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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
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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 evidencebased care for high-risk NSTEMI patients to reduce the need
for rehospitalization?
1
Not at all confident
2
3
4
5
Expert
Pre-activity Survey Question 2
How confident are you in your ability to adopt evidencebased care for STEMI patients to reduce the need for
rehospitalization?
1
Not at all confident
2
3
4
5
Expert
Pre-activity Survey Question 3
The choice between an initial conservative strategy or an
initial invasive strategy in patients diagnosed with NSTEACS 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
in culprit artery
- Troponin
Unstable angina
TIMI flow grade 0/1
in culprit artery
+ Troponin
+ Troponin
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
Non-occlusive thrombus
No diagnostic ECG changes, but
ischemic ST-T changes confer
higher risk
 Normal cardiac enzymes


–
NSTEMI
Occluding thrombus sufficient to
cause myocardial damage
 No diagnostic ECG changes, but
ischemic ST-T changes: higher
risk
 Elevated cardiac enzymes

– STEMI
Complete thrombus
occlusion
 ST elevation or new
LBBB
 Elevated cardiac
enzymes
 More severe
symptoms

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
STEMI
% Mortality
12
NSTEMI
8
UA
4
0
GRACE n=43,810
0
30
60
90
Days
Fox KAA et al. BMJ. 2006;333:1091.
120
150
180
“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
History
Presentation
TIMI
GRACE
Age
Hypertension
Diabetes
Smoking
↑ Cholesterol
Family history
History of CAD
Severe angina
Aspirin within 7 days
Elevated markers
ST-segment deviation
Age
Heart rate
Systolic BP
Elevated creatinine
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
GENERALLY PREFERRED
• Recurrent angina at rest or with low level
activities despite intensive medical therapy
• Elevated cardiac biomarkers (TnT or TnI)
• 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%)
INITIAL CONSERVATIVE STRATEGY
GENERALLY PREFERRED OR REASONABLE
• Low risk score (e.g. GRACE, TIMI)
• Patient or physician preference in the absence of
high-risk features
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
a
II
b
I
I
I
High-risk patients with:
- Refractory ischemia
-
Wright RS et al. Circulation. 2011;123:2022-2060.
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
TACTICS: Primary Endpoint
Death, MI, Rehospitalized for ACS at 6 Months
19.4%
20
15.9%
% Patients
16
12
O.R. 0.78
95% CI (0.62, 0.97)
P=0.025
8
4
Conservative
:Invasive:
0
0
1
Cannon CP et al. N Engl J Med. 2001;344:1879-1887.
4
2 3
Time (months)
5
6
ANTIPLATELET THERAPY
IN ACS
Platelet Aggregation and Mechanisms of
Action of Antiplatelet Therapies
ADP
clopidogrel
prasugrel
ADP
ticagrelor
ADP
cAMP
Glycoprotein IIb/IIIa inhibitors
Activation
abciximab
eptifibatide
tirofiban
Gp IIb/IIIa
(Aggregation)
COX
TXA2
aspirin
ADP = adenosine diphosphate; TXA2 = thromboxane A2; COX = cyclooxygenase
Adapted from Schafer AI. Am J Med. 1996;101:199-209.
Collagen
Thrombin
TXA2
Heparins
CURE Study
Primary End Point: MI/Stroke/CV Death
Cumulative Hazard Rate
0.14
20%
Relative
Risk
Reduction
Placebo
+ Aspirin
(n=6303)
0.12
0.10
0.08
Clopidogrel
+ Aspirin
(n=6259)
0.06
0.04
P<0.001
n=12,562
0.02
0.00
0
3
6
9
Months of Follow-up
Yusuf S et al. N Engl J Med. 2001;345:494-502.
12
ADP P2Y12 Receptor Blockers
Class
Reversibility
Activation
Clopidogrel
Prasugrel
Ticagrelor
Thienopyridine
Thienopyridine
Triazolopyrimidine
Irreversible
Irreversible
Reversible
Prodrug, limited by Prodrug, not limited
metabolism
by metabolism
Active drug
Onset of Effect^
2-4 hours
30 minutes
30 minutes
Duration of Effect
3-10 days
5-10 days
3-4 days
Withdrawal before
major surgery
5 days
7 days
5 days
^ 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
Intestinal
Absorption
Ticagrelor
Intestinal
Absorption
Intestinal Esterases
85%
Hepatic
CYP3A4
30%
1 Step
Intestinal/hepatic
55%
CYP-Conversion
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
Clopidogrel Standard 15% RRR
0.04
Cumulative Hazard
Clopidogrel Double
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
Days
Mehta SR et al. Presented at: European Society of Cardiology, September, 2009.
