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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

• The relevant financial relationships reported by they or their spouse/partner have with commercial interests are located on page 5 of your syllabus

faculty

that • The relevant financial relationships reported by the

steering committee

syllabus that they or their spouse/partner have with commercial interests are provided on page 5 of your • The relevant financial relationships reported by the

non faculty content contributors

and/or reviewers that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus

Off-label Discussion Disclosure

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Learning Objectives

• Identify high-risk ACS patients (high-risk NSTEMI, STEMI) and promptly initiate suitable risk stratification and patient management strategies • Adopt and adhere to guidelines-based treatment strategies for use of appropriate antiplatelet options to reduce the risk of recurrent events • Identify inefficiencies in discharge planning and patient education on the necessity of drug adherence to improve quality of care and long-term outcomes of high-risk ACS patients

Pre-activity Survey

• Please take out the Pre-activity Survey from your packet • Your answers are important to us and will be used to help shape future CME activities • It is important that you fill out the information at the top of the form: – Please select the best answer(s) for the questions below: – Degree: _ MD/DO _ Nursing Professional _ PharmD _Other:_____________________________ – Specialty: _ Cardiologist _ Emergency Room Physician _ Internal Medicine _Other:______________________

Pre-activity Survey Question 1

How confident are you in your ability to adopt evidence based care for high-risk NSTEMI patients to reduce the need for rehospitalization?

1 Not at all confident 2 3 4 5 Expert

Pre-activity Survey Question 2

How confident are you in your ability to adopt evidence based care for STEMI patients to reduce the need for rehospitalization?

1 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 NSTE ACS is made largely on the basis of: A.

Risk of ischemic complications B.

Whether symptoms are typical or atypical C.

Whether the ECG is interpretable Whether the patient can take a stress exercise test 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 Greater risk of major cardiovascular events and greater risk of major bleeding events Similar risk of major cardiovascular events and greater risk of major bleeding events 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 12 hours 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% 40%-50% More than 50%

HIGH-RISK ACS Overview

ACS Classification and Hospitalizations

Acute Coronary Syndromes TIMI flow grade 2/3 in culprit artery TIMI flow grade 0/1 in culprit artery - Troponin + Troponin + Troponin Unstable angina NSTEMI STEMI 0.81 million admissions per year 0.33 million admissions per year Shared pathophysiology; Shared core treatment targets

Gibson CM et al. Presented at: 2008 AHA Scientific Sessions. New Orleans, LA.

Go AS et al. Heart Disease and Stroke Statistics – 2013 update. Circulation. 2013;1127:e6-e245

Acute Coronary Syndromes

•

Common Features of ACS

–

Similar pathophysiology

–

Similar presentation and early management rules

•

Differentiating Features of ACS

– –      

Unstable Angina 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.

Mortality in Acute Coronary Syndromes

Death from Hospital Admission to 6 Months

16 12 8 STEMI NSTEMI UA 4 0 0 30 60 90 120 150 180

Days Fox KAA et al. BMJ. 2006;333:1091.

GRACE n=43,810

“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-mak ing

Risk Scores

TIMI Age Hypertension Diabetes Smoking ↑ Cholesterol Family history History of CAD Severe angina Aspirin within 7 days Elevated markers ST-segment deviation GRACE 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 Recurrent angina/ischemia Elevated cardiac biomarkers (T) New ST-segment depression New CHF or worsening MR High-risk on non-invasive testing LV dysfunction (EF <40%) Hemodynamic instability Sustained VT Diabetics with single-vessel disease Mild to moderate kidney disease PCI within 6 months, prior CABG high-risk score Not in low-risk women Wright RS et al. Circulation. 2011;123:2022-2060.

TACTICS: Primary Endpoint

Death, MI, Rehospitalized for ACS at 6 Months

20 16 19.4% 15.9% 12 8 O.R. 0.78

95% CI (0.62, 0.97) P=0.025

4 0 0 1

Cannon CP et al. N Engl J Med. 2001;344:1879-1887.

