ≥ 10%, occurring intracerebrally, or resulting in stroke or death.
Spencer FA, et al. Circulation. 2007;116:2793-2801.
Balancing risk of ischemia vs risk of
bleeding

Age, CKD Age, CKD, Female sex

Prior CHD Hemodynamic Δ
CHF/ LV dysfunction Low body weight
Hemodynamic Δ History of bleeding
ECG changes, Elevated Anemia
cTn
Major CV events Bleeding

Individualized decision-making
Regarding Cath and antiplatelet/anticoagulants
 Case 1

• 76 year old woman with hypertension

• No prior cardiac history
• No diabetes
• Intermittent chest pain (typical) for 2 hours
 Exam

• HR 114 BP 160/70
• Weight 58 kg
• Rales in both bases
• Cr 2.3
• Initial troponin I is 0.15 ng/mL
• BNP 180 pg/mL
Which statement is true about initial
risk stratification in this patient?
A. On the basis of the BNP level >100
pg/mL, we know she has CHF
B. Because her TIMI risk score is 3, she is
at intermediate risk
C. The troponin elevation could be due to
her renal insufficiency
D. She is at very high risk for poor outcome
Which statement do you most agree with?
A. Because of her age and renal insufficiency, an initial
trial of conservative therapy is prudent.
B. Because of her high risk status, an initial invasive
approach is preferred
C. She should undergo 48-72 hours of “cooling off”
followed by elective cath
D. Any of these strategies is appropriate
Non-ST Elevation ACS
Invasive Therapies
 UA/NSTEMI
HOSPITAL MANAGEMENT
Monitoring (rhythm and ischemia)
ASA, control rate/pressure product
Heparin/LMWH
GP IIb/IIIa inhibitor (?)
Clopidogrel (?)

Early invasive strategy Early conservative strategy

Recurrent Patient stabilizes

Immediate 12-48 hour symptoms/ischemia
angiography angiography Heart failure
Serious arrhythmia

Evaluate LV function

EF<.40 EF>.40
Stress Test

Not low risk Low risk

Medical Rx
Relative Risk for All-Cause Mortality
Early Invasive vs Conservative Therapy
Deaths, n
Follow-up,
Study Invasive Conservative Months
FRISC-II 45 67 24
TRUCS 3 9 12
TIMI-18 37 39 6
VINO 2 9 6
RITA-3 102 132 60
ISAR-COOL 0 3 1
ICTUS 15 15 12
Overall RR (95% CI)
0.75 (0.63-0.90)
0.1 1 10
Favors Favors
Early Invasive Conservative
Therapy Therapy

Bavry AA, et al. J Am Coll Cardiol. 2006;48:1319-1325.

 Benefit of Invasive Strategy by Troponin
and ST Changes
Death, MI, Rehosp ACS at 6 Months
Conservative
P<.001 P<.001
30 Invasive
30
P=NS 25.0*
P=NS 24.5*
25 25
CV Events (%)

20 20
16.0 15.3* 15.1 16.6 16.4*
15 15
12.4
10 10

5 5

0 0
TnT - TnT + No ST change ST change
Morrow DA. JAMA. 2001;286:2405-2412; Cannon CP. N Engl J Med. 2001;344:1879-1887.
 ACC/AHA UA/NSTEMI Guideline: Invasive
versus Conservative Strategy
Preferred
Patient Characteristics
Strategy
 Elevated cardiac  Recurrent angina or
biomarkers ischemia at rest
 New ST-segment  Ventricular tachycardia
depression
 PCI within 6 months
Invasive  HF or new or worsening
mitral regurgitation  Prior CABG
 High-risk findings from  High risk score (e.g.,
noninvasive testing TIMI, GRACE)
 Hemodynamic instability  LVEF < 40%

Low risk score

Conservative  Patient/physician preference
in absence of high-risk
features
Anderson JL et al., JACC. 2007;50(7):1-157.
Early vs. Delayed Invasive Intervention in ACS
New
2012 TIMACS trial
N= 3,031 ACS patients -
1:1 randomization ([routine/early ≤ 24] vs.
[delayed ≥ 36 h] invasive strategy) -
The primary outcome: 6 mo composite of death/MI/CVA
-
-

Sharma, et al. N Engl J Med 2009;360:2165.

