5/24/2010

This activity was supported by an independent medical

education grant from the Bristol-Myers Squibb/Sanofi
Pharmaceuticals partnership.
Sponsored by CME LLC

Deepak L. Bhatt, MD, MPH

Chief of Cardiology
VA Boston Healthcare System
Director, Integrated Interventional
Cardiovascular Program
Brigham and Women's Hospital and VA Boston
Healthcare System
Associate Professor of Medicine
Harvard Medical School
Senior Investigator, TIMI Study Group
Boston, MA

Joseph P. Frolkis, MD, PhD,

FACP, FAHA
Director of Primary Care
Associate Chief of General Medicine for Primary Care
Brigham and Women's Hospital
Boston, MA
Former Director of Clinical Operations
Preventive Cardiology Program
Cleveland Clinic
Cleveland, OH

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Learning Objectives

After completing this activity, participants

should be able to:
1. Demonstrate an understanding of the pathogenesis,
epidemiology, and risk factors of ACS and its relevance to long-
term care of ACS patients.
patients
2. Incorporate into practice an appropriate assessment of the
efficacy, safety, and quality of life outcomes associated with
current and emerging antithrombotic therapies in long-term care
of ACS.
3. Utilize evidence-based approaches to improve competence in
the long-term management of ACS, including approaches to
optimizing secondary prevention.

Polling Question
Please indicate your primary degree
(select only one)

a. MD/DO
b. PhD
c. PA
d. RN
e. NP
f. PharmD/ RPh
g. Other

Polling Question
Please indicate your primary specialty
(select only one)
a. Internal Medicine
b. Family Practice
c. General Practice
d. Cardiology
e. Pharmacology
f. Other

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Polling Question
How many years have you been in practice?
(select only one)

a. 1-5
b. 6-10
c. 11-15
d. 16-20
e. 21+
f. Not applicable

Polling Question
Approximately how many patients with ACS (or
patients who may be at risk for ACS)
do you see per week?
(Select only one)
a. 1-5
b. 6-10
c. 11-15
d. 16-20
e. 21+
f. Not applicable

Introduction

Pathogenesis, Epidemiology, and

Risk Factors
Deepak L. Bhatt, MD, MPH

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What is Acute Coronary Syndrome?

• ACS encompasses a spectrum of coronary

artery disease (CAD) including:
• Unstable Angina (UA)
• ST-elevation myocardial infarction (STEMI;
formerly known as Q-wave myocardial
infarction)
• Non-STEMI (NSTEMI; formerly known as
non– Q-wave myocardial infarction)

Atherothrombosis:
Clinical Manifestations
Stroke
Acute coronary Transient ischemic attack (TIA)
syndromes Intracranial stenosis
– STEMI Carotid artery
– NSTEMI stenosis
– Unstable angina
Stable CAD
Atrial Fibrillation R
Renal
l artery
t stenosis
t i

Abdominal Peripheral arterial

aortic disease
Acute limb ischemia
aneurysm Claudication
(AAA) Abnormal ankle
brachial index (ABI)

CAD: coronary artery disease.

Reproduced with permission from Meadows TA, Bhatt DL. Circ Res. 2007;100(9):1261-1275.

Case Scenario Question

Case: You have a busy clinical practice with a diverse patient
population and are interested in understanding which patient
population has the highest incidence of myocardial infarction
(MI) so that you can more effectively manage cardiovascular
risk.
Among the following patient groups,
groups which group has the highest
incidence of MI in the age range of 65-74 years? (select only one)
a. White men
b. Black men
c. White women
d. Black women
e. There is no significant difference in MI incidence between these
groups
f. I don’t know

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Incidence of Myocardial Infarction

By Age, Race and Sex
12
00 Person Years

10.3
10 9.2

8 7.2
6.1 6.2 5.1
6
4.3
Per 1,00

4 3.0 3.5
35 24
2.4
1.8
2 0.9 1.2 1.0
0.3 0.7
0
35-44 45-54 55-64 65-74
Ages in Years
White Men Black Men White Women Black Women

(ARIC Surveillance: 1987-2004). Source: NHLBI.

www.americanheartorg.org . Accessed March 1, 2009
MI diagnosed by expert committee based on review of hospital records.

Atherothrombosis* Is the
Leading Cause of Death Worldwide1
Pulmonary disease 6.3

Injuries 9

AIDS 9.7

Cancer 12 6
12.6

Infectious disease 19.3

Atherothrombosis* 22.3

0 5 10 15 20 25 30
Causes of Mortality, %
*Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.
1The World Health Report 2001, Geneva: WHO; Available at: www.theheart.org.

Mortality in Acute Coronary Syndromes

16 GRACE N=43,810
STEMI
ortality, %

12
NSTEMI

8 UA
Mo

0
0 30 60 90 120 150 180
Days
d/c: discharge.
Reproduced with permission from Fox KA, Dabbous OH, Goldberg RJ, et al. BMJ.
2006;333:1091. Goldberg RJ, Currie K, White K, et al. Am J Cardio. 2004;93(3):288-293.

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Mortality in Acute Coronary Syndromes

16 GRACE N=43,810
STEMI
12 Mortality from
Morrtality. %

NSTEMI
d/c to 6 mo.
STEMI – 3.6%
8 NSTEMI – 6.2% UA
UA – 4.8%

0
0 30 60 90 120 150 180
Days
d/c: discharge.
Reproduced with permission from Fox KA, Dabbous OH, Goldberg RJ, et al. BMJ.
2006;333:1091. Goldberg RJ, Currie K, White K, et al. Am J Cardio. 2004;93(3):288-293.

Diagnostic Recommendations

• Likelihood of ACS should be determined in all

patients presenting to the PCP with chest pain.
• A 12-Lead electrocardiogram (ECG) should be
obtained within 10 minutes of presentation.
p
• Cardiac markers (troponin T, troponin I, and/or
creatine kinase-MB isoenzyme of creatine
kinase) should be measured.

