STRIVE TM. STRIVE TM Learning Objectives Apply the current ACC/AHA guidelines for management of STEMI and UA/NSTEMI patients to the development of critical

STRIVETM

STRIVETM

Learning Objectives

Apply the current ACC/AHA guidelines for management of STEMI and UA/NSTEMI patients to the development of critical pathways for ACS

Develop or modify tools for effectively implementing critical pathways for ACS in the hospital

Interpret the findings of recent clinical trials in ACS and assess their applicability to the development of up-to-date critical pathways for ACS

After taking part in this activity, participants should be able to:

STRIVETM

Learning Objectives (cont.)

Outline the results from national quality improvement initiatives showing that critical pathways work to enhance patient outcomes

Work with hospital critical pathways teams to overcome barriers to developing, improving, and implementing critical pathways for ACS

After taking part in this activity, participants should be able to:

STRIVETM

Pathophysiology and Epidemiology of

Acute Coronary Syndromes

STRIVETM

Atherosclerosis

Atherothrombosis:A Progressive Phenomenon

Ischemicstroke/TIA

MI

Acute limbischemia

Cardiovascular death

Unstable angina

Adapted from Libby P. Circulation. 2001;104:365-372.

ACS

Thrombosis

Libby P. Sci Am. 2002;286:46-55.

STRIVETM

ACUTE CORONARY SYNDROMES

No ST elevation ST elevation

Unstableangina

NSTEMI STEMI

Spectrum of CAD/ACS

Stableangina

Source (Photos): Davies MJ. Heart. 2000;83:361-366.

CAD = coronary artery disease; NSTEMI = non-ST-segment elevation myocardial infarction;STEMI = ST-segment elevation myocardial infarction.

STRIVETM

UA/NSTEMI ~1.23 Million

Discharges Per Year~0.33 Million

Discharges Per Year

STEMI

Epidemiology of CAD/ACS

CAD = coronary artery disease; ACS = acute coronary syndrome; UA = unstable angina;MI = myocardial infarction; NSTEMI = non–ST-segment elevation MI; STEMI = ST-segment elevation MI.

American Heart Association. Heart Disease and Stroke Statistics—2006 Update.Circulation. 2006; e85-e151.Estimates for STEMI and NSTEMI proportions of MI extrapolated from statistics inWiviott S, et al. J Am Coll Cardiol. 2006;47;1553-1558.

1.56 Million Hospital Discharges for ACS

STRIVETM

Angiographic and angioscopic images of a 58-year-old man with anterior myocardial infarction

Multiple “vulnerable”

plaques detected in nonculprit

segments 9-12

Culprit lesion withthrombus (red) detected in #8

Multiple “vulnerable”

plaques detected in nonculprit

segments 1-7

Evidence of Multiple “Vulnerable” Plaques in ACS

Reprinted with permission from Asakura M, et al. J Am Coll Cardiol. 2001;37:1284-1288.

STRIVETM

Overlap of Atherosclerotic Disease

Coronary Artery Disease

CerebrovascularDisease

Peripheral ArterialDisease

Patients with 1 manifestation often have coexistent disease in other vascular beds

Ness J, Aronow WS. J Am Geriatr Soc. 1999;47:1255-1256.

38% overlap in 2 vascular beds

STRIVETM

The REACH Registry The REACH (REduction of Atherothrombosis for Continued Health)

Registry has recruited outpatients who have had, or are at high risk of having, symptoms of atherothrombosis

The Registry aims to study a contemporary stable patient population from various regions of the world in order to:

– Describe the characteristics and management of these patients and of each subgroup

– Assess the long-term risk of atherothrombotic events in the global population and in each subgroup

– Assess the amount of “cross-risk” across subgroups

– Compare outcomes within different subject profiles

– Define predictors of risk for subsequent atherothrombotic events

Follow-up planned at 12 and 21 months, extended to 3 and 4 years

Steg PG. Presented at: 55th Annual Scientific Session of the American Collegeof Cardiology; March 12, 2006; Atlanta, Ga.

STRIVETMBhatt DL, et al; for the REACH Registry Investigators. JAMA. 2006;295:180-189.

