ACS Slide Presentation

5/24/2010

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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, MPHChief of CardiologyChief of Cardiology

VA Boston Healthcare SystemDirector, Integrated Interventional

Cardiovascular ProgramBrigham 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, FAHAFACP, FAHA

Director of Primary Care Associate Chief of General Medicine for Primary Care

Brigham and Women's Hospital Boston, MA

Former Director of Clinical OperationsPreventive Cardiology Program

Cleveland ClinicCleveland, 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 patientsterm care of ACS 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

a. MD/DOb. PhD

Please indicate your primary degree (select only one)

c. PAd. RNe. NPf. PharmD/ RPhg. Other

a. Internal Medicineb. Family Practice

Polling Question

Please indicate your primary specialty(select only one)

c. General Practiced. Cardiologye. Pharmacologyf. Other

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a. 1-5

Polling Question

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

b. 6-10c. 11-15d. 16-20e. 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. 1-5b. 6-10c. 11-15d. 16-20e. 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

StrokeTransient ischemic attack (TIA)Intracranial stenosisCarotid artery stenosis

R l t t i

Acute coronary syndromes– STEMI– NSTEMI– Unstable anginaStable CADAtrial Fibrillation Renal artery stenosis

Peripheral arterial diseaseAcute limb ischemiaClaudicationAbnormal ankle brachial index (ABI)

Atrial Fibrillation

Abdominal aortic aneurysm (AAA)

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

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 which group has the highest

Case Scenario Question

Among the following patient groups, which group has the highest incidence of MI in the age range of 65-74 years? (select only one)

a. White menb. Black menc. White womend. Black womene. There is no significant difference in MI incidence between these

groupsf. I don’t know

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6.1

9.2

3 5

6.2

10.3

2 4

5.1

4.3

7.2

6

8

10

12

00 P

erso

n Ye

ars

Incidence of Myocardial Infarction By Age, Race and Sex

(ARIC Surveillance: 1987-2004). Source: NHLBI. www.americanheartorg.org . Accessed March 1, 2009 MI diagnosed by expert committee based on review of hospital records.

0.9

3.0

1.2

3.5

0.31.0

2.4

0.71.8

0

2

4

35-44 45-54 55-64 65-74

Per 1

,00

White Men Black Men White Women Black WomenAges in Years

Atherothrombosis* Is theLeading Cause of Death Worldwide1

12 6

9.7

9

6.3

Cancer

Injuries

Pulmonary disease

AIDS

*Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.1The World Health Report 2001, Geneva: WHO; Available at: www.theheart.org.

22.3

19.3

12.6

0 5 10 15 20 25 30

Atherothrombosis*

Infectious disease

Cancer

Causes of Mortality, %

Mortality in Acute Coronary Syndromes

16

12

8orta

lity,

% STEMI

NSTEMI

UA

GRACE N=43,810

4

0 0 30 60 90 120 150 180

Mo

Daysd/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.

UA

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Mortality in Acute Coronary Syndromes

16

12

8

rtal

ity. %

STEMI

NSTEMI

UA

Mortality fromd/c to 6 mo.

STEMI – 3.6%NSTEMI – 6.2%

GRACE N=43,810

4

00 30 60 90 120 150 180

Mor

Daysd/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.

UA – 4.8%

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• New transient mitral regurgitation, hypotension, g g 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

• At 30-days follow-up:– 5.5% T-wave inversion– 9.4% ST-segment

• At 6-months follow-up:– 8.1% T-wave inversion– 12.3% ST-segment

Presenting ECG can predict death or MI

gelevation

– 10.5% ST-segment depression

gelevation

– 15.4% ST-segment depression

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

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)


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 eventb. 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 troponinlevels do not correlate to higher mortality risk

d. Cardiac troponin I level does not predict risk of mortalitye. I don’t know

Cardiac Troponin Predicts the Risk of Mortality in UA/NSTEMI

3.43.7

6.0

7.5

4

6

8

at 4

2 D

ays,

%

1.0

1.7

0

2

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

831 174 148 134 6750

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.