Risk Stratification

• High Risk of ACS

• Chest or left arm pain
• Known history of CAD
g g
• New transient mitral regurgitation, hypotension,
yp
diaphoresis, pulmonary edema or rales
• New, or presumably, new transient ST-segment
deviation (>0.05 mV) or T-wave inversion (>0.2 mV)
with symptoms
• Elevated cardiac troponin T, I or CK-MB

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ECG Changes and Mortality in ACS

Presenting ECG can predict death or MI

• At 30-days follow-up: • At 6-months follow-up:
– 5.5% T-wave inversion – 8.1% T-wave inversion
– 9.4% ST-segment
g – 12.3% ST-segment
g
elevation elevation
– 10.5% ST-segment – 15.4% ST-segment
depression depression

Savonitto S, Ardissino D, Granger CG, et al. JAMA. 1999;281:753-754.

Case Scenario Question

Case: A 56-year-old man presents to the ER with intermittent chest
pain at rest, nausea, and dizziness. His ECG findings are
normal with no ST-segment changes or Q waves, however his
serum cardiac troponin levels are elevated. His past medical
history is significant for stable angina.
Which of the following is true regarding this patient’s risk of mortality
about 6 weeks after this acute cardiac event? (select only one)
a. The higher the cardiac troponin I level during the ACS event, the
progressively higher the risk of mortality 6 weeks after the event
b. An increased level of cardiac troponin I does not correlate to risk
of mortality 6 weeks after the event; it only correlates to
increased mortality risk during the ACS event
c. Any abnormal level of cardiac troponin I signifies an increased
risk of mortality 6 weeks after an ACS event, but higher troponin
levels do not correlate to higher mortality risk
d. Cardiac troponin I level does not predict risk of mortality
e. I don’t know

Cardiac Troponin Predicts the Risk

of Mortality in UA/NSTEMI
8 7.5
Mortality at 42 Days, %

6.0
6

4 3.7
3.4

1.7
2
1.0
831 174 148 134 50 67
0
0 to <0.4 0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0 ≥ 9.0
Cardiac Troponin I (ng/mL)
Risk Ratio 1.0 1.8 3.5 3.9 6.2 7.8

Reproduced with permission from Antman EM, Tanasijevic MJ, Thompson B, et al.
N Engl J Med. 1996;335(18):1342-1349.

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TIMI Risk Score

• Age ≥ 65
• Three or more CAD Risk Factors
• History of angina
• Hypertension
H i
• Hyperlipidemia
• Diabetic
• Smoker

TIMI Risk Score (cont)

• Presentation
• Recent (within 24 hours) severe angina
• Elevated cardiac markers
• ST-deviation ≥ 0.5 mm

TIMI Risk Score for UA/NSTEMI

HISTORICAL RISK OF CARDIAC EVENTS
Age ≥ 65 (%) BY 14 DAYS IN TIMI 11B
≥ 3 CAD risk factors
(FHx, HTN, ↑chol, DM, active smoker) RISK DEATH DEATH, MI OR
SCORE OR MI URGENT REVASC
Known CAD (stenosis ≥ 50%)
ASA use in past 7 days 0/1 3 5
2 3 8
PRESENTATION
3 5 13
Recent (≤ 24h) severe angina 4 7 20
↑ cardiac markers 5 12 26
ST deviation ≥ 0.5 mm 6/7 19 41
RISK SCORE = Total Points (0 - 7)
*Entry criteria: UA or NSTEMI defined as ischemic
pain at rest within past 24h, with evidence of CAD
(ST segment deviation or +marker)
TIMI: Thrombolysis in Myocardial Infarction.
Reproduced with permission from Antman EM, Cohen M, Bernink PJ, et al. JAMA. 2000;284:835-842.

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Pathogenesis of ACS
• Atherosclerotic plaque formation
• Rupture and thrombus formation seen in:
• 90% of STEMI patients
g
• 35-75% of unstable angina and NSTEMI
• 1% of stable angina patients
• Inflammation plays critical role in plaque
destabilization
• Platelets contribute to plaque inflammation
and thrombosis

Intravascular Ultrasound Study

(IVUS) of Ruptured Plaque

Reproduced with permission from Ziada K, Bhatt DL. In: Bhatt DL (ed). Essential
Concepts in Cardiovascular Intervention. Remedica, London, UK. 2004.

Virtual Histology of “Vulnerable”

Plaque

Reproduced with permission from Kelly P, Bhatt DL. J Invasive Cardiol.

2007;19(2):55-57.

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Case Scenario Question

Case: A 45-year-old man with substernal chest pressure and
shortness of breath presents to your office. ECG is normal, and
he is immediately transported to the hospital ER. With elevated
cardiac markers, he is diagnosed with NSTE ACS.
According to recent meta-analyses results, which of the
g is generally
following g y true for this patient
p with regard
g to long-
g
term survival? (select only one)
a. Conservative therapy would likely improve long-term survival
b. Early invasive therapy would likely improve long-term survival
c. Both conservative therapy and early invasive therapy have similar
rates of long-term survival
d. Long-term survival cannot be predicted based on either
management strategy
e. I don’t know

Routine vs Selective Invasive

Strategies in ACS

To Cath or Not to Cath

That Is No Longer the Question

Bhatt DL. JAMA. 2005;293(23);2935-2937.

Conservative vs Invasive Rx

• TACTICS Study found significant decrease in death,

myocardial infarction (MI), and rehospitalization for
ACS at 6 months with invasive treatment.1
• Meta-analysis of 7 studies found invasive
management of UA and NSTEMI decreased death
and MI at 17 months follow-up.2
• In-hospital mortality rates were significantly reduced
by early catheterization versus non-catheterization in
low, moderate, and high risk patients.3

1.Cannon CP, Weintraub WS, Demopoulos LA, et al. N Engl J Med. 2001;344(25):1879-1887.
2. Mehta SR, Cannon CP, Fox KA, et al. JAMA .2005;293(23):2908-2917. 3. Bhatt DL,
Roe MT, Peterson ED, et al. JAMA. 2004;292(17):2096-2104.

