Prior to the start of the program, please check your

syllabus to ensure you have the following printed

program materials:
• Pre-activity Survey
– Located at the front of your syllabus
• CME Evaluation with Post-activity Survey
– Located at the back of your syllabus
Disclosures
• The relevant financial relationships reported by faculty that
they or their spouse/partner have with commercial interests
are located on page 5 of your syllabus
• The relevant financial relationships reported by the
steering committee that they or their spouse/partner have
with commercial interests are provided on page 5 of your
syllabus
• The relevant financial relationships reported by the non-
faculty content contributors and/or reviewers that they
or their spouse/partner have with commercial interests are
located on page 5 of your syllabus
Off-label Discussion Disclosure
This educational activity may contain discussion of published
and/or investigational uses of agents that are not indicated
by the Food and Drug Administration. PCME does not
recommend the use of any agent outside of the labeled
indications. Please refer to the official prescribing information
for each product for discussion of approved indications,
contraindications and warnings. The opinions expressed are
those of the presenters and are not to be construed as those
of the publisher or grantors.
Learning Objectives
• Identify high-risk ACS patients (high-risk NSTEMI, STEMI)
and promptly initiate suitable risk stratification and patient
management strategies
• Adopt and adhere to guidelines-based treatment strategies
for use of appropriate antiplatelet options to reduce the risk
of recurrent events
• Identify inefficiencies in discharge planning and patient
education on the necessity of drug adherence to improve
quality of care and long-term outcomes of high-risk ACS
patients
Pre-activity Survey

• Please take out the Pre-activity Survey from your packet

• Your answers are important to us and will be used to help
shape future CME activities
• It is important that you fill out the information at the top of
the form:
– Please select the best answer(s) for the questions below:
– Degree: _ MD/DO _ Nursing Professional _ PharmD
_Other:_____________________________
– Specialty: _ Cardiologist _ Emergency Room Physician
_ Internal Medicine _Other:______________________
Pre-activity Survey Question 1
How confident are you in your ability to adopt evidence-
based care for high-risk NSTEMI patients to reduce the need
for rehospitalization?

1 2 3 4 5
Not at all confident Expert
Pre-activity Survey Question 2
How confident are you in your ability to adopt evidence-
based care for STEMI patients to reduce the need for
rehospitalization?

1 2 3 4 5
Not at all confident Expert
Pre-activity Survey Question 3
The choice between an initial conservative strategy or an
initial invasive strategy in patients diagnosed with NSTE-
ACS is made largely on the basis of:
A. Risk of ischemic complications
B. Whether symptoms are typical or atypical
C. Whether the ECG is interpretable
D. Whether the patient can take a stress exercise test
E. All of the above
Pre-activity Survey Question 4
Compared to ACS patients who do not have diabetes, those
who have diabetes mellitus are at:
A. Greater risk of major cardiovascular events and similar
risk of major bleeding events
B. Greater risk of major cardiovascular events and greater
risk of major bleeding events
C. Similar risk of major cardiovascular events and greater
risk of major bleeding events
D. Similar risk of major cardiovascular events and similar risk
of major bleeding events
Pre-activity Survey Question 5
In STEMI patients, primary PCI is superior to fibrinolytic
therapy to reduce in-hospital mortality if PCI can be
performed within ___ hours after the onset time of infarction:
A. <1.5 hours
B. 3 hours
C. 6 hours
D. 12 hours
E. 24 hours
Pre-activity Survey Question 6
According to the GRACE registry, use of 5 or more
medications for secondary prevention of ACS can reduce
6-month mortality by:
A. Less than 20%
B. 20%-30%
C. 30%-40%
D. 40%-50%
E. More than 50%
HIGH-RISK ACS
Overview
 ACS Classification and Hospitalizations

Acute Coronary Syndromes

TIMI flow grade 2/3 TIMI flow grade 0/1

in culprit artery in culprit artery

- Troponin + Troponin + Troponin

Unstable angina NSTEMI STEMI

0.81 million admissions per year 0.33 million admissions per year

Shared pathophysiology; Shared core treatment targets

Gibson CM et al. Presented at: 2008 AHA Scientific Sessions. New Orleans, LA.
Go AS et al. Heart Disease and Stroke Statistics – 2013 update. Circulation. 2013;1127:e6-e245
Acute Coronary Syndromes
• Common Features of ACS
– Similar pathophysiology
– Similar presentation and early management rules
• Differentiating Features of ACS
– Unstable Angina – STEMI
 Non-occlusive thrombus  Complete thrombus
 No diagnostic ECG changes, but occlusion
ischemic ST-T changes confer  ST elevation or new
higher risk LBBB
 Normal cardiac enzymes  Elevated cardiac
– NSTEMI enzymes
 More severe
 Occluding thrombus sufficient to symptoms
cause myocardial damage
 No diagnostic ECG changes, but
ischemic ST-T changes: higher
risk
 Elevated cardiac enzymes
Age- and Sex-adjusted Incidence Rates Of
Acute MI, 1999 to 2008.