Mor

talit

y

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TIMI Risk Score

• Age ≥ 65• Three or more CAD Risk Factors

• History of anginaH i• Hypertension

• 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/NSTEMIHISTORICAL RISK OF CARDIAC EVENTS

(%) BY 14 DAYS IN TIMI 11BAge ≥ 65≥ 3 CAD risk factors(FHx, HTN, ↑chol, DM, active smoker)

Known CAD (stenosis ≥ 50%)ASA use in past 7 days

RISKSCORE

DEATHOR MI

DEATH, MI ORURGENT REVASC

0/1 3 5 ASA use in past 7 daysPRESENTATIONRecent (≤ 24h) severe angina↑ cardiac markersST deviation ≥ 0.5 mm

RISK SCORE = Total Points (0 - 7)

2 3 83 5 134 7 205 12 26

6/7 19 41*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 • 35-75% of unstable angina and NSTEMIg• 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: 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 following is generally true for this patient with regard to long-


g g y p g gterm survival? (select only one)

a. Conservative therapy would likely improve long-term survivalb. Early invasive therapy would likely improve long-term survivalc. Both conservative therapy and early invasive therapy have similar

rates of long-term survivald. Long-term survival cannot be predicted based on either

management strategye. I don’t know

Routine vs Selective InvasiveStrategies in ACS

To Cath or Not to Cath

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

That Is No Longer the Question

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 deathmanagement 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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16

20

nts,

%

19.4%

15.9%

TACTICS: Primary EndpointDeath, MI, Rehospitalization for ACS at 6 Months

0 1 2 3 4 5 6Time in Months

0

4

8

12

Patie

n

CONSINV

OR 0.7895% CI (0.62, 0.97)

P=0.025

Reproduced with permission from Cannon CP, et al. N Engl J Med. 2001;344(25):1879-1887.

Favors Invasive Favors ConservativeOdds Ratio (OR) Death or MITrial

TIMI 3BVANQWISHMATE

Invasive Management of UA/NSTEMI Meta-analysis: ↓ Death/MI at 17 mo. F/U

11.6% 13.8%32.9% 30.3%14.4% 12.2%

Inv Cons

0.1 0. 5 1.0 2.0 10

OR 0.82, P<0.001

FRISC IITACTICS

RITA 3

TOTAL

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

10.4% 14.1%7.3% 9.5%

10.6% 12.9%VINO 6.3% 22.4%

12.2% 14.4%

Mortality Rates by Early Catheterization10

6

88.6Early Catheterization

No Early Catheterization

Mor

talit

y, %

Reproduced with permission from Bhatt DL, et al. JAMA. 2004;292(17):2096-2104.

4

2

0

0.7

2.3

1.1

2.5

3.9

In-H

ospi

tal

Low(n=4326)

Moderate(n=4492)

High(n=9108)

Modified PURSUIT Risk Category

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Deaths, n Follow-upInvasive Conservative Months

45 67 24

3 9 12

37 39 6

FRISC-II

TRUCS

TIMI-18

VINO

Updated Meta-Analysis: Mortality

Study

2 9 6

102 132 60

0 3 1

15 15 12

Reproduced with permission from Bavry AA, Kumbhani DJ, Rassi AN, et al. J Am CollCardiol. 2006;48(7):1319-1325.