24
27
30
PRINCIPLE TIMI 44:
Comparison of Prasugrel with Higher Dose Clopidogrel
IPA (%; 20 mM ADP)
N=201
100
IPA (%; 20 mM ADP)
P<0.0001 for each
100
P<0.0001
74.8
80
Prasugrel 60 mg
80
64.5
61.9
69.3
60
60
45.4
40
Clopidogrel 600 mg
31.8
30.8
20
4.9
40
32.6
20
20.3
0
0
0
4
8
12
16
Hours
Wiviott SD et al. Circulation. 2007;116:2923-2932.
20
24
28
Clopidogrel Prasugrel
150 mg
10 mg
14 Days
TRITON-TIMI 38 Efficacy and Safety
Prasugrel vs Clopidogrel
16
138
events
Endpoint (%)
14
12
CV Death/MI/Stroke
Clopidogrel
10
Prasugrel
8
12.1 HR 0.81
(0.73-0.90)
9.9 P < 0.001
NNT = 46
6
TIMI Major
Non-CABG Bleeds Prasugrel
4
2
0
Clopidogrel
0
30 60 90
180
270
Days After Randomization
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.
360
HR 1.32
2.4 (1.03-1.68)
1.8 P = 0.03
NNH = 167
450
35
events
Clopidogrel vs. Ticagrelor
ONSET/OFFSET Study
Loading
IPA (%; 20 mM ADP, Final)
100
* *
Maintenance and Offset
Ticagrelor 180mg
*
*
80
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
Cumulative incidence (%)
Efficacy Event (Composite of CV Death, MI, or Stroke)
13
12
11
10
9
8
7
6
5
4
3
2
1
0
9.8
Ticagrelor
HR = hazard ratio
CI = confidence
interval
HR 0.84 (95% CI 0.77–0.92), P=0.0003
0
No. at risk
Ticagrelor
Clopidogrel
11.7
Clopidogrel
60
120
180
240
300
360
5,161
5,096
4,147
4,047
Days after randomisation
9,333
9,291
8,628
8,521
Wallentin L et al. N Engl J Med. 2009;361:10451057.
8,460
8,362
8,219
8,124
6,743
6,743
Time to Major Bleeding: Primary Safety Event
K-M estimated rate (% per year)
15
Ticagrelor
10
Clopidogrel
11.58
11.20
5
HR 1.04 (95% CI 0.95–1.13), P=0.434
0
0
60
120
180
240
300
360
Days from first IP dose
No. at risk
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
Region
US
Non-US
Aspirin
(mg/day)
Ticagrelor
N / Events
Clopidogrel
N / Events
Hazard
Ratio
95% CI
≥300
>100 – <300
≤100
≥300
>100 – <300
≤100
324 / 40
22 / 2
284 / 19
140 / 28
503 / 62
7449 / 546
352 / 27
16 / 2
263 / 24
140 / 23
511 / 63
7443 / 699
1.62
0.73
1.23
1.00
0.78
0.99 – 2.64
0.40 – 1.33
0.71 – 2.14
0.71 – 1.42
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
Mortality Reduction (%)
100
80
Potential outcomes
E
60
D
A–
A–
B–
E–
C
40
B
20
B — no benefit
C — benefit
C — benefit
D — harm
A
Extent of salvage (% of area at risk)
0
1
3
6
Time to treatment is critical
Gersh BJ, et al. JAMA. 2005;293:979-986.
12
Hours
24
Opening the artery is the
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
In Hospital Events (%)
14
P=0.05
12
12
10
P=0.06
P=0.06
8
6.5
Lytic
6.5
6
4
5.1
2.6
2.6
P=0.02
N = 395
2
2
0
0
Death
MI
The Primary Angioplasty in Myocardial Infarction Study Group
Grines CL et al. N Engl J Med. 1993;328:673-679
Death/MI
PCI
ICH
TRITON TIMI 38: STEMI Cohort
N=3534
15
Percent (%)
CV Death / MI /
Clopidogrel
Stroke
10
9.5%
6.5%
5
Prasugrel
HR 0.68
(0.54-0.87)
P=0.002 TIMI Major
NonCABG Bleeds
12.4%
10.0%
HR 0.79
(0.65-0.97)
P=0.02
NNT = 42
2.4
Prasugrel
Clopidogrel 2.1
0
0 30 60 90
180
270
360
Days From Randomization
Montalescot g. et al Lancet 2009; 373:723-731
450
Stent Thrombosis
(ARC Definite + Probable)
3
Any Stent at Index PCI
N = 12,844
Endpoint (%)
Clopidogrel
2.4
(142)
2
1.1
(68)
1
Prasugrel
HR 0.48
P <0.0001
NNT= 77
0
0
30
60
90
180
270
Days
Wiviott SD et al N Engl J Med. 2007;357:2001-2015
360
450
PLATO STE-ACS
Primary Composite Endpoint
CV death, MI or stroke (%)
10.8%
9.4%
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
Hazard Ratio Total
(95% CI) Patients
Characteristic
Overall treatment effect
Primary Endpoint
8,430
KM % at
Month 12
Ti Cl.