O’Gara PT et al. Circulation 2013;127:e362-e425

Copyright © American Heart Association
Mortality in Acute Coronary Syndromes
Death from Hospital Admission to 6 Months

16

12 STEMI
% Mortality

NSTEMI
8

UA
4

0 GRACE n=43,810
0 30 60 90 120 150 180
Days
Fox KAA et al. BMJ. 2006;333:1091.
“Dynamic Risk Stratification” Tools
• History and physical
• Standard ECG and non-standard ECG leads
– 15-lead ECGs should perhaps become “standard” in all but very-low-risk patients
• Biomarkers
– CK-MB, troponins I and T, myoglobin
– High-sensitivity troponin
– Brain natriuretic peptide (BNP)
• Non-invasive imaging
– Echocardiogram
– Stress testing
– Technetium-99m-sestamibi
• Invasive imaging
– Cardiac computed tomography angiography (CCTA)
• Predictive indices/schemes
– Better as research tools than for real-time clinical decision-making
Risk Scores
TIMI GRACE
Age Age
Hypertension
Diabetes
History

Smoking
↑ Cholesterol
Family history
History of CAD
Severe angina Heart rate
Aspirin within 7 days Systolic BP
Presentation

Elevated markers Elevated creatinine

ST-segment deviation Heart failure
Cardiac arrest
Elevated markers
ST-segment deviation
GRACE = Global Registry of Acute Coronary Events;
TIMI = Thrombolysis in Myocardial Infarction

Antman EM et al. JAMA. 2000;284:835-842. Eagle KA et al. JAMA. 2004;291:2727-2733.

Early Invasive vs Initial Conservative Strategy
General Considerations in UA/NSTEMI
EARLY INVASIVE STRATEGY INITIAL CONSERVATIVE STRATEGY
GENERALLY PREFERRED GENERALLY PREFERRED OR REASONABLE
• Recurrent angina at rest or with low level • Low risk score (e.g. GRACE, TIMI)
activities despite intensive medical therapy • Patient or physician preference in the absence of
• Elevated cardiac biomarkers (TnT or TnI) high-risk features
• New or presumably new ST-depression
• Signs or symptoms of heart failure or new or
worsening mitral regurgitation
• High-risk findings from noninvasive testing
• Hemodynamic instability
• Sustained ventricular tachycardia
• PCI within 6 mo; prior CABG
• High risk score (e.g. GRACE, TIMI)
• Mild to moderate renal dysfunction
• Diabetes mellitus
• Reduced left ventricular function (LVEF <40%)
CABG = coronary artery bypass graft surgery; GRACE = Global Registry of Acute Coronary Events;
LV = left ventricular; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention;
TIMI = Thrombolysis in Myocardial Infarction; TnI = troponin I; TnT = troponin T

Anderson et al. J Am Coll Cardiol 2012;61:e1-e171

 ACCF/AHA Guidelines 2011 Focused Update
Early Invasive Strategies for High-Risk ACS Patients
I II II I High-risk patients with:
a b I
I - Refractory ischemia
- Recurrent angina/ischemia
- Elevated cardiac biomarkers (T)
- New ST-segment depression
- New CHF or worsening MR
- High-risk on non-invasive testing
- LV dysfunction (EF <40%)
- Hemodynamic instability
- Sustained VT
- Diabetics with single-vessel disease
- Mild to moderate kidney disease
- PCI within 6 months, prior CABG high-risk score
- Not in low-risk women
Wright RS et al. Circulation. 2011;123:2022-2060.
TACTICS: Primary Endpoint
Death, MI, Rehospitalized for ACS at 6 Months

20 19.4%

15.9%
16

12
% Patients

O.R. 0.78
95% CI (0.62, 0.97)
8
P=0.025

4 Conservative
:Invasive:
0
0 1 2 3 4 5 6
Time (months)
Cannon CP et al. N Engl J Med. 2001;344:1879-1887.
ANTIPLATELET THERAPY
IN ACS
 Platelet Aggregation and Mechanisms of
Action of Antiplatelet Therapies
clopidogrel ADP
prasugrel
ADP
ticagrelor
ADP

cAMP
Collagen
Glycoprotein IIb/IIIa inhibitors
Activation Thrombin Heparins
abciximab TXA2
eptifibatide Gp IIb/IIIa COX
(Aggregation)
tirofiban TXA2

aspirin

ADP = adenosine diphosphate; TXA2 = thromboxane A2; COX = cyclooxygenase

Adapted from Schafer AI. Am J Med. 1996;101:199-209.
CURE Study
Primary End Point: MI/Stroke/CV Death

0.14 20%
Placebo Relative
0.12 + Aspirin Risk
Cumulative Hazard Rate

Reduction
0.10 (n=6303)

0.08
Clopidogrel
0.06 + Aspirin P<0.001
(n=6259) n=12,562
0.04

0.02

0.00
0 3 6 9 12

Months of Follow-up
Yusuf S et al. N Engl J Med. 2001;345:494-502.
ADP P2Y12 Receptor Blockers

Clopidogrel Prasugrel Ticagrelor

Class Thienopyridine Thienopyridine Triazolopyrimidine
Reversibility Irreversible Irreversible Reversible
Prodrug, limited by Prodrug, not limited
Activation Active drug
metabolism by metabolism