 Plans are made to proceed with coronary
angiography in 6 hours. What is the most
appropriate initial antiplatelet/antithrombotic
strategy?
A. Aspirin + bivalirudin
B. Aspirin + prasugrel (60 mg) plus IV UFH
plus IV tirofiban
C. Aspirin + clopidogrel + UFH
D. Aspirin plus subcutaneous enoxaparin
Non-ST Elevation ACS
Antiplatelet Therapy
 CV Death/MI/Stroke in CURE
Overall Study Medical Rx
Cohort

0.20
0.14 Group

Cumulative Hazard Rates

0.12
Cumulative Hazard Rates
Placebo

0.10 0.15
0.10
0.08 Clopidogrel Placebo
0.06
Clopidogrel

0.05
0.04 P<.001
0.02 RR: 0.80 (0.72-0.90) RR: 0.80 (0.69-0.92)

0.0
0.0
0 3 6 9 12 0 100 200 300
Months of Follow-up Days of Follow-up
0.20

0.20
CABG Placebo

Cumulative Hazard Rates

PCI
Cumulative Hazard Rates

Group
0.15

0.15
Group Placebo
Clopidogrel
0.10

0.10
Clopidogrel Fox KA, et al. Circulation.
2004; Yusuf S, et al. N
0.05

0.05
RR: 0.89 (0.71-1.11) Engl J Med. 2001.
RR: 0.72 (0.57-0.90)
0.0

0.0
0 100 200 300 0 100 200 300
Days of Follow-up Days of Follow-up
 Primary Endpoint
CV Death,MI,Stroke
15
HR 0.81
(0.73-0.90) Clopidogrel

Primary Endpoint (%)

12.1
P=0.0004
(781)
10 9.9
Prasugrel (643)

HR 0.80
P=0.0003
HR 0.77
5 P=0.0001
NNT= 46

ITT= 13,608 LTFU = 14 (0.1%)

0
0 30 60 90 180 270 360 450
Days
 Bleeding Events
Safety Cohort
(N=13,457)
4
ICH in Pts w
Clopidogrel Prior Stroke/TIA
Prasugrel (N=518)
Clop 0 (0) %
2.4
% Events

Pras 6 (2.3)%
(P=0.02)
2 1.8
1.4
1.1
0.9 0.9
0.4 0.3 0.3
0.1
0
TIMI Major Life Nonfatal Fatal ICH
Bleeds Threatening
ARD 0.6% ARD 0.5% ARD 0.2% ARD 0.3% ARD 0%
HR 1.32 HR 1.52 P=0.23 P=0.002 P=0.74
P=0.03 P=0.01
 Net Clinical Benefit
Bleeding Risk Subgroups
Post-hoc analysis
Risk (%)
Yes + 37
Prior
Stroke / TIA No Pint = -16
0.006
>=75 -1
Age
< 75 Pint = -16
0.18
Wgt < 60 kg +3
>=60 kg Pint = -14
0.36
OVERALL -13
0.5 Prasugrel Better
1 Clopidogrel Better
2
HR
 ACCOAST: Design
NSTEMI + Troponin 1.5 times ULN local lab value
Clopidogrel naive or on long term clopidogrel 75 mg

Randomize 1:1
Double-blind N~4,100 (event driven)

Prasugrel 30 mg Placebo

CABG CABG
or Coronary Coronary or
Medical Angiography Angiography Medical
Management Management
(no more Prasugrel 30 (no more
Prasugrel) Prasugrel 60 mg Prasugrel)
mg