Baseline Prevalence of Polyvascular Disease in the REACH Registry

Single Arterial Bed %Overall 65.9CAD Alone 44.6CVD Alone 16.6PAD Alone 4.7

Polyvascular DiseaseOverall 15.9CAD + CVD 8.4CAD + PAD 4.7CVD + PAD 1.2CAD + CVD + PAD 1.6

Multiple Risk Factors 18.3

0 10 20 30 40 50 60 70

Patients, %

STRIVETM

REACH 1-Year Results: Single vs Multiple and Overlapping Atherothrombotic Locations:

The Example of CAD

Rates adjusted for age and risk factors.*TIA, unstable angina, other ischemic arterial event including worsening of PAD.

Steg PG. Presented at: 55th Annual Scientific Session of the American Collegeof Cardiology; March 12, 2006; Atlanta, Ga.

%

1.5 1.4 0.9

3.1

13.3

2 1.6

3.7

6.4

20

2.91.4 1.3

4.8

23.3

3.61.8

4

7.4

26.9

0

5

10

15

20

25

30

CV Death Nonfatal MI Nonfatal Stroke Death/MI/Stroke

Death/MI/Stroke/Hosp*

CAD alone

CAD+CVD

CAD+PAD

CAD+CVD+PAD

STRIVETM

ACS Treatment Strategies

PCI (with/ without stenting)

ThrombolysisMedicaltherapy

CABG

Antithrombotic Cotherapy

Acute and Long-term Medical Therapy

ADP antagonist

Nitrates BBs ACEIs CCBs Statins

Reperfusion/Revascularization Therapy

LMWHUFH PentaASAGP IIb/

IIIaDTI

ARBs

PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting; ASA = aspirin; UFH = unfractionated heparin; LMWH = low-molecular-weight heparin; Penta = pentasaccharide; DTI = direct thrombin inhibitors; GP IIb/IIIa = glycoprotein IIb/IIIa inhibitors; ADP antagonist = adenosinediphosphate antagonist; BBs = beta blockers; ACEI = angiotensin converting enzyme inhibitors; ARBs = angiotensin receptor blockers; CCBs = calcium channel blockers; APT = antiplatelet therapy.

APT

STRIVETM

ST-Segment ElevationMyocardial Infarction (STEMI) in

the Emergency Department

STRIVETMAntman EM, et al. J Am Coll Cardiol. 2004;44:671-719.

STEMI: Prehospital Issues EMS

– Early defibrillation– Use of automated external defibrillators (AEDs)– 9-1-1 dispatcher training– National protocols

Chest pain evaluation and treatment– Chewable ASA unless contraindicated– Prehospital ECG– Reperfusion checklist

Prehospital fibrinolysis– Upgraded to Class IIa (Level B) recommendation

STRIVETM

EMS Transport

Onset of symptoms of

STEMI

9-1-1EMS

dispatch

EMS on-scene• Encourage 12-lead ECGs• Consider prehospital fibrinolytic

if capable and EMS-to-needle within 30 min

GOALS

PCIcapable

Not PCIcapable

Hospital fibrinolysis: door-to-needle within 30 min

EMS triage plan

Inter-hospitaltransfer

Golden hr = 1st 60 min Total ischemic time: within 120 min

Patient EMS Prehospital fibrinolysisEMS-to-needlewithin 30 min

EMS transportEMS-to-balloon within 90 min

Patient self-transport Hospital door-to-balloon

within 90 min

Dispatch1 min

5 min

8 min

Options for Transport of Patients With STEMI and Initial Reperfusion Treatment

Adapted with permission from Antman EM, et al. Available at: http://www.acc.org/clinical/guidelines/stemi/index.pdf.Accessed September 1, 2006

STRIVETM

Ambulance arrival

ED arrival Inhospital lytic

Control

Prehosp

63 min (48–89)

31 min (24–37) 32 min saved

Data=Median Times (Q1-Q3)

P<.0001*

First r-PA bolus

ER-TIMI 19: Time Saved to First r-PA Bolus with Prehospital Administration

*Adjusted for any effect of site and interaction.Adapted with permission from Morrow DA, et al. J Am Coll Cardiol. 2002;40:71-77.