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TACTICS: Primary Endpoint

Death, MI, Rehospitalization for ACS at 6 Months

20 19.4%
nts, %

16 15.9%
Patien

12 OR 0.78
95% CI (0.62, 0.97)
8
P=0.025
4 CONS
INV
0
0 1 2 3 4 5 6
Time in Months
Reproduced with permission from Cannon CP, et al. N Engl J Med. 2001;344(25):1879-1887.

Invasive Management of UA/NSTEMI

Meta-analysis: ↓ Death/MI at 17 mo. F/U
Trial Inv Cons Odds Ratio (OR) Death or MI
Favors Invasive Favors Conservative

TIMI 3B 11.6% 13.8%

VANQWISH 32.9% 30.3%
MATE 14.4% 12.2%
FRISC II 10.4% 14.1%
TACTICS 7.3% 9.5%
VINO 6.3% 22.4%
RITA 3 10.6% 12.9%
OR 0.82, P<0.001
TOTAL 12.2% 14.4%

0.1 0. 5 1.0 2.0 10

Reproduced with permission from Mehta SR, Cannon CP, Fox KA, et al. JAMA. 2005;293(23):2908-
2917.

Mortality Rates by Early Catheterization

10
Early Catheterization
No Early Catheterization
8.6
In-Hospital Mortality, %

3.9
4
2.3 2.5
2
1.1
0.7

0
Low Moderate High
(n=4326) (n=4492) (n=9108)
Modified PURSUIT Risk Category
Reproduced with permission from Bhatt DL, et al. JAMA. 2004;292(17):2096-2104.

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Updated Meta-Analysis: Mortality

Deaths, n Follow-up
Invasive Conservative Months
Study
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
Overall RR (95% CI) 15 15 12
0.75 (0.63-0.90)
0.1 Favors
1 10
Favors
Early Invasive Conservative
Therapy Therapy
Reproduced with permission from Bavry AA, Kumbhani DJ, Rassi AN, et al. J Am Coll
Cardiol. 2006;48(7):1319-1325.

Death, MI or Rehospitalization with ACS

FEMALE n=3075 MALE n=7075

TIMI IIIB P heterogeneity (gender) = 0.26

MATE
VANQWISH
FRISC II
TACTICS-TIMI 18
RITA 3
VINO
ICTUS

OR 0.81 OR 0.73
OVERALL (95% CI 0.65-1.01) (95% CI 0.55-0.98)

Favors Invasive Favors Conservative Favors Invasive Favors Conservative

0.2 1.0 5 0.2 1.0 5
Reproduced with permission from O’Donoghue ML, Boden WE, Braunwald E, et al. JAMA.
2008;300(1):71-80.

High-Risk Subgroups
Death, MI or Rehospitalization with ACS
FEMALE
Number OR (95% CI)

CK--MB or Troponin +
CK 1110 0.67 (0.50
(0.50--0.88)

CK--MB or Troponin -
CK 1486 0.94 (0.61
(0.61--1.44)

MALE
Number OR (95% CI)

CK--MB or Troponin +
CK 2745 0.56 (0.46
(0.46--0.67)
CK--MB or Troponin -
CK 2294 0.72 (0.51
(0.51--1.01)

Favors Favors
0.2 1.0 5.0
Invasive Conservative
Restricted to TIMI IIIB, FRISC II, RITA 3, MATE, TACTICS-TIMI 18.
Reproduced with permission from O’Donoghue ML, Boden WE, Braunwald E, et al. JAMA. 2008;300(1):71-80.

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ACC/AHA Guidelines 2007

Early Invasive Strategies
I IIa IIb III
High-risk patients with :
- Refractory ischemia (’07)
- 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
- PCI within 6 months, prior CABG
- High risk score (TIMI, GRACE, FRISC)
- Not in low-risk women (’07)
National Guideline Clearinghouse at www.guidline.gov. Accessed on March 1, 2010.

TIMACS Trial Design

UA or NSTEMI
2 of 3: Age >60, ECG changes or +biomarker
and suitable for revascularization

Aspirin, clopidogrel, GP IIb/IIIa per practice

RANDOMIZE

Early Invasive Delayed Invasive

Angio ASAP Angio any time
No later than 24h >36h
TIMACS: Timing of Intervention in Acute Coronary Syndrome.
Mehta SR. Granger CB, Boden WE, et al. N Engl J Med. 2009;360(21)2165-2175.

Primary and Secondary Outcomes

Early Delayed HR 95% CI P
N=1593 N=1438

Death, MI, Stroke 9.6% 11.3% 0.85 0.68-1.06 0.15

Death, MI, refractory 9.5 12.9 0.72 0.58-0.89 0.003
ischemia
Death MI,
Death, MI Stroke,
Stroke 16 6
16.6 19 5
19.5 0 84
0.84 0 71 0 99
0.71-0.99 0 04
0.04
refractory ischemia
+ repeat intervention
Death 4.8 5.9 0.81 0.60-1.11 0.19
MI 4.8 5.7 0.83 0.61-1.14 0.25
Stroke 1.3 1.4 0.90 0.48-1.68 0.74
Ref. Ischemia 1.0 3.3 0.30 0.17-0.53 <0.001
Rep. Intervention 8.7 8.5 1.04 0.82-1.34 0.73

Mehta SR. Granger CB, Boden WE, et al. N Engl J Med. 2009;360(21)2165-2175.

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TIMACS: GRACE Score and 10 EP

HR= 0.65
(0.48-0.88)
Death, MI or Strroke at 6 mo

25 P= 0.006
21.0
20

15 HR= 1.12 13.9

(0.81-1.56) Delayed
10 P=0.48
7.6 Early
6.7
5

0
Low/Inter Risk High Risk
Score <140 Score >140
N=2070 N=961
Mehta SR, et al. N Engl J Med. 2009;360(21)2165-2175.

Restenosis and Thrombosis with Stents

Reproduced with permission from Curfman GD, Morrissey S, Jarcho

JA, et al. N Engl J Med. 2007;356(10):1059-1060.