.
9.3 11.0
p-value
HR (95% CI) (Interaction)
0.85 (0.74, 0.97)
Definition of STEMI*
0.49
6,284
720
886
Persist. ST-segment elev.
LBBB
Final diagnosis (only)
8.9 10.4
14.5 14.5
8.4 12.5
0.87 (0.74, 1.02)
0.89 (0.59, 1.34)
0.67 (0.44, 1.02)
Intended clop dose ≤24h post first dose
0.90
5,505
2,922
300 mg
600 mg
Time from index event to therapy
<12 hours
≥12 hours
0.2
10.1 11.9
7.9 9.3
0.84 (0.71, 0.99)
0.86 (0.67, 1.11)
0.89
6,072
2,270
0.5
Ticagrelor better
1.0
8.3 9.5
12.0 14.2
0.86 (0.73, 1.03)
0.85 (0.67, 1.07)
2.0
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
Stent thrombosis,*
%[Steg 2010:K]
Ticagrelor Clopidogrel
(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]
†Denominator is number of patients receiving at least one stent.
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.
Ticagrelor
better
Clopidogrel
better
PLATO STE-ACS
Kaplan–Meier estimated rate (% after 1 year)
Non-CABG- and CABG-related Major Bleeding
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
High Bleeding Risk
Or Other Concerns
Yes
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
Standard
Clopidogrel
Pathway
STEMI
High Bleeding Risk
Or Other Concerns
Yes
Standard
Clopidogrel
Pathway
No
Planned
PPCI
No
DAPT
Load Prasugrel or Ticagrelor
if Rapidly Available
Prior DAPT
Load Ticagrelor
If Rapidly Available
Dx Catheterization
CABG
No DAPT
early,
clopidogrel/tic
agrelor late
PCI
Prasugrel*
Ticagrelor
* Without Contraindication (STROKE/TIA)
Dx Catheterization
Med Rx
Clopidogrel
Ticagrelor
CABG
PCI
Med Rx
Stop DAPT
early,
clopidogrel/tic
agrelor late
Ticagrelor
Clopidogrel
Ticagrelor
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
PCI (DES)
Ideally up to 12 months
At least 12 months
12 months
All
ACCP
“Data suggest … SES or PES … may benefit from prolonged
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
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
Pitt et al. N Engl J. Med. 2003;348:1309-1321
• Lipid management
15% risk reduction
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
11 TIMI Trials, >62,000 pts
10,613 diabetics (17.1%)
STEMI
UA/STEMI
Diabetes
No Diabetes
14
Diabetes
No Diabetes
Mortality, %
12
P<0.0001 STEMI
10
8
P<0.0001
6
P<0.0001 UA/NSTEMI
4
2
P<0.0001
0
0
30
No. at Risk
STEMI
Diabetes
7156 6508
No diabetes 39421 37136
UA/NSTEMI
Diabetes
3457 3313
No diabetes 12002 11658
Donahoe SM et al. JAMA. 2007;298:765-775.