Onset of Effect^ 2-4 hours 30 minutes 30 minutes

Duration of Effect 3-10 days 5-10 days 3-4 days

Withdrawal before
5 days 7 days 5 days
major surgery

^ 50% inhibition of platelet aggregation

Hamm CW et al. Eur Heart J. 2011;32:2999-3054
Metabolism of Novel P2Y12 Receptor Blockers
P-Glycoprotein
Prasugrel Ticagrelor
Intestinal
Absorption Intestinal
Intestinal Esterases Absorption
85% Hepatic
CYP3A4
30%

1 Step
Intestinal/hepatic
CYP-Conversion
55%
3A4
2B6
2C9
2C19

Efficient active metabolite

generation

Rapid Consistent /Greater IPA Rapid Consistent /Greater IPA

IPA = individual platelet adhesion assay

Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-2259
CURRENT: Clopidogrel Double vs
Standard Dose Primary Outcome: PCI Patients
CV Death, MI or Stroke

0.04 Clopidogrel Standard 15% RRR

Clopidogrel Double
Cumulative Hazard

0.03

0.02

HR 0.85
95% CI 0.74-0.99
P=0.036
0.0
0 3 6 9 12 15 18 21 24 27 30
Days
Mehta SR et al. Presented at: European Society of Cardiology, September, 2009.
PRINCIPLE TIMI 44:
Comparison of Prasugrel with Higher Dose Clopidogrel
IPA (%; 20 mM ADP) IPA (%; 20 mM ADP)
100
N=201 P<0.0001 for each 100

P<0.0001
80 74.8 Prasugrel 60 mg 80
64.5

61.9
69.3
60 60

45.4

40 40
Clopidogrel 600 mg 32.6

30.8 31.8
20 20
20.3
4.9

0 0
0 4 8 12 16 20 24 28 Clopidogrel Prasugrel
150 mg 10 mg
Hours 14 Days
Wiviott SD et al. Circulation. 2007;116:2923-2932.
TRITON-TIMI 38 Efficacy and Safety
Prasugrel vs Clopidogrel
16 138
events
14
Clopidogrel
12 CV Death/MI/Stroke 12.1 HR 0.81
Endpoint (%)

(0.73-0.90)
10 9.9 P < 0.001
NNT = 46
8 Prasugrel
6
TIMI Major
4 HR 1.32
Non-CABG Bleeds Prasugrel
2.4 (1.03-1.68)
2 1.8 P = 0.03
Clopidogrel NNH = 167
0
0 30 60 90 180 270 360 450
35
Days After Randomization events
CABG = coronary-artery bypass surgery; NNH = number needed to harm; NNT =
number needed to treat; TIMI = Thrombolysis in Myocardial Infarction.
All Cause Mortality: Clopidogrel 3.2%, Prasugrel 3.0%, P = 0.64.
Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
Clopidogrel vs. Ticagrelor
ONSET/OFFSET Study

Loading Maintenance and Offset

100 * Ticagrelor 180mg

* *
*
80
IPA (%; 20 mM ADP, Final)

60
*
40
Clopidogrel 600 mg
20

0
0 .5 4 8 12 16 20 24
Hours

*P<0.0001; †P<0.005; ‡, P<0.05, ticagrelor vs clopidogrel.

Gurbel PA et al. Circulation. 2009;120:2577-2585.
PLATO: Kaplan-Meier Estimate of Time to First Primary
Efficacy Event (Composite of CV Death, MI, or Stroke)
13
12
Clopidogrel 11.7
11
10
Cumulative incidence (%)
9.8
9
8 Ticagrelor
7
6
5 HR = hazard ratio
4
CI = confidence
3 interval
2
1 HR 0.84 (95% CI 0.77–0.92), P=0.0003
0
0 60 120 180 240 300 360

No. at risk
Days after randomisation
Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147
Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047

Wallentin L et al. N Engl J Med. 2009;361:1045-

1057.
Time to Major Bleeding: Primary Safety Event
15

K-M estimated rate (% per year) Ticagrelor 11.58

11.20
10 Clopidogrel

HR 1.04 (95% CI 0.95–1.13), P=0.434

0
0 60 120 180 240 300 360

No. at risk Days from first IP dose

Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433
Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479

Wallentin L et al. N Engl J Med. 2009;361:1045-1057.

Ticagrelor Interaction with Aspirin Dose
Hazard Ratio (CV Death, MI, Stroke) Compared With Clopidogrel

Aspirin Ticagrelor Clopidogrel Hazard

Region 95% CI
(mg/day) N / Events N / Events Ratio
US ≥300 324 / 40 352 / 27 1.62 0.99 – 2.64
>100 – <300 22 / 2 16 / 2 - -
≤100 284 / 19 263 / 24 0.73 0.40 – 1.33
Non-US ≥300 140 / 28 140 / 23 1.23 0.71 – 2.14
>100 – <300 503 / 62 511 / 63 1.00 0.71 – 1.42
≤100 7449 / 546 7443 / 699 0.78 0.69 – 0.87
Warning: Aspirin Dose and Ticagrelor Effectiveness
• Maintenance doses of aspirin > 100 mg reduce effectiveness of ticagrelor; should be avoided.
• After any initial dose, use with aspirin 75-100 mg per day.

Mahaffey KW et al. Circulation. 2011;124:544-554.