PCI PCI

Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days

1o Endpoint: CV Death, Stroke, Urgent Revascularization,

GP IIb/llla inhibitor Bailout, at 7 days
Montalescot G, et al. Am Heart J. 2011.
ACCOAST: Primary Efficacy Endpoint
15 CV Death, MI, Stroke,UR,GPIIb/IIIa Bailout

Pre-treatment Pre-treatment
Endpoint (%)
10.0 10.8
10
No Pre-treatment
No Pre-treatment 10.8
9.8
HR at day 7, 1.02 HR at day 30, 0.997
5
(95% CI, 0.84-1.25) (95% CI, 0.83-1.20)
P=.81 P=.98

0
0 5 10 15 20 25 30

UR=Urgent Revascularization
Days from First Dose
Montalescot G, et al. N Engl J Med. 2013.
 ACCOAST: Primary Safety
Endpoint
5 HR at day 30, 1.97
HR at day 7, 1.90 (95% CI, 1.26-3.08)
(95% CI, 1.19-3.02) P=.002
4 P=.006
Pre-treatment
Endpoint (%) 3 Pre-treatment 2.9
2.6
2

No Pre-treatment No Pre-treatment
0
1.4 1.5
0 5 10 15 20 25 30

Days from First Dose

Montalescot G, et al. N Engl J Med. 2013.
 PLATO: Major efficacy endpoints
Ticagrelor Clopidogrel HR for
(n=9,333) (n=9,291) (95% CI) p value†

Primary objective, n (%)

CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001

Secondary objectives, n (%)

Total death + MI + stroke 901 (10.2) 1,065 (12.3) 0.84 (0.77–0.92) <0.001

CV death + MI + stroke + 1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95) <0.001

ischaemia + TIA + arterial
thrombotic events
Myocardial infarction 504 (5.8) 593 (6.9) 0.84 (0.75–0.95) 0.005
CV death 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.001
Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.22

Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001

Wallentin NEJM 2009;361:1045-57

 PLATO:
Medical Therapy Subgroup

Cardiovascular death, MI, or Stroke (%)

2
0
Ticagrelor Non-invasive
1 Clopidogrel Invasive
6 14.3% HR 0.85
1 12.0% P=.04
2

0
0 60 120 180 240 300 360
Days after Randomization
James SK, et al. BMJ. 2011.
Non-CABG and CABG-related major
bleeding 9 Ticagrelor

K-M estimated rate (% per year)

Clopidogrel
NS 7.9
8
7.4

7
NS
5.8
6
5.3
p=0.026
5
4.5

4 3.8
p=0.025
2.8
3
2.2
2

0
Non-CABG Non-CABG CABG CABG
PLATO major TIMI major PLATO major TIMI major
bleeding bleeding bleeding bleeding
Wallentin NEJM 2009;361:1045-57
 P2 Y12 “Cheat Sheet”
Indication Clopidogrel Prasugrel Ticagrelor

Elective PCI √ No No

STEMI PPCI √ √ √

STEMI Lytics √ No No

NSTE ACS

Invasive √ (600 mg) √ √

Pre-treat? √ No +/-

Conservative √ (300 mg) No √

Triple therapy √ No No

Surgery early after PCI √ Switch to clopidogrel Switch to clopidogrel

 GP IIb/IIIa Summary (for the board exam)
• Selected use in high risk patients in whom early invasive
strategy is planned
– cath lab initiation (IIa) now preferable to upstream (IIb)
• Still with class I indication for “high risk patients not
adequately pretreated with clopidogrel or ticagrelor”
• Avoid in medically treated pts
• Avoid upstream use in low risk pts
• Avoid with bivalirudin
• Beware of relative contraindications!
Non-ST Elevation ACS
Anticoagulant Therapy
ACC/AHA UA/NSTEMI Guideline: Initial Anticoagulant
Algorithm in Invasive and Conservative Strategies
Diagnosis of UA/NSTEMI likely/definite

Select management strategy

Invasive strategy Conservative strategy

Acceptable options: Acceptable options:
enoxaparin or UFH (I LOE A) enoxaparin or UFH (I LOE A)
or or
bivalirudin or fondaparinux fondaparinux (I LOE B)
but
(I LOE B)
enoxaparin or fondaparinux are
preferable (IIa)

Anderson JL et al., JACC. 2007;50(7):1-157.