STRIVETM

STEMI: Brief Physical Exam in ED Airway, breathing, circulation (ABC) Vital signs, general observation Presence or absence of

– Jugular venous distention– Stroke– Pulses– Systemic hypoperfusion (cool, clammy,

pale/ashen) Pulmonary auscultation for rales Cardiac auscultation for murmurs or gallops

Antman EM, et al. Available at: http://www.acc.org/clinical/guidelines/stemi/index.pdf.Accessed September 1, 2006.

STRIVETM

ACC/AHA 2004 STEMI Guidelines: Acute Medical Therapy

General treatment measures

Antman EM, et al. Available at: http://www.acc.org/clinical/guidelines/stemi/index.pdf.Accessed September 1, 2006.

Analgesics Nitrates Oxygen β-blockers (Note: not for acute use in patients

with evidence of heart failure) Primary PCI or coronary thrombolysis

(primary PCI preferred after 3 hr)

ASA (162–325 mg, acute dose) Heparin If PCI

– Clopidogrel

– GP IIb/IIIa inhibitors

Infarct sizelimitation

Reperfusion

Antithrombotic and antiplatelet therapy

STRIVETM

Primary PCI vs Thrombolysis in STEMI: Quantitative Analysis (23 RCTs, N=7739)

Adapted with permission from Keeley EC, et al. Lancet. 2003;361:13-20.

PCI

Thrombolytic therapy

0

5

10

25

15

20

Fre

qu

ency

(%

)

Short-term outcomes(4-6 wk)

Death

P=.0002

NonfatalMI

P<.0001

RecurrentIschemia

P<.0001

Hemor-rhagicStroke

P<.0001

MajorBleed

P=.032

Death, Nonfatal

Reinfarction,or Stroke

P<.0001

STRIVETM

PCI-related Time Delay (Door-to-Balloon minus Door-to-Needle)

Circle sizes = sample size of individual study

Solid line = weighted meta-regression

For every 10-min delay to PCI: 1% reduction in mortality difference vs lytics.

Nallamothu BK, Bates ER. Am J Cardiol. 2003;92:824-826.

Favors PCI

Favors lysis

P=.006

62 min

Ab

solu

te R

isk

Dif

fere

nce

in

Dea

th (

%)

15

10

5

0

-50 20 40 60 80 100

Mortality With 1° PCI vs Time Delay

STRIVETM

Clinical Trials of Interhospital Transferfor PCI vs Fibrinolysis

Mo

rta

lity

(%)

(N=200) (N=137) (N=850) (N=1129)(N=150)

6.7

1412.1

8.57

8.46.8 6.5

10

6.7

0

5

10

15

20

LIMI1 PRAGUE-12 AIR-PAMI3 PRAGUE-24 DANAMI5

On-site fibrinolysis Transfer for PCI

1. Vermeer F, et al. Heart . 1999;82:426-431.2. Widimsky P, et al. Eur Heart J. 2000;21:823-831.3. Grines CL, et al. J Am Coll Cardiol. 2002;39:1713-1719. 4. Widimsky P, et al. Eur Heart J. 2003;24:94-104. 5. Andersen HR, et al. N Engl J Med. 2003;349:733-742.

STRIVETMNallamothu BK, et al. Circulation. 2005;111:761-767.

STEMI: Transfer for PCI NRMI (1999-2002) 4278 Patients

28.4>4 h

55.42–4 h

16.2<2 h

4.2<90 min

% of PatientsDoor-to-Balloon Time

STRIVETM

Facilitated PCI, Rescue PCI, and Adjunctive

Therapy for STEMI

STRIVETM

Facilitated PCI and Rescue PCI:Definition of Terms

Facilitated PCI– Fibrinolytics or other pharmacologic agents

to “facilitate” immediate percutaneous coronary intervention

Rescue PCI– Percutaneous coronary intervention for

failed fibrinolysis

Dauerman HL, Sobel BE. J Am Coll Cardiol. 2003;42:646-651.Antman EM, et al. Available at: http://www.acc.org/clinical/guidelines/stemi/index.pdf.