 TRITON vs PLATO
Proof of concept: Higher Inhibition of Platelet
Activityi to Support ACS
Differences between trials
1. Patient Population
TRITON: ACS undergoing PCI (indication only for ACS undergoing PCI)
PLATO: Full spectrum ACS (indication for ACS irrespective of management)
2. Pretreatment
TRITON: No pretreatment (except STEMI)
PLATO: Pretreatment
3. Clopidogrel Loading Dose
TRITON: 300mg
PLATO: 300-600mg
4. Duration of trial (median)
TRITON: 14.5 months
PLATO: 9 months
Novel P2Y12 Receptor Antagonists

Prasugrel
• Contraindicated: high-risk bleeding; prior TIA/stroke; hypersensitivity

• Precautions: elderly (>75y), low-weight (<60kg); CABG/surgery (7days).

Ticagrelor
• Contraindicated: high-risk bleeding; prior hemorrhagic stroke; severe
hepatic dysfunction; hypersensitivity

• Precautions: compliance (b.i.d. administration), drug interactions

(CYP 3A4 interfering agents); regional differences (North America/ASA
dose <100mg), COPD/asthma, bradyarythmia, gout syndromes,
CABG/surgery (5 days).
What are We Treating with Extended Dual
Antiplatelet Therapy?
Long-Term Treatment (Stable Atherosclerosis)
“Vulnerable” Stent “Vulnerable” Patient

OR

Curfman GD, et al. N Engl J Med. 2007;356:1059-1060

Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
CHARISMA Prior MI Cohort
Management of STEMI
A Focus On Antiplatelet Therapy
Time and Myocardial Salvage
An Essential Fact Regardless of Mode of Reperfusion
100

80
E Potential outcomes
Mortality Reduction (%)

A– B — no benefit
60
A– C — benefit
C
D B– C — benefit
40 E– D — harm

20 B
A

Extent of salvage (% of area at risk)

0
1 3 6 12 24

Time to treatment is critical Hours Opening the artery is the

Gersh BJ, et al. JAMA. 2005;293:979-986.
primary goal (PCI > lysis)
STEMI: Relationship Between PCI–Related
Delay and In-Hospital Mortality (NRMI 2,3,4,5)

NRMI 2,3,4,5 = National Registry of Myocardial Infarction, registries 2, 3, 4, 5

X-PCI = transfer PCI
O-FT = onsite fibrinolytic therapy
XDB-DN = transfer door to balloon time
Pinto D S et al. Circulation 2011;124:2512-2521
Regional Systems of STEMI Care, Reperfusion
Therapy, and Time-to-Treatment Goals
I IIaIIb III
Reperfusion therapy should be administered to all eligible patients
with STEMI with symptom onset within the prior 12 hours.

I IIaIIb III
Primary PCI is the recommended method of reperfusion when it can
be performed in a timely fashion by experienced operators.

I IIaIIb III
EMS transport directly to a PCI-capable hospital for primary PCI is
the recommended triage strategy for patients with STEMI with an
ideal FMC-to-device time system goal of 90 minutes or less.*
*The proposed time windows are system goals. For any individual patient, every effort
should be made to provide reperfusion therapy as rapidly as possible.

O’Gara PT et al. J Am Coll Cardiol. 2013;61:e78-e140

 Streptokinase, Aspirin, or Both in Patients
with Acute MI
ASA Improves Outcomes in STEMI – We Haven’t Looked Back

17187 Patients

2x2
Randomization
SK vs Placebo
ASA (162. 5 mg)
vs Placebo

ISIS-2 Collaborative Group. Lancet 1988;2(8607):349-360

Acute MI
Immediate Angioplasty Versus Thrombolytic Therapy

14
P=0.05
12 12
In Hospital Events (%)

P=0.06
10 P=0.06

8
6.5 6.5 Lytic
6 5.1
P=0.02 PCI
4
2.6 2.6
2 N = 395
2
0
0
Death MI Death/MI ICH

The Primary Angioplasty in Myocardial Infarction Study Group

Grines CL et al. N Engl J Med. 1993;328:673-679
 TRITON TIMI 38: STEMI Cohort
N=3534
15
CV Death / MI /
Stroke Clopidogrel
12.4%
9.5%
10 10.0%
Percent (%)

HR 0.79
6.5% Prasugrel (0.65-0.97)
P=0.02
HR 0.68 NNT = 42
5 (0.54-0.87)
P=0.002 TIMI Major
Prasugrel 2.4
NonCABG Bleeds
Clopidogrel 2.1
0
0 30 60 90 180 270 360 450
Days From Randomization
Montalescot g. et al Lancet 2009; 373:723-731
Stent Thrombosis
(ARC Definite + Probable)
3
Any Stent at Index PCI
N = 12,844 2.4
Clopidogrel (142)
Endpoint (%)

1.1
1 (68)
Prasugrel
HR 0.48
P <0.0001

NNT= 77
0
0 30 60 90 180 270 360 450

Days
Wiviott SD et al N Engl J Med. 2007;357:2001-2015
PLATO STE-ACS
Primary Composite Endpoint

10.8%
9.4%
CV death, MI or stroke (%)

STE-ACS
Ticagrelor (n=3752)
Clopidogrel (n=3792)
HR (95% CI) =
0.87(0.75–1.01)
p=0.07

Months after randomisation

Primary endpoint benefit with ticagrelor was
consistent with the overall PLATO trial results