RITA-3

ISAR-COOL

ICTUS

0.1 1 10FavorsEarly Invasive

Therapy

FavorsConservative

Therapy

Overall RR (95% CI)0.75 (0.63-0.90)

TIMI IIIB

MATE

VANQWISH

FRISC II

TACTICS-TIMI 18

Death, MI or Rehospitalization with ACSFEMALE MALE

P heterogeneity (gender) = 0.26

n=3075 n=7075

RITA 3

VINO

ICTUS

OVERALL

51.00.2Favors Invasive Favors Conservative

51.00.2Favors Invasive Favors Conservative

OR 0.81 (95% CI 0.65-1.01)

OR 0.73(95% CI 0.55-0.98)

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

NumberNumber OR (95% CI)OR (95% CI)

CKCK--MB or MB or TroponinTroponin ++ 11101110 0.67 (0.500.67 (0.50--0.88) 0.88)

CKCK--MB or MB or TroponinTroponin -- 14861486 0.94 (0.610.94 (0.61--1.44)1.44)

Death, MI or Rehospitalization with ACS

High-Risk Subgroups

FEMALE

NumberNumber OR (95% CI)OR (95% CI)

CKCK--MB or MB or TroponinTroponin ++ 27452745 0.56 (0.460.56 (0.46--0.67)0.67)

CKCK--MB or MB or TroponinTroponin -- 22942294 0.72 (0.510.72 (0.51--1.01)1.01)

5.01.00.2

MALE

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.

Favors Invasive

Favors Conservative

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ACC/AHA Guidelines 2007Early Invasive Strategies

High-risk patients with :- Refractory ischemia (’07)- Recurrent angina/ischemia- Elevated cardiac biomarkers (T)- New ST-segment depression

II IIaIIa IIbIIb IIIIII

- 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 NSTEMI2 of 3: Age >60, ECG changes or +biomarker

and suitable for revascularization

UA or NSTEMI2 of 3: Age >60, ECG changes or +biomarker

and suitable for revascularization

Aspirin, clopidogrel, GP IIb/IIIa per practice

Early InvasiveAngio ASAP

No later than 24h

Early InvasiveAngio ASAP

No later than 24h

Delayed InvasiveAngio any time

>36h

Delayed InvasiveAngio any time

>36h

RANDOMIZE

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 OutcomesEarlyN=1593

DelayedN=1438

HR 95% CI P

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

9.5 12.9 0.72 0.58-0.89 0.003

Death MI Stroke 16 6 19 5 0 84 0 71 0 99 0 04Death, MI, Stroke, refractory ischemia + repeat intervention

16.6 19.5 0.84 0.71-0.99 0.04

Death 4.8 5.9 0.81 0.60-1.11 0.19MI 4.8 5.7 0.83 0.61-1.14 0.25Stroke 1.3 1.4 0.90 0.48-1.68 0.74Ref. Ischemia 1.0 3.3 0.30 0.17-0.53 <0.001Rep. 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

21.0

13.915

20

25

roke

at 6

mo

HR= 0.65(0.48-0.88)P= 0.006

HR= 1.12

6.7 7.6

0

5

10

15Delayed

Early

Dea

th, M

I or S

tr (0.81-1.56)P=0.48

Low/Inter RiskScore <140N=2070

High RiskScore >140N=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

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.

• Other correlates: Prior MI, PAD, ulcerated lesion

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

• Presented with MI: 2.1%

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DES vs BMS – No Mortality DifferenceFrequency (%) DES BMS

- - - - - -- - - - - -6.1 6.66.7 5.35 4 5 2

Relative Risk (95% CI)All-cause mortality

Stettlers, 4 years PESSES

Stone, 4 years PESSESDES

DES, drug eluding stent; BMS, bare metal stent. Reproduced with permission from Bavry AA, Bhatt DL. Lancet 2008;371:2134–2143.

5.4 5.25.9 6.06.7 5.44.1 3.22.1 1.62.6 2.64.6 3.9

DESKastrati, 5 years SESSpaulding, 4 years SESHolmes, 3 years SESSchampaert, 2 years SESNordmann, 3 years PES4 years SES

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 how long would you


Assuming no bleeding complications, how long would you continue dual antiplatelet therapy in this patient after she is discharged? (select only one)

a. 1 monthb. 3 monthsc. 6 monthsd. 9 monthse. 12 monthsf. Indefinitely

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

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No

Yes ConsiderCABG

No

Yes ConsiderBMS

Is there an increased risk for both stentthrombosis and restenosis?