STRIVETM

Meta-analysis of 17 Facilitated PCI Trials*

Event Facilitated PCI (%) PCI (%) P

Death 5.0 3.0 .04

Reinfarction 3.0 2.0 .006

Urgent TVR 4.0 1.0 .010

Major bleeding 7.0 5.0 .010

Stroke 1.1 0.3 .0008

*Includes 9 GP IIb/IIIa inhibitor trials (N=1148); 6 thrombolytic therapy trials (N=2957); 2 combination therapy trials (N=399).

Keeley EC. Lancet. 2006;367:579-588.

STRIVETM

Rescue Angioplasty Versus Conservative Treatment

or Repeat Thrombolysis (REACT) Trial

Primary End PointComposite of death, reinfarction, stroke, or severe heart failure

within 6 months

Conservative TreatmentIncluding IV UFH for 24 h

(n=141)

Rescue PCIAngiography with or withoutrevascularization (n=144)

Repeated thrombolysiswith alteplase or reteplase

(n=142)

Gershlick AH, et al. N Engl J Med. 2005;353:2758-2768.

427 STEMI patients with failed thrombolysisASA and thrombolytic therapy (60% rec’d streptokinase) within 6 h of chest pain onset,

<50% ST-segment resolution within 90 minutes

STRIVETM

RESCUE PCI:REACT Trial — Primary End Point

Primary End Point = death, recurrent MI, severe heart failure, or cerebrovascular event within 6 months

REACT = Rescue Angioplasty versus Conservative Treatment or Repeat Thrombolysis.Adapted with permission from Gershlick AH, et al. N Engl J Med. 2005; 353:2758-2768.

1.00

0.90

0.80

0.70

0.60

0.000 20 40 60 80 100 120 140 160 180 200

Days After Randomization

Pro

bab

ility

of

Eve

nt-

free

Su

rviv

al

Rescue PCI 84.6%95% Cl, 78.7-90.5

Conservative therapy 70.1%95% Cl, 62.5-77.7

Repeated thrombolysis 68.795% Cl, 61.1-76.4

P=.004

STRIVETM

STEMI < 6 hLytic eligible

Lytic choice by MD(TNK, tPA, rPA, SK)

Double-blind, double-dummy

ASA

Day 301° Efficacy End Point: Death or Nonfatal MI

1° Safety End Point: TIMI Major Hemorrhage

ExTRACT-TIMI 25: Protocol Design

UFH (N = 10,223)60 U / kg bolus (4000 U)

Inf 12 U / kg / h (1000 U / h)Duration: at least 48 hCont’d at MD discretion

ExTRACT = Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial InfarctionAntman EM et al. N Engl J Med. 2006;354:1477-1488.Adapted with permission from http://www.clinicaltrialresults.com.

ENOXAPARIN (N=10,256)< 75 y: 30 mg IV bolus

SC 1.0 mg / kg q 12 h (Hosp DC)≥ 75 y: No bolus

SC 0.75 mg / kg q 12 h (Hosp DC)CrCl < 30: 1.0 mg / kg q 24 h

ENOXAPARIN (N=10,256)< 75 y: 30 mg IV bolus

SC 1.0 mg / kg q 12 h (Hosp DC)≥ 75 y: No bolus

SC 0.75 mg / kg q 12 h (Hosp DC)CrCl < 30: 1.0 mg / kg q 24 h

STRIVETM

Main Results From ExTRACT-TIMI 25Primary End point:

Death or nonfatal re-MI by 30 daysMain Secondary Endpoint:

Death, non-fatal re-MI, urgent revascularization by 30 days

12.0

9.9

UFH UFH

ENOX ENOX

14.5

11.7

Days Days

%%

RR = 0.83p = 0.000003

RR = 0.81p = 0.000001

Adapted with permission from www.clinicaltrialresults.org.

0 5 10 15 20 25 30

12

9

6

3

00 5 10 15 20 25 30

12

9

6

3

0

15

Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:1477-1488.