ACS, acute coronary syndromes; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; STE, ST-segment elevation.
Steg PG, et al. Circulation 2010;122:2131–2141;
Wallentin L, et al. N Engl J Med 2009;361:1045–1057.
Primary Efficacy Endpoint In Selected
Pre-defined Subgroups
KM % at
Hazard Ratio Total Month 12 p-value
Characteristic (95% CI) Patients Ti Cl. HR (95% CI) (Interaction)
.
Overall treatment effect
Primary Endpoint 8,430 9.3 11.0 0.85 (0.74, 0.97)
Definition of STEMI* 0.49
Persist. ST-segment elev. 6,284 8.9 10.4 0.87 (0.74, 1.02)
LBBB 720 14.5 14.5 0.89 (0.59, 1.34)
Final diagnosis (only) 886 8.4 12.5 0.67 (0.44, 1.02)
Intended clop dose ≤24h post first dose 0.90
300 mg 5,505 10.1 11.9 0.84 (0.71, 0.99)
600 mg 2,922 7.9 9.3 0.86 (0.67, 1.11)
Time from index event to therapy 0.89
<12 hours 6,072 8.3 9.5 0.86 (0.73, 1.03)
≥12 hours 2,270 12.0 14.2 0.85 (0.67, 1.07)

0.2 0.5 1.0 2.0

Ticagrelor better Clopidogrel better

*Patients with LBBB and ST-elevation were classified as LBBB
Steg PG, et al. Circulation 2010;122:2131–2141; Wallentin L, et al. N Engl J Med 2009;361:1045–1057.
PLATO STE-ACS: Stent Thrombosis

Ticagrelor Clopidogrel
Stent thrombosis,* %[Steg 2010:K] (n=3752) (n=3792) HR (95% CI) p value

Definite† 1.6 2.4 0.03

Probable or definite† 2.6 3.4 0.05

Possible, probable, or 3.3 4.3 0.04

definite†

1.0

*As per Academic Research Consortium definitions.[Cutlip 2007:A] Ticagrelor Clopidogrel

†Denominator is number of patients receiving at least one stent.
better better
ACS, acute coronary syndromes; CI, confidence interval; HR, hazard ratio;
STE, ST-segment elevation.
Cutlip DE, et al. Circulation 2007;155:2344–2351;
Steg PG, et al. Circulation 2010;122:2131–2141.
PLATO STE-ACS
Non-CABG- and CABG-related Major Bleeding
Kaplan–Meier estimated rate (% after 1 year)

ACS, acute coronary syndromes; CABG, coronary artery bypass graft; NS, not significant; STE, ST-segment elevation;
TIMI, thrombolysis in myocardial infarction.
Steg PG, et al. Circulation 2010;122:2131–2141.
ACS
Standard
High Bleeding Risk
Clopidogrel
Or Other Concerns Yes Pathway

Bleeding Risks
• Active Bleeding
• Major Surgery
• Thrombolytic Therapy
• Oral anticoagulants
• Prior ICH or Previous Severe Bleeding
• Severe Liver Disease
• Any history of STROKE/TIA for Prasugrel

Other (Mostly Long Term)

• Cost
• Coverage
• Compliance Concerns
 STEMI
Standard
High Bleeding Risk
Clopidogrel
Or Other Concerns Yes Pathway
No

No Planned Prior DAPT

DAPT PPCI
Load Prasugrel or Ticagrelor Load Ticagrelor
if Rapidly Available If Rapidly Available

Dx Catheterization

CABG PCI Med Rx Dx Catheterization

No DAPT Prasugrel* Clopidogrel

CABG PCI Med Rx
early, Ticagrelor Ticagrelor
clopidogrel/tic
agrelor late Stop DAPT Ticagrelor Clopidogrel
early, Ticagrelor
clopidogrel/tic
agrelor late

* Without Contraindication (STROKE/TIA)

2013 ACC/AHA STEMI Guidelines
Antithrombotic Therapy – Primary PCI
Class of Level of
Recommendation Evidence

O’Gara et al. J Am Coll Cardiol..2013;61:e78–e140

Guideline Recommendations for Duration of
P2Y12 Inhibitor Therapy
Society Management Recommended Duration
Medical Ideally up to 12 months

PCI (DES) At least 12 months

12 months
“Data suggest … SES or PES … may benefit from prolonged
All DAPT beyond 1 year.”
“… data suggest that DAPT for 6 mos might be sufficient
because late and very late ST correlate poorly with d/c of DAPT.”

Medical 12 months
PCI 12 months
(After 12 mos, recommend single antiplatelet therapy
ACCP
over continuation of DAPT)
2011 ACCF/AHA UA/NSTEMI; 2011 ACCF/AHA/SCAI PCI; 2010 ESC Myocardial Revascularization;
2011 ESC NSTEACS; 2012 ACCP Antithrombotic Therapy
Antiplatelet Therapy to Support
Primary PCI for STEMI
I IIaIIb III
It is reasonable to use 81 mg of aspirin per day in
preference to higher maintenance doses after primary PCI.

I IIaIIb III
P2Y12 inhibitor therapy should be given for 1 year to patients
with STEMI who receive a stent (BMS or DES) during
primary PCI using the following maintenance doses:
• Clopidogrel 75 mg daily; or

• Prasugrel 10 mg daily; or

• Ticagrelor 90 mg twice a day*

*The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.