Example: Diabetics with diffuse multivesseldisease, bifurcation lesions

Is there a low risk for restenosis?

Example: Non-diabetics, focal lesions,large vessels

Are there relative contraindications to DES?

Drug-Eluting Stents

Yes ConsiderBMS

No

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

Example: ● Medical non-compliance● ACS, especially STEMI● Chronic anti-coagulation● Anticipated surgery● High risk for bleeding

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

Conclusions

• NSTEMI-ACS remains prevalent and has high event rates

• ST deviation or positive troponin defines very high riskvery 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?long-term care of patients with ACS?

(select only one)a. 100% confidentb. 75% confidentc. 50% confidentd. 25% confidente. 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?long-term care of patients with ACS?

(select only one)a. 100% of the timeb. 75% of the timec. 50% of the timed. 25% of the timee. 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)patients with ACS? (select only one)a. 100% confidentb. 75% confidentc. 50% confidentd. 25% confidente. 0% confident

Long-Term Management and Secondary Prevention

The Critical Role of the Primary Care PhysicianJoseph P. Frolkis MD, PhD, FACP, FAHA

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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 through diet is reasonable since LDL-C is g g100mg/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 RxAspirin 75 - 162 mg/day (162 - 325 mg/d after stents)Clopidogrel 75 mg/day with aspirin

Beta BlockerConsider chronic therapy for all MI, ACS, or left ventricular d f ti ti tdysfunction patients

ACEI / ARBStart and continue especially if diabetic, HF, EF < 40%, HTN

StatinGive 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 orBlood 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

ASA 162 to 325 mg/d for at least 3 to 6 months, then 75 to

New

Medical Therapy without Stent

Bare Metal Stent Group

Drug Eluting Stent Group

ASA 162 to 325 mg/d for at least 1 month, then 75 to 162 mg/d

ASA 75 to 162 mg/d indefinitely (Class I LOE: A)

UA/NSTEMI Patient Groups

at Discharge

Add: Warfarin (INR 2.0 to 2.5) (Class IIb, LOE: B)

Continue with dual antiplatelet therapy as above

least 3 to 6 months, then 75 to 162 mg/d indefinitely

(Class I, LOE: A)

&

Clopidogrel 75 mg/d for at least 1 year (Class I, LOE: B)

INR = international normalized ratio; LOE = level of evidence.Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157

, gindefinitely (Class I, LOE: A)

&

Clopidogrel 75 mg/d for at least 1 month and up to 1 year

(Class I, LOE:B)

Yes No

(Class I, LOE: A)

&

Clopidogrel 75 mg/d at least 1 month (Class I, LOE: A) and up

to 1 year (Class I, LOE: B)

Indication for Anticoagulation?


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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 cardiovascularb. 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 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 +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

Clopidogrel

Placebo + Aspirin(n=6303)

20%Relative RiskReduction

0.120.14

0.100.08H

azar

d R

ate

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.

Clopidogrel+ Aspirin(n=6259)

P <0.001

3 6 90 12

0.06

0.00

0.040.02

Cum

ulat

ive

H

5/24/2010

21

0.10

0.15

Haz

ard

Rat

e 31%RelativeRisk Reduction

Placebo + Aspirin(n=1345)Median time

to PCI12.6%

8.8%

PCI-CURE Study: CV Death or MIFrom Randomization

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

0.00

0.05

010 100 300 400200

Cum

ulat

ive

H

Clopidogrel + Aspirin(n=1313)

Days of Follow-up

P=0.002

15

HR 0.81

Endp

oint

, %

TRITON – TIMI 38: CV Death, MI, Stroke

10

Prasugrel

Clopidogrel12.1%(781)

9.9% (643)

(0.73-0.90)P<0.001

Days of Follow-up

Prim

ary

E

NNT= 46

LTFU = 14 (0.1%)

NNT, number needed to treat; ITT, intent to treat; LTFU, lost to follow-upReproduced with permission from Wiviott SD, et al. N Engl J Med. 007;357(2):2001-2015.