Mayo Clinic Experience

• Cumulative 10-year rate of BMS thrombosis: 2.0%

• Off-label use, primarily SVG, increased incidence

• Other correlates: Prior MI, PAD, ulcerated lesion

• 10-year incidence of clinical BMS restenosis: 18.1%

• Presented with MI: 2.1%

BMS, bare-metal stents; PAD, peripheral artery disease; SVG, saphenous vein graft,
Doyle B, Rihal CS, O’Sullivan CJ, et al. Circulation. 2007;116(21):2391-2398.

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DES vs BMS – No Mortality Difference

Frequency (%)
All-cause mortality Relative Risk (95% CI) DES BMS

Stettlers, 4 years PES --- ---

SES --- ---
Stone, 4 years PES 6.1 6.6
SES 6.7 5.3
DES 54
5.4 52
5.2
Kastrati, 5 years SES 5.9 6.0
Spaulding, 4 years SES 6.7 5.4
Holmes, 3 years SES 4.1 3.2
Schampaert, 2 years SES 2.1 1.6
Nordmann, 3 years PES 2.6 2.6
4 years SES 4.6 3.9

DES, drug eluding stent; BMS, bare metal stent.

Reproduced with permission from Bavry AA, Bhatt DL. Lancet 2008;371:2134–2143.

Case Scenario Question

Case: A 60-year-old woman with STEMI undergoes cardiac
catheterization and placement of a bare metal stent in the left
anterior descending coronary artery. She is started on aspirin
and clopidogrel in the hospital and will be discharged soon.

Assuming no bleeding complications,

complications how long would you
continue dual antiplatelet therapy in this patient after she is
discharged? (select only one)
a. 1 month
b. 3 months
c. 6 months
d. 9 months
e. 12 months
f. Indefinitely

Bavry AA, Bhatt DL. Circulation. 2007;116:696–699

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Drug- Is there an increased risk for both stent

thrombosis and restenosis? Yes Consider
Eluting Example: Diabetics with diffuse multivessel
CABG
disease, bifurcation lesions
Stents No

Is there a low risk for restenosis?

Yes Consider
Example: Non-diabetics, focal lesions, BMS
large vessels

No

Are there relative contraindications to DES?

Example: ● Medical non-compliance Yes Consider
● ACS, especially STEMI BMS
● Chronic anti-coagulation
● Anticipated surgery
● High risk for bleeding
No

Optimization of DES implantation

Example: ● High pressure implantation with non-compliant balloon
● Consider IVUS
● Dual antiplatelet therapy for at least 1 year
● If no bleeding, consider longer duration of clopidogrel,
pending further data

Reproduced with permission from Bavry AA, Bhatt DL. Circulation. 2007;116:696–699

Conclusions

• NSTEMI-ACS remains prevalent and has

high event rates
• ST deviation or positive troponin defines
very high risk
• Early invasive strategy preferred
• Need to individualize revascularization
strategy

Polling Question

How confident are you in your knowledge

of recent clinical trial data regarding
current and emerging treatments for
long-term care of patients with ACS?
(select only one)
a. 100% confident
b. 75% confident
c. 50% confident
d. 25% confident
e. 0% confident

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Polling Question

How often do you implement the most

recent ACC/AHA guideline
recommendations when managing
long-term care of patients with ACS?
(select only one)
a. 100% of the time
b. 75% of the time
c. 50% of the time
d. 25% of the time
e. 0% of the time

Polling Question

How confident are you in your ability to

utilize evidence-based approaches to
optimize secondary prevention in
patients with ACS? (select only one)
a. 100% confident
b. 75% confident
c. 50% confident
d. 25% confident
e. 0% confident

Long-Term Management and

Secondary Prevention

The Critical Role of the Primary Care Physician

Joseph P. Frolkis MD, PhD, FACP, FAHA

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Case Scenario Question

Case: A 57-year-old man with new-onset NSTE ACS admitted to the hospital
undergoes cardiac catheterization and placement of two drug eluting stents.
He has an unremarkable post-catheterization course and is now ready for
discharge. His LDL cholesterol measured in the hospital is 100 mg/dL. In
preparation for discharge and to prevent another future cardiac event,
secondary preventive measures are discussed.

Assuming no contraindications, what secondary preventive measures for

cholesterol management upon discharge and for physical activity once the
patient is stable should be taken? (select only one)

a. Cholesterol management
g through
g diet is reasonable since LDL-C is
100mg/dL; patient should do 30-60 min. of exercise at least 3 days/week
b. Cholesterol management through diet is reasonable since LDL-C is
100mg/dL; patient should do 30-60 min. of exercise at least 5 days/week
c. Start a statin since all UA/NSTEMI patients should receive a statin regardless
of baseline LDL-C; patient should do 30-60 min. of exercise at least 3
days/week
d. Start a statin since all UA/NSTEMI patients should receive a statin regardless
of baseline LDL-C; patient should do 30-60 min. of exercise at least 5
days/week
e. I don’t know

Guidelines for Preparation for

Discharge After UA/NSTEMI
Antiplatelet Rx
Aspirin 75 - 162 mg/day (162 - 325 mg/d after stents)
Clopidogrel 75 mg/day with aspirin
Beta Blocker
Consider chronic therapy for all MI, ACS, or left ventricular
d f
dysfunction
ti patients
ti t
ACEI / ARB
Start and continue especially if diabetic, HF, EF < 40%, HTN
Statin
Give statins to all UA/NSTEMI patients, regardless of LDL (IA)
Target LDL << 100 mg/dL (ideally < 70)

Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157

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AHA/ACC Guidelines for Secondary

Prevention
Secondary Prevention Measures
• Smoking Cessation. Discuss tobacco use at every
visit, assess willingness to quit, counsel and develop
smoking cessation plan.
• Blood pressure control (Goal: BP < 140/90 mm Hg or
<130/80 mm Hg for diabetics or chronic kidney
disease)
• Diabetes Management (Goal: HbA1C < 7%)
• Weight loss program (Goal: BMI 18.5-24.9 kg/m2)
• Physical Exercise 30-60 min at least 5 days/wk

Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157

Guideline for Long-Term Antithrombotic Therapy

at Hospital Discharge after UA/NSTEMI
UA/NSTEMI
New Patient Groups
at Discharge

Medical Therapy without Bare Metal Drug Eluting Stent

Stent Stent Group Group

ASA 75 to 162 mg/d indefinitely
(Class II, LOE: A)
&
Clopidogrel 75 mg/d at least 1
month (Class I, LOE: A) and up
to 1 year (Class I, LOE: B)
ASA 162 to 325 mg/d for at least 1 ASA 162 to 325 mg/d for at
month,, then 75 to 162 mg/d
g least 3 to 6 months, then 75 to
indefinitely (Class I, LOE: A) 162 mg/d indefinitely
& (Class I, LOE: A)
Clopidogrel 75 mg/d for at least 1 &
month and up to 1 year
Clopidogrel 75 mg/d for at least
(Class I, LOE:B) 1 year (Class I, LOE: B)

Yes Indication for No

Anticoagulation?
Add: Warfarin (INR 2.0 to 2.5) Continue with dual
(Class IIb, LOE: B) antiplatelet therapy as above

INR = international normalized ratio; LOE = level of evidence.

Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157

Case Scenario Question

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Case: In a patient with new onset ACS, the choice of antiplatelet therapy is
currently being considered. When considering all treatment options,
clinical trial findings of current and emerging therapies may be used to
effectively manage patients with ACS and help with individualizing
treatment.
Which of the following is consistent with the TRITON-TIMI 38 study
results? (select only one)
a. There were no significant differences in rate of death from cardiovascular
causes, MI, and stroke after intervention between prasugrel and
clopidogrel, but there was an increased rate of major bleeding with
prasugrel
b There were no significant differences in rate of death from cardiovascular
b.
causes, MI, and stroke after intervention between prasugrel and
clopidogrel, but there was an increased rate of major bleeding with
clopidogrel
c. Patients taking prasugrel had a reduced rate of death from cardiovascular
causes, MI, and stroke after intervention compared to those taking
clopidogrel, but had an increased rate of major bleeding
d. Patients taking prasugrel had an increased rate of death from
cardiovascular causes, MI, and stroke after intervention compared to those
taking clopidogrel, but had a decreased rate of major bleeding
e. I don’t know

Long-Term Management
• CURE Study found 20% relative risk reduction in MI,
stroke or death when patients were given clopidogrel +
aspirin compared with aspirin alone as their long-term
pharmacotherapy.1
• PCI-CURE study found 31% relative risk reduction in MI
and death in patients randomized to receive clopidogrel +
aspirin after PCI, compared to aspirin alone. 2
• TRITON-TIMI 38 study found prasugrel significantly
reduced MI, stroke and death15 months after intervention,
but increased rate of major bleeding, compared with
clopidogrel.3

1. Yusuf S, Zhao F, Mehta SR, et al. N Engl J Med. 2001;345(7):494-502. 2. Mehta SR, Yusaf S,
Peters RJ, et al. Lancet. 2001;358:527-533. 3. Wiviott SD, Braunwald E. McCabe CH, et al. N
Engl J Med. 2007;357(2):2001-2015.

CURE Study: Primary End Point--

MI/Stroke/CV Death
20%
Hazard Rate

0.14 Placebo Relative

0.12 + Aspirin Risk
(n=6303) Reduction
0.10
0.08
Cumulative H

Clopidogrel
0.06 + Aspirin P <0.001
(n=6259)
0.04
0.02
0.00
0 3 6 9 12
Months of Follow-up

Reproduced with permission from Yusuf S, Zhao F, Mehta SR, et al. N Engl J Med.
2001;345(7):494-502.

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 5/24/2010

PCI-CURE Study: CV Death or MI

From Randomization
Placebo + Aspirin
0.15 12.6%
Hazard Rate

Median time (n=1345) 31%

to PCI Relative
Risk
0.10 8.8% Reduction
Cumulative H

Clopidogrel + Aspirin
(n=1313)
0.05

P=0.002
0.00
0 10 100 200 300 400

Days of Follow-up
Reproduced with permission Mehta SR, Yusaf S, Peters RJ, et al. Lancet. 2001;358:527-533.

TRITON – TIMI 38: CV Death, MI, Stroke

15

Clopidogrel
12.1%
(781)
Endpoint, %

10 9.9%
(643)
Prasugrel
HR 0.81
Primary E

HR 0.80
P=0.0003
(0.73-0.90)
HR 0.77 P<0.001
5 P=0.0001
NNT= 46

ITT= 13,608
LTFU = 14 (0.1%)
0
0 30 60 90 180 270 360 450
Days of Follow-up
NNT, number needed to treat; ITT, intent to treat; LTFU, lost to follow-up
Reproduced with permission from Wiviott SD, et al. N Engl J Med. 007;357(2):2001-2015.

Bleeding Events - Safety Cohort

Clopidogrel (N=13,457) Intracranial Bleed in Pts
Prasugrel with Prior Stroke/TIA
4 (N=518)
Clop 0 (0) %
Pras 6 (2.3)%
2.4 (P=0.02)
% Events

2 1.8
14
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
NNH=167
Reproduced with permission from Wiviott SD, Braunwald E, McCabe CH, et al. N Engl J Med. 2007;357(2):2001-2015.

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 5/24/2010

Beta Blockers
Beta blockers are indicated for all patients
I IIa IIb III recovering from UA/NSTEMI unless
contraindicated. (For those at low risk, see
Class IIa on the next slide). Treatment
should begin within a few days of the event,
if not initiated acutely, and should be
continued indefinitely.

I IIa IIb III

Patients recovering from UA/NSTEMI with
moderate or severe LV failure should receive
beta-blocker therapy with a gradual titration
scheme.
LV, left ventricle
Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

Beta Blockers

I IIa IIb III It is reasonable to prescribe beta blockers to low-

risk patients (i.e., normal LV function,
revascularized, no high-risk features) recovering
from UA/NSTEMI in the absence of absolute
contraindications
contraindications.