• Major bleeding: 1.4% with UFH vs 2.1% with enoxaparin (P<.001)

• ICH: .7% for UFH vs .8% for enoxaparin (P=.14)

STRIVETM

ExTRACT-TIMI 25: Net Clinical Benefit at 30 Days

1 1.250.90.8

Death or Nonfatal MI or Nonfatal ICH

Death or Nonfatal MI or Nonfatal Major Bleed

Death or Nonfatal MI or Nonfatal Disabling Stroke

Enoxaparin Better UFH BetterRR

UFH (%) Enox (%) RRR (%)

12.3 10.1 18

12.8 11.0 14

12.2 10.1 17

Prespecified Definitions

P<.001

P<.001

P<.001

Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:1477-1488.

STRIVETM

ExTRACT-TIMI 25 PCI Cohort: PrimaryEnd point Death or Nonfatal MI by 30 days

ENOX10.7%

Days

0

5

10

15

0 5 10 15 20 25 30

De

ath

or

MI (

%)

UFH13.8%

RR 0.77P=0.001

Gibson M. Presented at World Congress of Cardiology; September 4, 2006; Barcelona, Spain. Adapted with permission from www.clinicaltrialresults.org.

STRIVETM

ExTRACT-TIMI 25 PCI Cohort: Safety

Event ENOX UFH RR P-Value n=2,238 n=2,377

TIMI Major Bleed 1.4% 1.6% 0.87 (0.55-1.39) .56

TIMI Minor Bleed 3.3% 2.4% 1.34 (0.95-1.88) .09

TIMI Major or 4.6% 4.0% 1.15 (0.88-1.51) .31 Minor Bleed

ICH 0.2% 0.4% 0.42 (0.13-1.35) .18

Stroke 0.3% 0.9% 0.30 (0.12-0.75) .006

Gibson M. Presented at World Congress of Cardiology; September 4, 2006; Barcelona, Spain.Adapted with permission from www.clinicaltrialresults.org.

STRIVETM

OASIS-6 Trial: Study Design12,092 patients presenting with STEMI within 24 hours of symptom onset

(shortened to 12 hours of symptom onset midway through trial) Randomized, Blinded, Factorial

28% female; mean age, 62 years; mean follow-up, 3-6 months

Fondaparinuxn=2,823

2.5 mg/day for up to 8 days or hospital discharge

Placebon=2,835

Fondaparinux n=3,213

2.5 mg/day for up to 8 days or hospital discharge

UFHn=3,221

Primary end point: Composite of death or reinfarction at 30 days Secondary end point: Composite of death or reinfarction at 9 days and

at final follow-up

Stratum 1 (No UFH)n=5,658

Stratum 2 (UFH)n=6,434

Yusuf S, et al. JAMA. 2006;295:1519-1530.Adapted with permission from www.clinicaltrialresults.org.

STRIVETM

OASIS-6 Trial: Results

15%

Primary End Point: Death/Reinfarction (%)

P=.008 P=.003 P=.008

Fre

qu

enc

y

12%

9%

6%

3%

0%

9.7

11.2

7.4

8.9

13.4

14.8

30 days 9 days 3-6 months

Fondaparinux (n=6036) Control (n=6056)

14%

Reduction in Death/MI at 30 days: Stratum 1 (No UFH indicated)

P<.05

Reduction in Death/MI: Stratum 2(UFH Indicated)

P=NS

p=0.97p=0.97

12%

10%

8%

6%

4%

2%

0%

11.2

14

Fondaparinux Placebo

14%

12%

10%

8%

6%

4%

2%

0%Fondaparinux UFH

8.3 8.7

Yusuf S, et al. JAMA. 2006;295:1519-1530.Adapted with permission from www.clinicaltrialresults.org

STRIVETM

CLARITY–TIMI 28: Study Design

Fibrinolytic, ASA, Heparin

Clopidogrel300 mg + 75 mg qd

Coronary Angiogram(2-8 days)

Primary end point:Occluded artery (TIMI flow grade 0/1) or death/MI by time of angio

Randomized

Placebo

Double-blind, randomized, placebo-controlled trial in3491 patients, aged 18-75 yrs, with STEMI <12 hours

StudyDrug

30-day clinical follow-up

Open-labelclopidogrelper MD in

both groups

CLARITY-TIMI 28 = CLopidogrel as Adjunctive ReperfusIon TherapY – Thrombolysis In Myocardial Infarction.

Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.