90
180
270
360
Days after ACS
2947
16685
2653
15274
2118
12276
1610
9351
2923
10505
2339
8191
1317
5141
924
4008
Mechanisms Involved in Platelet Dysfunction
in Diabetes Mellitus
Hyperglycemia
Increased P-selectin
expression
Osmotic effect
Activation of PKC
Decreased membrane
fluidity by glycation
of surface proteins
Deficient Insulin
Action
Impaired response to
NO and PGI2
IRS-dependent factors:
Increased intracellular Ca++
Degranulation
Associated
Metabolic
Conditions
Obesity
Other Cellular
Abnormalities
Platelet
Endothelial
Dysfunction
Dyslipidemia
Inflammation
Increased platelet turnover
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
Control
Antiplatelet therapy
Adjusted (%) of pts (+1 SD)
with vascular events
30
20
10
0
Benefit/1000 pts (SD):
2P:
No Diabetes
Diabetes
36 (3)
<0.00001
38 (12)
<0.002
Antiplatelet Trialists Collaboration BMJ 1994;308:81-106
Platelet Function (COX-1 Independent)
In DM Vs Non-DM On Aspirin
LTA
p<0.05
80
60
40
20
0
DM
Non-DM
100
% Patients CEPI-CT<300 sec
% Platelet aggregation
100
PFA-100
p<0.01
80
60
40
20
0
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
Characteristic
Patients
Overall
12562
Associated MI
3283
No associated MI
9279
Male sex
7726
Female sex
4836
65 yr
old
6354
> 65 yr old
6208
ST-segment
deviation
6275
o ST-segment deviation
6287
Enzymes elevated at entry
3176
Enzymes not elevated at entry
9386
Diabetes
2840
No diabetes
9722
Low risk
4187
Intermediate risk
4185
High risk
4184
History of revascularization
2246
No history of revascularization
10316
Revascularization after randomization
4577
No revascularization after randomization
7985
Yusf S et al. N Engl J Med. 2001;345:494-502.
Clopidogr Placebo
+ ASA
el + ASA
9.3
11.4
11.3
13.7
8.6
10.6
9.1
11.9
9.5
10.7
5.4
13.3
7.6
15.3
11.5
7.0
10.7
8.8
14.2
7.9
5.1
6.5
16.3
8.4
9.5
11.5
8.1
14.3 N
8.6
13.0
10.9
16.7
9.9
6.7
9.4
18.0
14.4
10.7
13.9
10.0 0.4 0.6 0.8 1.0 1.2
Relative Risk (95% CI)
Clopidogrel Better
Placebo Better
Influence of Diabetes Mellitus on
Clopidogrel-induced Antiplatelet Effects
Acute Phase of Treatment
P=0.002
8%
14%
56%
24 hrs post 300 mg LD
Non-responders
(Platelet inhibition <10%)
Low responders
(Platelet inhibition 10-29%)
Responders
(Platelet inhibition >30%)
Angiolillo DJ et al. Diabetes. 2005;54:2430-2435.
78%
Platelet aggregation (%)
P=0.04
6%
80
No-DM
DM
38%
Long-term Phase of Treatment
P<0.0001
60
40
20
0
DM No DM
ADP 20M
DM No DM
ADP 6M
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
Odds/hazard ratio
5
4
OR=2.0
(0.8-4.9)
OR=2.8
(1.7-4.3)
HR=3.7
(1.7-7.9)
HR=2.03
(1.07-3.83)
IDDM
IDDM
Diabetes
Diabetes
3
2
1
0
Kuchulakanti PK et al. Urban P et al.
Iakovou I et al.
Circulation
Circulation
JAMA
2006;113:1108-1113 2006;113:1434-1441 2005;293:2126-2130
Daemen J et al.
Lancet
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
Standard
Hazard Ratio (95% confidence interval)
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)
5.6
4.9
0.87 (0.66 – 1.15)
CURRENT OASIS 7
(PCI Cohort)
0
0.5
New Drug/Approach
Better
1
1.5
Standard Clopidogrel
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
16
CV Death/MI/Stroke
14
Endpoint (%)
17.0
12
Prasugrel
10
8
12.2
HR 0.70
P<0.001
NNT = 21
6
TIMI Major
Non-CABG Bleeds
4
2
Clopidogrel
Prasugrel
2.6
2.5
0
0
30 60 90
180
270
Days
Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:1626-1636.
360
450
TRITON TIMI-38:
CV Death/MI/Stroke by Diabetic Status
Pras
Clop
Reduction in Risk
9.2%
10.6%
14%
DM No Insulin
11.5% 15.3%
26%
DM on Insulin
14.3% 22.2%
37%
No DM
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
PRU
250
200
150
***
***
100
50
0
***
Mean±SE
0 4
***
***p<0.0001
24
7 days
Hours post LD
No study drug
(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
C Cholesterol-LDL: <70 mg/dl
Platelet Reactivity
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
(vs 0 or 1 therapy)
OR
(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
OR = odds ratio
*Registry of patients with ACS
Chew DP et al. Heart. 2010;96:1201-1206.
0.5
1
OR
1.5
2
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
Not at all confident
2
3
4
5
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
Not at all confident
2
3
4
5
Expert
Pre-activity Survey Question 3
The choice between an initial conservative strategy or an
initial invasive strategy in patients diagnosed with NSTEACS 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.