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157

Inhibition of the Renin-Angiotensin-

Aldosterone System

I IIa IIb III ACE inhibitors should be given and continued

indefinitely for patients recovering from
UA/NSTEMI with HF, LV dysfunction (LVEF <
40%), hypertension, or diabetes mellitus, unless
contraindicated.

I IIa IIb III

An ARB should be prescribed at discharge to
those UA/NSTEMI patients who are intolerant of
an ACE inhibitor and who have either clinical or
radiological signs of HF and LVEF < 40%.

HF, heart failure; LVEF, left ventricular ejection flow

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

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 5/24/2010

Inhibition of the Renin-Angiotensin-

Aldosterone System
I IIa IIb III ACE inhibitors are reasonable for patients
recovering from UA/NSTEMI in the absence of
LV dysfunction, hypertension, or diabetes
mellitus unless contraindicated.
I IIa IIb III
ACE inhibitors are reasonable for patients
with HF and LVEF > 0.40.

In UA/NSTEMI patients who do not tolerate

I IIa IIb III ACE inhibitors, an ARB can be useful as an
alternative to ACE inhibitors in long-term
management provided there are either clinical
or radiological signs of HF and LVEF < 40%.

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

Lipid Management

I IIa IIb III Lipid management should include assessment of

a fasting lipid profile for all patients, within 24 h of
hospitalization.

Hydroxymethyl glutaryl-coenzyme A reductase

I IIa IIb III inhibitors (statins),
(statins) in the absence of
contraindications, regardless of baseline LDL-C
and diet modification, should be given to post-
UA/NSTEMI patients, including post-
revascularization patients.
I IIa IIb III
For hospitalized patients, lipid-lowering
medications should be initiated before discharge.

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

Lipid Management
I IIa IIb III For UA/NSTEMI patients with elevated LDL-C
(≥ 100 mg/dL), cholesterol-lowering therapy
should be initiated or intensified to achieve an
LDL-C < 100 mg/dL.
New Lower Further titration to less than 70 mg/dL is
LDL-C Goal reasonable. (Class IIa, Level of Evidence: A)

I IIa IIb III

Further reduction of LDL-C to < 70 mg/dL is
reasonable.

I IIa IIb III If baseline LDL cholesterol is 70 to 100 mg/dL, it

is reasonable to treat LDL-C to < 70 mg/dL.

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

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 5/24/2010

In-Hospital Initiation of Lipid Therapy

Improves Long-Term Compliance
Prescribed Statins at Discharge
• NO • YES
• 40% of 278 patients • 77% of 65 patients
said theyy were taking
g said they were taking
statins at long-term statins at long-term
follow-up follow-up

Nearly twice as many patients were taking statins

at follow-up than had received a prescription at
the time of hospital discharge.

Muhlestein JB, Horne BD, Blair TL, et al. Am J Cardiol. 2001;87:257-261.

Early Initiation of Statin Treatment is Associated

With Reduced 1-Year Mortality in Acute MI:
Registry Data from 58 Swedish Hospitals (1995-1998)
of Death, %

5
No Statin
4
(n=14,071)
3
Probability o

Statin
2 (n=5528)

1
P=0.001
0
0 100 200 300 400
Postadmission Days

Reproduced with permission from Stenestrand U, Wallentin L. JAMA. 2001;285:430-436.

Blood Pressure Control

I IIa IIb III Blood pressure control according to JNC 7

guidelines* is recommended (i.e., BP < 140/90
mmHg or < 130/80 mmHg if the patient has
diabetes mellitus or chronic kidney disease).

*Chobanian AV, et al. JAMA .2003;289:2560-2572.

JNC 7, 7th report of the Joint National Committee on Prevention, Detection,
Evaluation and Treatment of High Blood Pressure.
Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

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 5/24/2010

Prevalence of High Blood Pressure in Adults

Age 20 and Older, By Age and Sex
NHANES: (2003-2006).
of Population

90
80 77.3
70.8
70 65.4 64.6
60 53.2 54.1
50 38.8 38.4
40
Percent o

30 24 4
24.4
20 16.2
12.2
10 6.6
0
20-34 35-44 45-54 55-64 65-74 75+

Men Women

AHA Heart Disease and Stroke Statistics-2010 Update

Available at www.americanheart.org/presenter.jhtml?identifier=3018163.
Accessed on April 16, 2010.

JNC 7:New Features and Key Messages

ƒ Hypertention (HTN) Prevalence – 50 million people in the

United States
ƒ For persons over age 50, systolic blood pressure (SBP) is
a more important than diastolic blood pressure (DBP) as
CVD risk
i k ffactor.
t
ƒ Starting at 115/75 mmHg, CVD risk doubles with each
increment of 20/10 mmHg throughout the BP range.
ƒ Persons who are normotensive at age 55 have a 90%
lifetime risk for developing HTN.
Available at http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf
Accessed on April 16, 2010

Extent of Awareness, Treatment, and

Control of High Blood Pressure by Age
(NHANES: 2003-2006).
Population

90
ertension

80 78.3 81.5 75.6

70 65.6
60 53.4
50 46.8 44.6
Percent of P
With Hype

40 36.1
29.2
30
20
10
0
Awareness Treatment Controlled
20-39 40-59 60+
AHA Heart Disease and Stroke Statistics-2010 Update
Available at www.americanheart.org/presenter.jhtml?identifier=3018163
Accessed on April 16, 2010

25
 5/24/2010

Smoking Cessation

I IIa IIb III Smoking cessation and avoidance of exposure

to environmental tobacco smoke at work and
home are recommended. Follow-up, referral to
special programs, or pharmacotherapy
(including nicotine replacement) is useful, as is
adopting
d ti a stepwise
t i strategy
t t aimed
i d att smoking
ki
cessation (the 5 As are: Ask, Advise, Assess,
Assist, and Arrange).