0

5

0 30 60 90 180 270 360 450

HR 0.80P=0.0003

HR 0.77P=0.0001

ITT= 13,608

1.8

2.4

1 42

4

Bleeding Events - Safety Cohort

vent

s

ClopidogrelPrasugrel

Intracranial Bleed in Pts with Prior Stroke/TIA (N=518)

Clop 0 (0) % Pras 6 (2.3)%(P=0.02)

(N=13,457)

0.9 0.9

0.1 0.3

1.41.1

0.4 0.30

TIMI Major Bleeds

Life Threatening

Nonfatal Fatal ICH

% E

ARD 0.6%HR 1.32P=0.03NNH=167

ARD 0.5%HR 1.52P=0.01

ARD 0.2%P=0.23

ARD 0%P=0.74

ARD 0.3%P=0.002

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

5/24/2010

22

Beta Blockers

Beta blockers are indicated for all patients 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

I IIa IIb III

continued indefinitely.

Patients recovering from UA/NSTEMI with moderate or severe LV failure should receive beta-blocker therapy with a gradual titration scheme.

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

I IIa IIb III

Beta Blockers

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

I IIa IIb III

contraindications.

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

Inhibition of the Renin-Angiotensin-Aldosterone System

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

I IIa IIb III

5/24/2010

23

ACE inhibitors are reasonable for patients recovering from UA/NSTEMI in the absence of LV dysfunction, hypertension, or diabetes mellitus unless contraindicated.

ACE inhibitors are reasonable for patients

Inhibition of the Renin-Angiotensin-Aldosterone System

I IIa IIb III

I IIa IIb III

with HF and LVEF > 0.40.

In UA/NSTEMI patients who do not tolerate 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.

I IIa IIb III

Lipid Management

Lipid management should include assessment of a fasting lipid profile for all patients, within 24 h of hospitalization.

Hydroxymethyl glutaryl-coenzyme A reductaseinhibitors (statins) in the absence ofI IIa IIb III

I IIa IIb III

inhibitors (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.

For hospitalized patients, lipid-lowering medications should be initiated before discharge.


I IIa IIb III

Lipid Management

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.Further titration to less than 70 mg/dL is reasonable. (Class IIa, Level of Evidence: A)

New Lower LDL-C Goal

I IIa IIb III

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

If baseline LDL cholesterol is 70 to 100 mg/dL, it is reasonable to treat LDL-C to < 70 mg/dL.


I IIa IIb III

I IIa IIb III

5/24/2010

24

Prescribed Statins at Discharge• NO• 40% of 278 patients

said they were taking

• YES• 77% of 65 patients

said they were taking

In-Hospital Initiation of Lipid Therapy Improves Long-Term Compliance

y gstatins at long-term follow-up

said they were taking statins at long-term follow-up

Nearly twice as many patients were taking statinsat 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.

3

4

5

of D

eath

, %

No Statin(n=14,071)

Statin

Early Initiation of Statin Treatment is Associated With Reduced 1-Year Mortality in Acute MI:

Registry Data from 58 Swedish Hospitals (1995-1998)

0

1

2

Prob

abili

ty o

Postadmission Days0 400

P=0.001

Statin(n=5528)

300100 200

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

Blood Pressure Control

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).

I IIa IIb III

*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.

5/24/2010

25

24 4

38.8

53.265.4 64.6

38.4

54.1

70.877.3

405060708090

of P

opul

atio

n

Prevalence of High Blood Pressure in Adults Age 20 and Older, By Age and Sex

NHANES: (2003-2006).