2 3 4

Time (months)

Conservative : Invasive: 5 6

ANTIPLATELET THERAPY IN ACS

Platelet Aggregation and Mechanisms of Action of Antiplatelet Therapies

clopidogrel prasugrel ticagrelor ADP ADP Glycoprotein IIb/IIIa inhibitors abciximab eptifibatide tirofiban Gp IIb/IIIa (Aggregation) aspirin COX TXA 2 ADP cAMP Activation ADP = adenosine diphosphate; TXA 2 = thromboxane A 2 ; COX = cyclooxygenase Adapted from Schafer AI. Am J Med. 1996;101:199-209.

Collagen Thrombin TXA 2 Heparins

CURE Study

Primary End Point: MI/Stroke/CV Death

0.14

0.12

0.10

0.08

0.06

0.04

0.02

0.00

0 Placebo + Aspirin (n=6303)

Yusuf S et al. N Engl J Med. 2001;345:494-502.

Clopidogrel + Aspirin (n=6259) 3 6 9

Months of Follow-up

12 20% Relative Risk Reduction P<0.001

n=12,562

ADP P2Y

Receptor Blockers

Class Reversibility Activation Onset of Effect^ Duration of Effect Withdrawal before major surgery Clopidogrel

Thienopyridine

Prasugrel

Thienopyridine Irreversible Irreversible Prodrug, limited by metabolism Prodrug, not limited by metabolism

Ticagrelor

Triazolopyrimidine Reversible Active drug 2-4 hours 30 minutes 30 minutes 3-10 days 5 days 5-10 days 7 days 3-4 days 5 days ^ 50% inhibition of platelet aggregation

Hamm CW et al. Eur Heart J. 2011;32:2999-3054

Metabolism of Novel P2Y

Receptor Blockers

P-Glycoprotein Prasugrel Ticagrelor Intestinal Absorption Intestinal Esterases 85% Intestinal Absorption Hepatic CYP3A4 30% 1 Step Intestinal/hepatic CYP-Conversion 55% 3A4 2B6 2C9 2C19 Efficient active metabolite generation Rapid Consistent /Greater IPA Rapid Consistent /Greater IPA

IPA = individual platelet adhesion assay

Gurbel PA et al. Expert Opin Pharmacother. 2010;11:2251-2259

CURRENT: Clopidogrel Double vs Standard Dose

Primary Outcome: PCI Patients

0.04

CV Death, MI or Stroke

Clopidogrel Standard 15% RRR 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

100 80 60

IPA (%; 20 mM ADP) N=201 P<0.0001 for each

64,5 74,8

Prasugrel 60 mg

69,3 40 20 30,8 4,9 20,3 31,8

Clopidogrel 600 mg

32,6 100

IPA (%; 20 mM ADP) P<0.0001

61,9

45,4

40 20 0 0 4 8 12 16

Hours Wiviott SD et al. Circulation. 2007;116:2923-2932.

20 24 28 0

Clopidogrel 150 mg Prasugrel 10 mg 14 Days

TRITON-TIMI 38 Efficacy and Safety

Prasugrel vs Clopidogrel

16 14 12 10 8

CV Death/MI/Stroke Clopidogrel Prasugrel 138 events 12.1

9.9

HR 0.81

(0.73-0.90) P < 0.001

NNT = 46

6 4

TIMI Major Non-CABG Bleeds Prasugrel

Clopidogrel

0 0 30 60 90 180 270

Days After Randomization

360 450

2.4

1.8

HR 1.32

(1.03-1.68) P = 0.03

NNH = 167 35 events CABG = coronary-artery bypass surgery; NNH = number needed to harm; NNT = number needed to treat; TIMI = Thrombolysis in Myocardial Infarction.

All Cause Mortality: Clopidogrel 3.2%, Prasugrel 3.0%, P = 0.64.

Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

Clopidogrel vs. Ticagrelor

ONSET/OFFSET Study

100 80 60 * 40 * * 20 0

0 .5

* Loading Ticagrelor 180mg * Clopidogrel 600 mg

8 12

Hours

16 20 24

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

Gurbel PA et al. Circulation. 2009;120:2577-2585.