Anderson JL, et al. J Am Coll Cardiol . 2007;50:e1–e157

Prevalence of Current Smoking for Adults Age

18 and Older by Race/Ethnicity and Sex
(NHIS:2007)
40 36.7 36.0
35
Population

30
24.8
25 23.1
19.8
20 18.0
15.9 15.8
Percent of P

15
10 8.3
5 4.0
0
Men Women
NH White NH Black Hispanic NH Asian NH American Indian/Alaska Native

NH, non-Hispanic.
AHA Heart Disease and Stroke Statistics-2010 Update
Available at www.americanheart.org/presenter.jhtml?identifier=3018163
Accessed on April 16, 2010

Coronary Heart Disease - Smokers

• Two of every 5 smoking-related deaths are from

cardiovascular disease
• One in 5 deaths from cardiovascular diseases
are attributable to smoking
• Risk
Ri k off dying
d i ffollowing
ll i an MI was 40% greater
t
for daily smokers
• Approximately 40,000 nonsmokers die each
year from CVD as a result of exposure to
environmental tobacco smoke

Njlstad I, et al. Arch. Int. Med. 1998;158(12):1326-1332.

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 5/24/2010

Weight Management

I IIa IIb III Weight management, as measured by body

mass index (BMI) and/or waist circumference,
should be assessed on each visit. A BMI of 18.5
to 24.9 kg/m2 and a waist circumference
(measured horizontally at the iliac crest) of < 40
i h ffor men and
inches d < 35 iinches
h ffor women iis
recommended.

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

Age-adjusted Prevalence Of Obesity In

Adults Ages 20-74 By Sex And Survey
NHES, 1960-62; NHANES, 1971-74, 1976-80, 1988-94 and 2003-2006
Percent of Population

40
35.2
33.1
30 26.0
20.6
20 15.7 16.8 17.1
12.8
10.7 12.2
10

0
Men Women
1960-62 1971-75 1976-80 1988-94 2003-06
Note: Obesity is defined as a BMI of 30.0 kg/m2 or higher.
AHA Heart Disease and Stroke Statistics-2010 Update
Available at www.americanheart.org/presenter.jhtml?identifier=3018163
Accessed on April 16, 2010

Diabetes Mellitus
I IIa IIb III Diabetes management should include lifestyle and
pharmacotherapy measures to achieve a near-normal
HbA1c level of < 7%.

Diabetes management should also include the

I IIa IIb III following:
• Vigorous modification of other risk factors (e.g.,
physical activity, weight management, BP control,
and cholesterol management) as recommended
I IIa IIb III should be initiated and maintained.
• It is useful to coordinate the patient’s diabetic care
with the patient’s primary care physician or
endocrinologist.

Anderson JL, et al. J Am Coll Cardiol . 2007;50:e1–e157.

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 5/24/2010

Parallel Epidemics of Diabetes and

Obesity
1994 2004

Diabetes

<4% 4%–4.9% 5%–5.9% >6%

Obesity
(BMI ≥30 kg/m2)

10%–14% 15%–19% 20%– 24% >25%

Centers for Disease Control and Prevention. Available at www.cdc.gov.

90% of Patients With Newly Diagnosed

Diabetes are Overweight or Obese
National Health Interview Survey, 2003; N ≈ 31,000, aged 18 to 79 years
100
90%
abetics

80
Obese
60 (BMI ≥30)
Percent of Dia

60

40

20
30 Overweight

0 (BMI 25 to <30)
BMI ≥25 kg/m2

Geiss LS, Pan L, Cadwell B, et al. Am J Prev Med. 2006;30:371-377.

Even Mild Glucose Elevations Increase

Mortality in Patients Undergoing PCI
• 1612 Patients With CAD, mean age 62
– 1.9% mortality rate in patients with normal
fasting glucose (<110 mg/dL)
– 6.6%
6 6% mortality rate with impaired fasting
glucose (110-125 mg/dL)
– 9.5% mortality rate with undiagnosed type 2
diabetes (DM2) (≥126 mg/dL)
– 11.2% mortality rate DM2 (≥126 mg/dL)
– P-trend < 0.001
Muhlestein JB, Anderson JL, Horne BD, et al. Am Heart J. 2003;146:351-358.

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 5/24/2010

Benefits of Aggressive LDL-C

Lowering in Diabetes
Primary event rate (%) Aggressive Aggressive lipid- Difference in
lipid-lowering lowering LDL-C
Treatment Control better worse P
(mg/dL)
0.75
TNT
Diabetes, CHD 13.8 17.9 0.026 22*

ASCOT-LLA 0.77
Diabetes HTN
Diabetes, 9.2 11.9 0 036
0.036 35†

CARDS 0.63
5.8 9.0
Diabetes, no CVD 0.001 46†

HPS 9.4 12.6 0.73

All diabetes <0.0001 39†
13.5 0.67
Diabetes, no CVD 9.3
0.0003 39†
*Atorvastatin 10 vs 80 mg/day 0.5 0.7 0.9 1 1.7
†Statin vs placebo
Relative risk
Shepherd J et al. Diabetes Care 2006. Sever PS et al. Diabetes Care 2005. HPS Collaborative
Group. Lancet 2003. Colhoun HM et al. Lancet 2004.

Physical Activity

I IIa IIb III Guided/modified by an individualized exercise

prescription, patients recovering from
UA/NSTEMI generally should be encouraged to
achieve physical activity duration of 30 to 60 min
New per day,
p y, p
preferablyy 7 ((but at least 5)) days
y pper
week of moderate aerobic activity, such as brisk
walking, supplemented by an increase in daily
lifestyle activities (e.g., walking breaks at work,
gardening, and household work).

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1–e157.