O’Gara PT et al. J Am Coll Cardiol. 2013;61:e78-e140
Periprocedural Anti Thrombotic
Medication in Primary PCI

ADP = adenosine diphosphata.

Steg PG et al. Eur Heart J. 2012;33:2569-2619 doi:1093/eurheatj/ehs215
Guideline for STEMI
Reperfusion at a
Non–PCI-Capable Hospital
Secondary Protection Against Post-MI Mortality

• Beta blocker 15% risk reduction

ISIS 1. Lancet. 1986;2(8498):57-66

• ACEI 19% risk reduction

Pfeffer et al. N Engl J Med. 1992;327:669-677

• CAB comparable to ACEI

Pfeffer et al. N Engl J Med. 2003;349:1893-1906

• Aldosterone antagonist 15% risk reduction

Pitt et al. N Engl J. Med. 2003;348:1309-1321

• Lipid management
Secondary Prevention and Long Term Management
• Smoking cessation – complete
• Blood pressure control goal
– < 140/90 mm Hg
– <130/80 mm Hg if chronic kidney disease or diabetes
• Physical activity
– Minimum goal: 30 minutes 3 to 4 days per week
– Optimal goal: daily
• Diabetes management
– Goal: HbA1c < 7%
• Weight management
– BMI Goal: 18.5 to 24.9 kg/m2
– Waist circumference goal
• Women: < 35 in.
• Men: < 40 in.
 Management of
High-Risk NSTEMI
ACS with Diabetes Mellitus Comorbidity
Case Study: Presentation
• Caucasian male age 67 years presents to ED with
increasing dyspnea associated with substernal chest
pressure over the past 1-2 hours
• Subtle increase in exertional dyspnea, fatigue, and chest
pressure over past 2 weeks
• ECG: ST segment depression (2 mm) in II, III, aVF
• Physical exam:
– Heart rate, 70 bpm; occasional PVCs; blood pressure,
125/80 mm Hg
– Lungs: Soft bibasilar rales; heart: soft gallop, 1/6 SM
Case Study: Additional Medical History

• Known history of CAD – CABG X 4 performed ~ 8 years ago

• Patient 15-year history of type 2 diabetes with variable
control; currently on insulin therapy
• History of hypertension, mixed dyslipidemia
• Prior tobacco use
• Peripheral artery disease, mild chronic kidney disease
• Current medications: aspirin, insulin, lisinopril, metoprolol,
simvastatin
Case Study: Additional Medical History

• No medical records available

• He knows he had a CABG x 4 and last year underwent a
LHC for “chest pain” and he states that “the doctor said
that everything looks great and that all my vessels are OK
except for the one going to the back of my heart which has
a small blockage, but does not need a stent because
doesn’t look too bad”
Case Study: Test Results
• K+, 4.0; glucose, 165 mg/dL; creatinine, 1.2
• CBC: WBC, 10.1; Hct, 43; Plt, 320; Hb, 13.4
• Troponin T: 0.1 μg/L
• Chest radiograph: Mild vascular congestion
• Symptoms and ECG changes resolve with nitroglycerin sl
• Patient is treated with aspirin 325mg loading dose and
enoxaparin 1mg/kg in the ED
• He is admitted to the CCU
• EF: 55%
• Sent for LHC
Cumulative Incidence of All-Cause
Mortality Through 1 Year After ACS
Diabetes Subgroup Analysis
STEMI UA/STEMI
11 TIMI Trials, >62,000 pts
10,613 diabetics (17.1%) Diabetes Diabetes
14 No Diabetes No Diabetes

12
P<0.0001 STEMI
Mortality, %

10
8 P<0.0001
6
P<0.0001 UA/NSTEMI
4
2 P<0.0001
0
0 30 90 180 270 360
No. at Risk
Days after ACS
STEMI
Diabetes 7156 6508 2947 2653 2118 1610
No diabetes 39421 37136 16685 15274 12276 9351
UA/NSTEMI
Diabetes 3457 3313 2923 2339 1317 924
No diabetes 12002 11658 10505 8191 5141 4008

Donahoe SM et al. JAMA. 2007;298:765-775.

Mechanisms Involved in Platelet Dysfunction
in Diabetes Mellitus
Hyperglycemia Deficient Insulin Associated Other Cellular
Action Metabolic Abnormalities
Increased P-selectin
Impaired response to Conditions
expression Platelet Endothelial
NO and PGI2
Osmotic effect
IRS-dependent factors:
Obesity Dysfunction
Activation of PKC Increased intracellular Ca++ Dyslipidemia
Decreased membrane Degranulation
Inflammation Increased platelet turnover
fluidity by glycation
of surface proteins
Increased intracellular Ca++

Upregulation of P2Y12
signaling
Oxidative stress
H2O
Increased P-selectin and
GP expression

Increased production of TF

Decreased NO and
PGI2 production

ACP=adenosine disphosphate;
GP=glycoprotein;
IRS-1=insulin receptor substrate-1;
NO=nitric oxide; PGI2=prostacyclin; Endothelial Cells
PKC= protein kinase C; TF=tissue factor.
Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation 2011;123:798-813
 Optimal Antithrombotic
Management of the Patient
With Diabetes and ACS/PCI
Acute and post-discharge phase
(eg., oral agents)
Effect of Antiplatelet Therapy in Reducing
Vascular Events in Diabetic Patients