PLATO:

Kaplan-Meier Estimate of Time to First Primary Efficacy Event (Composite of CV Death, MI, or Stroke)

1 0 4 3 2 13 12 11 10 9 8 7 6 5

Clopidogrel

HR = hazard ratio CI = confidence interval

Ticagrelor HR 0.84 (95% CI 0.77–0.92), P=0.0003

No. at risk

Ticagrelor Clopidogrel 9,333 9,291

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

60 120 180 240 8,628 8,521

Days after randomisation

8,460 8,362 8,219 8,124 6,743 6,743 300 5,161 5,096 360

11.7

9.8

4,147 4,047

Time to Major Bleeding:

Primary Safety Event

15 10

Ticagrelor Clopidogrel 11.58

11.20

5 0 0 60

HR 1.04 (95% CI 0.95–1.13), P=0.434

120 180 240 300 360 No. at risk Ticagrelor Clopidogrel 9,235 9,186 7,246 7,305

Days from first IP dose

6,826 6,930 6,545 6,670 5,129 5,209 3,783 3,841 3,433 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)

≥300 >100 – <300 ≤100 ≥300 >100 – <300 ≤100

Ticagrelor N / Events

324 / 40 22 / 2 284 / 19 140 / 28 503 / 62 7449 / 546

Clopidogrel N / Events

352 / 27 16 / 2 263 / 24 140 / 23 511 / 63 7443 / 699

Hazard Ratio

1.62

0.73

1.23

1.00

0.78

95% CI

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

Curfman GD, et al. N Engl J Med. 2007;356:1059-1060 Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

CHARISMA Prior MI Cohort

Management of STEMI

A Focus On Antiplatelet Therapy

Time and Myocardial Salvage

An Essential Fact Regardless of Mode of Reperfusion

100 80

D C Potential outcomes A – A – B – E – B — no benefit C — benefit C — benefit D — harm

40 20

B A

0 1 3 6

Time to treatment is critical Gersh BJ, et al. JAMA. 2005;293:979-986.

Extent of salvage (% of area at risk)

12 24

Hours 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 2 x 2 Randomization SK vs Placebo ASA (162. 5 mg) vs Placebo ISIS-2 Collaborative Group. Lancet 1988;2(8607):349-360

Acute MI

Immediate Angioplasty Versus Thrombolytic Therapy

14 12 10 2 0 8 6 4 6,5

P=0.06

P=0.05

12 2,6 6,5 2,6 Death MI 5,1 Death/MI

P=0.02

2 ICH 0 Lytic PCI

N = 395

The Primary Angioplasty in Myocardial Infarction Study Group Grines CL et al. N Engl J Med. 1993;328:673-679

TRITON TIMI 38: STEMI Cohort

N=3534

15 10 5

CV Death / MI / Stroke Clopidogrel 12.4% 9.5% 6.5% Prasugrel HR 0.68

(0.54-0.87) P=0.002

TIMI Major NonCABG Bleeds Prasugrel 10.0% HR 0.79

(0.65-0.97) P=0.02

NNT = 42 2.4

Clopidogrel 2.1

0 0 30 60 90 180 270 360

Days From Randomization

450

Montalescot g. et al Lancet 2009; 373:723-731

Stent Thrombosis

(ARC Definite + Probable)

Any Stent at Index PCI N = 12,844

2 Clopidogrel 2.4

(142) 1 0 0 30 60 90

Wiviott SD et al N Engl J Med. 2007;357:2001-2015

180

Days

270 Prasugrel 360 1.1 (68) HR 0.48

P <0.0001

NNT= 77 450

PLATO STE-ACS

Primary Composite Endpoint

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

Characteristic Hazard Ratio (95% CI) Overall treatment effect Primary Endpoint Definition of STEMI* Persist. ST-segment elev.

LBBB Final diagnosis (only) Intended clop dose ≤24h post first dose 300 mg 600 mg Time from index event to therapy <12 hours ≥12 hours Total Patients 8,430 6,284 720 886 5,505 2,922 6,072 2,270 KM % at Month 12 Ti .