Prevalence of Regular Leisure-Time Physical Activity Among

Adults Age 18 and Older by Race/Ethnicity, and Sex

60
Population

50.6 46.0 52.3 49.6

41.9 41.2 45.7 46.6
50 31.4 45.3 43.1
42.0 36.3 40.5
40.3
40 36.1
30
Percent of P

20
10
0
NH White NH Black Hispanic Other race

Men '01 Women '01 Men '05 Women '05

AHA Heart Disease and Stroke Statistics-2010 Update

Available at www.americanheart.org/presenter.jhtml?identifier=3018163
Accessed on April 16, 2010

29
 5/24/2010

Exercise

• Reduces weight, blood pressure, and

triglycerides – and raises HDL
• Prevents diabetes and stroke
• Normalizes endothelial function
• Slows progression of atherosclerosis (carotid,
coronary, peripheral)
• Reduces inflammatory and thrombogenic
markers (fibrinogen, fibrin D-dimer, CRP, plasma
viscosity, PAI-1)

Exercise and Endothelial Function

FBF responses to acetylcholine in sedentary and endurance-trained men
L tissue/min)

Young Sedentary Young Endurance-Trained

20 20
Older Sedentary Older Endurance-Trained
18 18
16 16
14 14
FBF (mL/100 mL

12 12
10 10
8 8
6 6
4 4
2 2
0 Baseline
0 Baseline 1.0 2.0 4.0 8.0 16.0
1.0 2.0 4.0 8.0 16.0
Acetylcholine (ug/100 mL tissue/min) Acetylcholine (ug/100 mL tissue/min)
FBF, forearm blood flow; Values are mean + SEM.
Reproduced with permission from DeSouza CA, Shapiro LF, Clevenger CM, et al. Circulation.
2000;102(12):1351-7.

Relationship of Adjusted Probability of Receiving Statins With Baseline Risk

According to Age and Age According to Baseline Risk
(The Treatment-Risk Paradox in the Elderly)

Baseline Risk
Probability of Stattin Prescription

Age
A Baseline Risk Younger
B Age Low
0.45 Median 0.45 Median
Older
0.40 0.40 High
0.35 0.35
0.30 0.30
0.25 0.25
0.20 0.20
0.15 0.15
0.10 0.10
0.05 0.05
0 0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.00 65 70 75 80 85 90 95
Baseline Risk Age, Y

Reproduced with permission from Ko DT, Mamdani M, Alter DA, et al. JAMA. 2004;291:1864-1870.

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 5/24/2010

Utilization of Lipid-Lowering Medications

at Discharge in Patients with AMI
100
Male (N=83,806)
Female (N=54,195)
80

60
P<0.0001 P<0.0001
40 P<0 0001
P<0.0001
P=NS

20 P=NS

0
<55 55-64 65-74 75-84 85+

Age in Years

Reproduced with permission from Fonarow GC, French WJ, Parsons LS, et al. Circulation.
2001;102:38-44

Survival After Coronary

Revascularization in the Elderly
Adjusted Survival Rates at 4 Years for Each Age Group
ARR,%
Adjusted Survival, % (Vs. Medical Therapy) NNT

Age y
Age, Medical PCI CABG PCI CABG PCI CABG
<70 90.8 93.8 95.0 3.0 4.2 33.1 23.4

70-79 79.1 83.9 87.3 4.9 8.2 20.6 12.1

>80 60.3 71.6 77.4 11.3 17.0 8.9 5.9

(N= 15,392, 5198; 983, respectively)

ARR, absolute relative risk

Reproduced with permission from Graham MM, Ghali WA, Faris PD, et al. Circulation. 2002;105:2378-2384.

Established Therapies are Consistently

Underused in All Patient Types
Patients not receiving therapy
(% of subpopulation)
Patients Not Receiving

60 Antiplatelets Lipid-lowering Statin

erapy, %

50 44 46
39
40 36
Proven The

30 28
30 24
19 18 18 19
20 14
10

0
CAD (n=40,258) CVD (n=18,843) PAD (n=8,273) Multiple Risk
Factors (n=12,389)

Adapted from Bhatt DL, Steg PG, Ohman EM, et al. JAMA. 2006; 295(2):180-189.

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 5/24/2010

CRUSADE: Underutilization of
Hospital Discharge Medications
Discharge Medication Use*
100 93
89
90 84
80
67 67
70
Perrcent

60
50
40
30
20
10
0
ASA Beta-Blockers ACE Lipid- Clopidogrel
Inhibitors Lowering
†

Agents ‡

*In patients without contradictions; †LVEF <40%, CHF, DM, HTN; ‡Known
hyperlipidemia; ↑TC, ↑LDL; Q4 2003 data; CRUSADE Web site. Available at:
http://www.crusadeqi.com. Accessed on April 20, 2004

LDL Cholesterol (LDL-C) Values Over

Time by Group
200
L–C (mg/dL

150

Group 1
100
Group 2

50
LDL

0
Baseline F/U 1 F/U 2
Visit
Mean LDL-C levels at baseline, first follow-up visit (F/U 1),
and second follow-up visit (F/U 2) by group (group 1 at ATP
III goal at F/U1, group 2 not at ATP III goal at F/U 1).

Frolkis JP, Pearce GL, Sprecher DL, et al. Am J Cardiol. 2004;94:1310–1312

L-TAP: Majority of Patients With CHD

Do Not Reach NCEP LDL-C Targets

25 n = 1,460

20 18
Patiients, %

16.6
14.4
15 13
11.2
9.9 9.4
10 79
7.9

0
≤100 101-110 111-120 121-130 131-140 141-150 151-160 >160

LDL-C (mg/dL) on-treatment

Adapted from Pearson TA, et al. Arch Intern Med. 2000;160:459-467.

Other L-TAP data courtesy of TA Pearson.

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 5/24/2010

Conclusions

• CHD is prevalent, costly, and lethal

• Unacceptably high numbers of Americans have
modifiable risk factors for CHD
• The epidemics of obesity and DM will continue to fuel
CHD p prevalence, as will the aging
g g of the ppopulation
p
• We are far from reaching treatment targets for these risk
factors, especially in the secondary prevention setting
• The elderly appear to be at particularly high risk of
under-treatment
• Primary care physicians must partner with their patients
to improve our adherence to evidence-based guidelines

Thank you for participating in this activity.

33