30 Control
Antiplatelet therapy
Adjusted (%) of pts (+1 SD)
with vascular events

20

10

0
No Diabetes Diabetes
Benefit/1000 pts (SD): 36 (3) 38 (12)
2P: <0.00001 <0.002

Antiplatelet Trialists Collaboration BMJ 1994;308:81-106

Platelet Function (COX-1 Independent)
In DM Vs Non-DM On Aspirin

100
LTA 100
PFA-100

% Patients CEPI-CT<300 sec

80 p<0.05 80 p<0.01
% Platelet aggregation

60 60

40 40

20 20

0 0
DM Non-DM DM Non-DM
LTA = Light Transmission Aggregation
Angiolillo DJ et al. Diabetes 2005; 54:2430-2435 Angiolillo DJ et al. Am J Cardiol 2006; 97:38-43
Schematic of Circadian Release of Platelets into
Bloodstream from Bone Marrow and Impact of a
Single Daily Dose of Aspirin in Newly Generated
Platelets in Type 2 DM

Twice daily aspirin is associated with better platelet inhibition than

increasing once daily dosing in DM patients.
Capodanno D et al. Circ Cardiovasc Interv. 2011;4:180-187.
CURE: Outcomes With Clopidogrel
in Various Subgroups
Percentage of Patients with Event
No. of Clopidogr Placebo
Characteristic Patients el + ASA + ASA
Overall 12562 9.3 11.4
Associated MI 3283 11.3 13.7
No associated MI 9279 8.6 10.6
Male sex 7726 9.1 11.9
Female sex 4836 9.5 10.7
65 yr
old 6354 5.4 7.6
> 65 yr old 6208 13.3 15.3
ST-segment
deviation 6275 11.5 14.3 N
o ST-segment deviation 6287 7.0 8.6
Enzymes elevated at entry 3176 10.7 13.0
Enzymes not elevated at entry 9386 8.8 10.9
Diabetes 2840 14.2 16.7
No diabetes 9722 7.9 9.9
Low risk 4187 5.1 6.7
Intermediate risk 4185 6.5 9.4
High risk 4184 16.3 18.0
History of revascularization 2246 8.4 14.4
No history of revascularization 10316 9.5 10.7
Revascularization after randomization 4577 11.5 13.9
No revascularization after randomization 7985 8.1 10.0 0.4 0.6 0.8 1.0 1.2
Relative Risk (95% CI)
Yusf S et al. N Engl J Med. 2001;345:494-502. Clopidogrel Better Placebo Better
Influence of Diabetes Mellitus on
Clopidogrel-induced Antiplatelet Effects
Acute Phase of Treatment Long-term Phase of Treatment

DM No-DM 80
P=0.002
P=0.04 P<0.0001

Platelet aggregation (%)

8%
60
38% 14%
56%
6% 78% 40

24 hrs post 300 mg LD

20
Non-responders
(Platelet inhibition <10%)
Low responders 0
(Platelet inhibition 10-29%) DM No DM DM No DM
Responders ADP 20M ADP 6M
(Platelet inhibition >30%)

Angiolillo DJ et al. Diabetes. 2005;54:2430-2435. Angiolillo DJ et al. J Am Coll Cardiol. 2006;48:298-304.

Diabetes as Predictor of Stent Thrombosis
at 1 Year in the Era of DES
5
OR=2.0 OR=2.8 HR=3.7 HR=2.03
(0.8-4.9) (1.7-4.3) (1.7-7.9) (1.07-3.83)
4
Odds/hazard ratio

0
IDDM IDDM Diabetes Diabetes
Kuchulakanti PK et al. Urban P et al. Iakovou I et al. Daemen J et al.
Circulation Circulation JAMA Lancet
2006;113:1108-1113 2006;113:1434-1441 2005;293:2126-2130 2007;116:961-968
Strategies to Enhance P2Y12
Inhibition in Patients With Diabetes

• Increase clopidogrel dosing

(eg, 150 mg maintenance dosing)

• Adding agents that modulate

intraplatelet cAMP
(eg, triple therapy: ASA + clopidogrel + cilostazol)

• Using novel potent P2Y12 inhibitors

(eg, prasugrel, ticagrelor)
Efficacy of New Drugs/Approaches in
Reducing Adverse Outcomes in Diabetes
Mellitus From Large-Scale Clinical Trials
Study % of Events Hazard Ratio (95% confidence interval)
Standard New Drug/Approach

TRITON-TIMI 38 17.0 12.2 0.70 (0.58 – 0.85)

PLATO 16.2 14.1 0.88 (0.76 – 1.03)

CURRENT OASIS 7 5.6 4.9 0.87 (0.66 – 1.15)

(PCI Cohort)
0 0.5 1 1.5
New Drug/Approach Standard Clopidogrel
Better Better

CURRENT-OASIS= Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Optimal Antiplatelet Strategy
for Interventions; PCI=percutaneous intervention; PLATO= A Study of Platelet Inhibition and Patient Outcomes; TRITON-TIMI=
Trial To Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in
Myocardial Infarction.
Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation 2011;123:798-813
TRITON TIMI-38: Diabetic Subgroup
(n=3146)
18
Clopidogrel 17.0
16

14
CV Death/MI/Stroke

12 12.2
Endpoint (%)

HR 0.70
10 Prasugrel P<0.001
8 NNT = 21
6

4 TIMI Major Clopidogrel 2.6

Non-CABG Bleeds
2 2.5
Prasugrel
0
0 30 60 90 180 270 360 450
Days
Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:1626-1636.
TRITON TIMI-38:
CV Death/MI/Stroke by Diabetic Status

Pras Clop Reduction in Risk

No DM 9.2% 10.6% 14%

DM No Insulin 11.5% 15.3% 26%

DM on Insulin 14.3% 22.2% 37%

0.3 1 2
Prasugrel better Clopidogrel better

Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:1626-1636.