12.2

24.4

6.616.2

0102030

20-34 35-44 45-54 55-64 65-74 75+Perc

ent o

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

Hypertention (HTN) Prevalence – 50 million people in the United States

For persons over age 50, systolic blood pressure (SBP) is a more important than diastolic blood pressure (DBP) as CVD i k f t

Available at http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf Accessed on April 16, 2010

CVD risk factor.

Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range.

Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN.

53.4

78.365.6

46.8

81.5 75.6

44.65060708090

Popu

latio

n er

tens

ion

(NHANES: 2003-2006).

Extent of Awareness, Treatment, and Control of High Blood Pressure by Age

36.129.2

44.6

010203040

Awareness Treatment Controlled

Perc

ent o

f PW

ith H

ype

20-39 40-59 60+

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

5/24/2010

26

Smoking Cessation

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

d ti t i t t i d t ki

I IIa IIb III

adopting a stepwise strategy aimed at smoking cessation (the 5 As are: Ask, Advise, Assess, Assist, and Arrange).

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

23.119.8

24.8

15.818.0 15.9

36.7 36.0

152025303540

Popu

latio

n

Prevalence of Current Smoking for Adults Age 18 and Older by Race/Ethnicity and Sex

(NHIS:2007)

8.34.0

05

1015

Men WomenPerc

ent o

f P

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 smokingRi k f d i f ll i MI 40% t• Risk of dying following an MI was 40% greater 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.

5/24/2010

27

Weight Management

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 f d 35 i h f i

I IIa IIb III

inches for men and < 35 inches for women is recommended.


15.7 16.8 17.120.6

26.0

33.1 35.2

20

30

40

f Pop

ulat

ion

Age-adjusted Prevalence Of Obesity In Adults Ages 20-74 By Sex And SurveyNHES, 1960-62; NHANES, 1971-74, 1976-80, 1988-94 and 2003-2006

Note: Obesity is defined as a BMI of 30.0 kg/m2 or higher.

10.7 12.2 12.8

0

10

Men Women

Perc

ent o

1960-62 1971-75 1976-80 1988-94 2003-06

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

Diabetes Mellitus

Diabetes management should include lifestyle andpharmacotherapy measures to achieve a near-normalHbA1c level of < 7%.

Diabetes management should also include thefollowing:

I IIa IIb III

I IIa IIb III following:• Vigorous modification of other risk factors (e.g.,

physical activity, weight management, BP control, and cholesterol management) as recommended should be initiated and maintained.

• It is useful to coordinate the patient’s diabetic care with the patient’s primary care physician or endocrinologist.

I IIa IIb III

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

5/24/2010

28

Parallel Epidemics of Diabetes and Obesity

Diabetes

2004 1994

ObesityObesity(BMI ≥30 kg/m2)

<4% 4%–4.9% 5%–5.9% >6%

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

6060

80

100

Obese

(BMI ≥30)

National Health Interview Survey, 2003; N ≈ 31,000, aged 18 to 79 years

90%

abet

ics

30

60

0

20

40

60

BMI ≥25 kg/m2

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

(BMI ≥30)

Overweight

(BMI 25 to <30)

Perc

ent o

f Dia

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% mortality rate with impaired fasting6.6% 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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29

Benefits of Aggressive LDL-C Lowering in Diabetes

Difference in LDL-C

(mg/dL)

Aggressive lipid-lowering

better

Aggressive lipid-loweringworse

0.026

0 036

Primary event rate (%)

17.9

11.9

Control

13.8

9.2

Treatment P

TNTDiabetes, CHD

ASCOT-LLADiabetes HTN

0.7722*

35†

0.75

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.