9.3

8.9

14.5

8.4

10.4

14.5

12.5

10.1

7.9

11.9

9.3

8.3

12.0

Cl.

11.0

9.5

14.2

HR (95% CI) 0.85 (0.74, 0.97) 0.87 (0.74, 1.02) 0.89 (0.59, 1.34) 0.67 (0.44, 1.02) 0.84 (0.71, 0.99) 0.86 (0.67, 1.11) 0.86 (0.73, 1.03) 0.85 (0.67, 1.07)

0.2

0.5

1.0

2.0

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

p-value (Interaction) 0.49

0.90

0.89

PLATO STE-ACS: Stent Thrombosis

Stent thrombosis,* % [Steg 2010:K] Ticagrelor (n=3752) Clopidogrel (n=3792) Definite † 1.6

2.4

Probable or definite definite † † Possible, probable, or 2.6

3.3

3.4

4.3

HR (95% CI) p value 0.03

0.05

0.04

*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 1.0

Clopidogrel better

PLATO STE-ACS

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

Standard Clopidogrel Pathway

Other (Mostly Long Term)

• • •

Cost Coverage Compliance Concerns

STEMI

No DAPT Load Prasugrel or Ticagrelor if Rapidly Available High Bleeding Risk Or Other Concerns No Planned PPCI Yes Standard Clopidogrel Pathway Prior DAPT Load Ticagrelor If Rapidly Available Dx Catheterization

CABG

PCI

Med Rx CABG

Dx Catheterization PCI

Med Rx No DAPT early, clopidogrel/tic agrelor late Prasugrel* Ticagrelor Clopidogrel Ticagrelor

Stop DAPT early, clopidogrel/tic agrelor late Ticagrelor Clopidogrel Ticagrelor * Without Contraindication (STROKE/TIA)

2013 ACC/AHA STEMI Guidelines

Antithrombotic Therapy – Primary PCI

Class of Recommendation Level of Evidence O’Gara et al. J Am Coll Cardiol..2013;61:e78–e140

Guideline Recommendations for Duration of P2Y

Inhibitor Therapy

Society Management Recommended Duration Medical Ideally up to 12 months PCI (DES) At least 12 months ACCP All Medical PCI 12 months

“ 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.

”

12 months 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

P2Y 12 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 ISIS 1. Lancet. 1986;2(8498):57-66 • ACEI Pfeffer et al. N Engl J Med. 1992;327:669-677 • CAB 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 19% risk reduction comparable to ACEI 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/m 2 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%) 14 12 10 8 6 P<0.0001

4 2 P<0.0001

0 0 30 90

No. at Risk

STEMI Diabetes 7156 6508 2947 No diabetes 39421 37136 UA/NSTEMI Diabetes 3457 3313 No diabetes 12002 11658 16685 2923 10505

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

STEMI

Diabetes No Diabetes

UA/STEMI

Diabetes No Diabetes 180

Days after ACS

2653 15274 2339 8191 270 2118 12276 1317 5141 P<0.0001 STEMI P<0.0001 UA/NSTEMI 360 1610 9351 924 4008

Mechanisms Involved in Platelet Dysfunction in Diabetes Mellitus

H 2 O 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 PGI 2 IRS-dependent factors: Increased intracellular Ca++ Degranulation Associated Metabolic Conditions Obesity Dyslipidemia Inflammation Other Cellular Abnormalities Platelet Endothelial Dysfunction Increased platelet turnover Increased intracellular Ca++ Upregulation of P2Y 12 signaling Oxidative stress Increased P-selectin and GP expression Increased production of TF Decreased NO and PGI 2 production

ACP=adenosine disphosphate; GP=glycoprotein; IRS-1=insulin receptor substrate-1; NO=nitric oxide; PGI 2 =prostacyclin; PKC= protein kinase C; TF=tissue factor.