 Enoxaparin vs Unfractionated Heparin
in UA/NSTEMI: A Systematic Overview (N=21,946)
Death or MI at 30 Days (ITT*)
Favors Favors
Trial OR (95% CI) Enoxaparin UFH
ESSENCE 0.76 (0.58–1.01)
TIMI 11B 0.88 (0.70–1.11)
ACUTE II 0.97 (0.51–1.83)
INTERACT 0.54 (0.30–0.96)
A to Z 0.94 (0.73–1.20)
SYNERGY 0.96 (0.86–1.07)
Overall 0.91 (0.83–0.99)
0.2 1.0
Petersen JL, et al. JAMA. 2004;292:89-96. OR (95% CI)
 A-to-Z Trial: Death, MI, or Refractory Ischemia
with Planned Early Conservative Management
Bleeding events and transfusions from start
of tirofiban to 24 h post-tirofiban infusion
Bleed category Unfractionated Enoxaparin
UFH Enoxaparin heparin (n=905)
(n=868)
14
13 TIMI major bleed 0 (0.0%) 7 (0.8%)a
12
Event rate, %

11
10 TIMI minor/loss 11 (1.3%) 9 (1.0%)
9 no site
8
7
6 TIMI major or 7 (0.8%) 14 (1.5%)
5 minor
4
3
2 TIMI 11 (1.3%) 16 (1.8%)
1 major/minor/loss
0
no site
0 5 10 15 20 25 30
Transfusions of 4 (0.5%) 4 (0.4%)
Days from randomization PRBC
aP<.05 for difference between treatment groups.

.
de Lemos JA, et al. Eur Heart J. 2004;25:1688-1694.
2007 ACC/AHA UA/NSTEMI Guideline Revision

Beta Blockers
• -blocker therapy
– Initiate oral therapy within first 24 h unless HF,
low-output state, increased risk for cardiogenic
shock, or relative contraindications (I, B)
– IV therapy for high blood pressure without
contraindications (IIa, B)
– IV therapy may be harmful with contraindications
to beta blockade, signs of HF or low-output
state, or other risk factors for cardiogenic shock
(III, A)
Anderson JL, et al. J Am Coll Cardiol. 2007;50:652-726.
 RAAS Blockade
I IIa IIb III An ACE inhibitor should be administered orally
within the first 24 h to UA/NSTEMI patients with
pulmonary congestion or LV ejection fraction
(LVEF) ≤ 40%, in the absence of hypotension
(systolic blood pressure < 100 mm Hg or < 30 mm
Hg below baseline) or known contraindications to
that class of medications.

I IIa IIb III An angiotensin receptor blocker should be

administered to UA/NSTEMI patients who are
intolerant of ACE inhibitors and have either clinical
or radiological signs of HF or LVEF ≤ 40%.
 CV Outcomes Trials Comparing
Intensive vs Moderate Statin Therapy
Reduction in Risk of Coronary Death or MI
Odds Event Rates
Reduction No./Total (%)
Odds Ratio (95% CI) High Dose Std Dose

PROVE IT- 147/2099 172/2063

-17%
TIMI 22 (7.0) (8.3)
A-to-Z 205/2265 235/2232
-15%
(9.1) (10.5)
TNT 334/4995 418/5006
-21%
(6.7) (8.3)
IDEAL 411/4439 463/4449
-12%
OR, 0.84 (9.3) (10.4)
Total 95% CI, 0.77-0.91
P=.00003
1097/13798 1288/13750
-16%
(8.0) (9.4)
.66 1 1.5
High dose better High dose worse

Adapted with permission from Cannon CP, et al. J Am Coll Cardiol. 2006;48:438-445.