OPTIMUS-3: Optimizing Antiplatelet
Therapy in Diabetes Mellitus
Prasugrel (standard dose) vs Clopidogrel (high dose) in DM patients
350 B LD MD Washout
300

250

200
PRU

150
***
***
100

50 ***
***
0 ***p<0.0001
Mean±SE
0 4 24 7 days No study drug
Hours post LD (7 days)

prasugrel 60 mg LD/10 mg MD
clopidogrel 600 mg LD/150 mg MD

Verify Now®-P2Y12 % Inhibition

Similar findings obtained with MPA to 5 and 20 µM ADP, VASP PRI, and Verify Now® PRU
Angiolillo DJ et al. Eur Heart J. 2011;32:838-846
PLATO: Diabetes
PLATO: Diabetes
PLATO: Diabetes
ABCs of Treatment of Diabetic
Patients and Impact on Thrombosis

A HbA1C (blood glucose): <7%

B Blood pressure: <130/80 mm Hg Platelet Reactivity

C Cholesterol-LDL: <70 mg/dl

Discharge Strategies for Patients Post-ACS

Long-term Dual Antiplatelet Therapy, ACEI or ARB,

β-blocker, Statin Therapy
+
Lifestyle Modification
(Smoking cessation, nutrition, and exercise)

+
Cardiac Rehabilitation
(PCP + cardiologist + other team members)

+
Patient Education
(Disease state, medication use, side effects)

+
Medication Compliance
(Counseling, other strategies)

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; PCP = primary care physician.
Antman EM et al. J Am Coll Cardiol. 2008;51:210-247; Levine GN et al. Circulation. 2011;124:e547-e651.
Evidence-based Therapies on 6-month
Survival GRACE Registry Cohort*
NUMBER OF THERAPIES OR
(vs 0 or 1 therapy) (95% CI)

2 therapies 0.80 (0.52-1.26)

3 therapies 0.74 (0.48-1.13)
4 therapies 0.59 (0.39-0.90)
5 therapies 0.51 (0.33-0.78)
6 therapies 0.40 (0.26-0.62)
7 therapies 0.27 (0.16-0.44)
8 therapies 0.31 (0.17-0.57)

0 0.5 1 1.5 2
OR = odds ratio OR
*Registry of patients with ACS
Chew DP et al. Heart. 2010;96:1201-1206.
Participant CME Evaluation

• Please take out the Participant CME Post-survey and

Evaluation from the back of your packet
• If you are not seeking credit, we ask that you fill out the
information pertaining to your degree and specialty, as well
as the few questions we will read through now measuring
the knowledge and competence you have garnered from
this program. The post-survey is located on page 1 of the
evaluation form.
Post-activity Survey Question 1
After participating in this activity, how confident are you in
adopting evidence-based care for high-risk NSTEMI patients
to reduce the need for rehospitalization?

1 2 3 4 5
Not at all confident Expert
Post-activity Survey Question 2
After participating in this activity, how confident are you in
adopting evidence-based care for STEMI patients to reduce
the need for rehospitalization?

1 2 3 4 5
Not at all confident Expert
Pre-activity Survey Question 3
The choice between an initial conservative strategy or an
initial invasive strategy in patients diagnosed with NSTE-
ACS is made largely on the basis of:
A. Risk of ischemic complications
B. Whether symptoms are typical or atypical
C. Whether the ECG is interpretable
D. Whether the patient can take a stress exercise test
E. All of the above
Pre-activity Survey Question 4
Compared to ACS patients who do not have diabetes, those
who have diabetes mellitus are at:
A. Greater risk of major cardiovascular events and similar
risk of major bleeding events
B. Greater risk of major cardiovascular events and greater
risk of major bleeding events
C. Similar risk of major cardiovascular events and greater
risk of major bleeding events
D. Similar risk of major cardiovascular events and similar risk
of major bleeding events
Pre-activity Survey Question 5
In STEMI patients, primary PCI is superior to fibrinolytic
therapy to reduce in-hospital mortality if PCI can be
performed within ___ hours after the onset time of infarction:
A. <1.5 hours
B. 3 hours
C. 6 hours
D. 12 hours
E. 24 hours
Pre-activity Survey Question 6
According to the GRACE registry, use of 5 or more
medications for secondary prevention of ACS can reduce
6-month mortality by:
A. Less than 20%
B. 20%-30%
C. 30%-40%
D. 40%-50%
E. More than 50%
 Thank you for joining us today!
Please remember to turn in your
evaluation form.

Your participation will help shape future

CME activities.