Endothelial Cells 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

20 10 0

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

Antiplatelet Trialists Collaboration BMJ 1994;308:81-106 Diabetes 38 (12) <0.002

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

LTA

100 80

p<0.05

60 40 20 0

DM Non-DM

LTA = Light Transmission Aggregation

Angiolillo DJ et al. Diabetes 2005; 54:2430-2435

100 80 60 40 20 0

PFA-100

p<0.01

DM Non-DM

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

Characteristic

Overall Associated MI No associated MI Male sex Female sex old  65 yr > 65 yr old ST-segment deviation o ST-segment deviation Enzymes elevated at entry Enzymes not elevated at entry Diabetes No diabetes Low risk Intermediate risk High risk History of revascularization No history of revascularization Revascularization after randomization No revascularization after randomization

Percentage of Patients with Event No. of Patients

12562 3283 9279 7726 4836

Clopidogr el + ASA

9.3

11.3

8.6

9.1

9.5

Placebo + ASA

11.4

13.7

10.6

11.9

10.7

6354 6208 6275 6287 3176 9386 2840 9722 4187 4185 4184 2246 10316 4577 7985 5.4

13.3

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

7.6

15.3

Yusf S et al. N Engl J Med. 2001;345:494-502.

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

Relative Risk (95% CI) 1.2

Clopidogrel Better Placebo Better

Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects Acute Phase of Treatment

38% DM 56% No-DM P=0.04

14% 8% 6% 78%

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. 80

Long-term Phase of Treatment

P=0.002

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

5 4 OR=2.0

(0.8-4.9) 3 OR=2.8

(1.7-4.3) HR=3.7

(1.7-7.9) HR=2.03

(1.07-3.83) 2 1 0

IDDM IDDM Diabetes

Kuchulakanti PK et al.

Circulation

2006;113:1108-1113 Urban P et al.

Circulation

2006;113:1434-1441 Iakovou I et al.

JAMA

2005;293:2126-2130

Diabetes

Daemen J et al.

Lancet

2007;116:961-968

Strategies to Enhance P2Y

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 P2Y

(eg, prasugrel, ticagrelor)

inhibitors

Efficacy of New Drugs/Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical Trials

Study

TRITON-TIMI 38 PLATO CURRENT OASIS 7 (PCI Cohort)

% of Events Standard Hazard Ratio (95% confidence interval) New Drug/Approach

17.0

12.2

0.70 (0.58 – 0.85) 16.2

5.6

14.1

4.9

0.88 (0.76 – 1.03) 0.87 (0.66 – 1.15) 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 16 14 12 10 8 6 4 2 CV Death/MI/Stroke 0 0 30 60 90 TIMI Major Non-CABG Bleeds 180

Days

270 Clopidogrel Prasugrel Clopidogrel Prasugrel 360

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

450 17.0

12.2 HR 0.70

P<0.001 NNT = 21 2.6

2.5

TRITON TIMI-38:

CV Death/MI/Stroke by Diabetic Status

No DM 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%

0.3

Prasugrel better

1 2

Clopidogrel better 37% 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

LD MD Washout 300 250 200 150 100 *** *** 50 0 *** Mean ± SE 0 4 Hours post LD 24 *** ***p<0.0001

7 days No study drug (7 days) prasugrel 60 mg LD/10 mg MD clopidogrel 600 mg LD/150 mg MD

Verify Now ® -P2Y 12 % 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

ABCs of Treatment of Diabetic Patients and Impact on Thrombosis

A HbA 1C (blood glucose): <7% B B lood pressure: <130/80 mm Hg C C holesterol-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)

2 therapies 3 therapies 4 therapies 5 therapies 6 therapies 7 therapies 8 therapies OR = odds ratio *Registry of patients with ACS Chew DP et al. Heart. 2010;96:1201-1206.

0 0.5

1 OR OR

(95% CI)

0.80 (0.52-1.26) 0.74 (0.48-1.13) 0.59 (0.39-0.90) 0.51 (0.33-0.78) 0.40 (0.26-0.62) 0.27 (0.16-0.44) 0.31 (0.17-0.57) 1.5

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 NSTE ACS is made largely on the basis of: A.

Risk of ischemic complications B.

Whether symptoms are typical or atypical C.

Whether the ECG is interpretable Whether the patient can take a stress exercise test 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.

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 12 hours 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% 40%-50% 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.