0.036

0.001

<0.0001

0.0003

9.0

12.6

13.5

5.8

9.4

9.3

0.63

0.67

0.73

Diabetes, HTN

CARDSDiabetes, no CVD

HPSAll diabetesDiabetes, no CVD

*Atorvastatin 10 vs 80 mg/day†Statin vs placebo Relative risk

0.7 0.9 10.5 1.7

35

46†

39†

39†

Physical Activity

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 per day, preferably 7 (but at least 5) days per New

I IIa IIb III

p y, p y ( ) y pweek 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).

New


50.6

40.3 42.0 43.146.0

31.4 36.341.2

52.345.3 41.9 45.749.6

36.140.5

46.6

30

40

50

60

Popu

latio

n

Prevalence of Regular Leisure-Time Physical Activity Among Adults Age 18 and Older by Race/Ethnicity, and Sex

0

10

20

NH White NH Black Hispanic Other racePerc

ent o

f P

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

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

5/24/2010

30

Exercise

• Reduces weight, blood pressure, and triglycerides – and raises HDL

• Prevents diabetes and stroke• Normalizes endothelial functionNormalizes 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

Young Endurance-Trained

Older Endurance-Trained

121416

2018

121416

2018

L tis

sue/

min

)

Young SedentaryOlder Sedentary

FBF responses to acetylcholine in sedentary and endurance-trained men

02468

1012

02468

1012

FBF

(mL/

100

mL

Reproduced with permission from DeSouza CA, Shapiro LF, Clevenger CM, et al. Circulation. 2000;102(12):1351-7.

Acetylcholine (ug/100 mL tissue/min) Acetylcholine (ug/100 mL tissue/min)Baseline

FBF, forearm blood flow; Values are mean + SEM.

1.0 2.0 4.0 8.0 16.0 Baseline 1.0 2.0 4.0 8.0 16.0

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)

0.300.350.400.45

0.300.350.400.45

AgeBA Baseline Risk LowMedianHigh

Baseline RiskYoungerMedianOlder

Age

tinPr

escr

iptio

n

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

Baseline Risk Age, Y

00.050.100.150.200.25

00.050.100.150.200.25

65 70 80 90 9575 850 0.1 0.3 0.5 0.7 0.9 1.000.2 0.4 0.6 0.8Prob

abili

ty o

f Sta

t

5/24/2010

31

40

60

80

100Male (N=83,806)Female (N=54,195)

P<0.0001 P<0.0001P<0 0001

Utilization of Lipid-Lowering Medications at Discharge in Patients with AMI

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

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

Age in Years

0

20

40 P<0.0001P=NS

P=NS

Adjusted Survival Rates at 4 Years for Each Age Group

Age y Medical PCI CABG PCI CABG PCI CABG

Adjusted Survival, %ARR,%

(Vs. Medical Therapy) NNT

Survival After Coronary Revascularization in the Elderly

Age, y 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.

4639

30

443640

50

60

Rec

eivi

ng

erap

y, %

Antiplatelets Lipid-lowering Statin

Established Therapies are Consistently Underused in All Patient Types

Patients not receiving therapy(% of subpopulation)

1418 1819

30

1924

28

0

10

20

30

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

Patie

nts

Not

Pr

oven

The

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

5/24/2010

32

Discharge Medication Use*

CRUSADE: Underutilization ofHospital Discharge Medications

93 89

67

84

67

5060708090

100

rcen

t

*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

‡

†

01020304050

ASA Beta-Blockers ACEInhibitors

Lipid-LoweringAgents

Clopidogrel

Per

LDL Cholesterol (LDL-C) Values Over Time by Group

50

100

150

200

Group 1Group 2

L–C

(m

g/dL

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

0

50

Baseline F/U 1 F/U 2

LDL

Visit

18

9.913

14.411.2

9.47 9

16.6

10

15

20

25

ient

s, %

n = 1,460

L-TAP: Majority of Patients With CHD Do Not Reach NCEP LDL-C Targets

7.9

0

5

10

Pati

≤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.

5/24/2010

33

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 prevalence, as will the aging of the populationp g g p 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.

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