STRIVETM

CLARITY–TIMI 28: End Points

PlaceboClopidogreln=1752 n=1739

36%Odds Reduction

15.0

21.7

Occ

lud

ed A

rter

y o

r D

eath

/MI (

%)

0

5

10

15

20

25

Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.

Days

En

dp

oin

t (%

)

0

5

10

15

0 5 10 15 20 25 30

Placebo

Clopidogrel

Odds Ratio: 0.80(95% CI, 0.65-0.97)

P=.03

20%

CV Death, MI, RI Urg RevascPrimary End Point Occluded Artery (or Death/MI Through

Angio/HD)

STRIVETM

Treatment: Clopidogrel 75 mg daily vs placebo(aspirin 162 mg daily in both groups)

Inclusion: Suspected acute MI (ST change or LBBB) within 24 h of symptom onset

Exclusion: Primary PCI or high risk of bleeding

1 Outcomes: Death and death, re-MI, or stroke up to 4 weeks in hospital (or prior discharge)

COMMIT/CCS-2: Study Design

Mean treatment and follow-up: 16 days

COMMIT = ClOpidogrel & Metoprolol in Myocardial Infarction Trial.

COMMIT Collaborative Group. Lancet. 2005;366:1607-1621.

STRIVETM

COMMIT: Effect of Clopidogrel on Death, Re-MI, or Stroke

9% (SE3) relative risk reduction (2P=.002)

Placebo + ASA: 2311 events (10.1%)

Clopidogrel + ASA: 2125 events (9.3%)

Days Since Randomization (up to 28 days)

Eve

nt

(%)

9

8

7

6

5

4

3

2

1

00

COMMIT Collaborative Group. Lancet. 2005;366:1607-1621.

Mo

rtal

ity

(%)

Days Since Randomization (up to 28 days)

Placebo + ASA: 1846 deaths (8.1%)

Clopidogrel + ASA: 1728 deaths (7.5%)

7% (SE3) relative risk reduction (2P=.03)

7

6

5

4

3

2

1

07 14 21 28 0 7 14 21 28

COMMIT = ClOpidogrel & Metoprolol in Myocardial Infarction Trial.

STRIVETM

2004 ACC/AHA STEMI GuidelinesSecondary Prevention Goals

Preventive Measure GoalSmoking → Complete cessation

BP control → <140/90 mm Hg or <130/80 mm Hg if chronic kidney disease or diabetes

Physical activity → Minimum: 30 min 3-4 days per week; optimal: daily

Lipid management (TG <200 mg/dL) →

Primary goal: LDL-C <<100 mg/dL

Lipid management (TG >200 mg/dL) →

Primary goal: Non–HDL-C <<130 mg/dL

Weight management → Goal: BMI 18.5 to 24.9 kg/m2

Diabetes management → Goal: HbA1c <7%

Antman EM, et al. J Am Coll Cardiol. 2004;44:E1-E211. Available at: http://www.acc.org/clinical/guidelines/stemi/index.pdf.

STRIVETM

Managing STEMI in 2006: Summary Acute therapy focuses on reperfusion and antithrombotic therapy

PCI generally preferred over fibrinolysis when a skilled PCI lab is available with surgical backup and door-to-balloon time is <90 min

Fibrinolysis generally preferred when invasive strategy is not an option or when delay to PCI is anticipated (>90 min door-to-balloon)

Current ACC/AHA STEMI guidelines recommend IV UFH as ancillary therapy to reperfusion therapy (Class I)

ExTRACT-TIMI 25 showed enoxaparin superior to current standard of UFH as the antithrombin to support fibrinolysis

Fondaparinux effective in STEMI without increasing risk of bleeding or stroke (OASIS-6), but some subsets did not benefit (patients heading for PCI; patients in whom UFH, not placebo, was the control)

Clopidogrel on top of aspirin results in significant further improvements in the reperfusion of patients with STEMI (CLARITY/COMMIT)

STRIVETM

Unstable Angina/Non–ST-Segment Elevation

Myocardial Infarction (UA/NSTEMI)

Risk Stratification and Medical Management

STRIVETM

ACC/AHA Class I Recommendations For Evaluation of Chest Pain

Patients with suspected ACS with chest discomfort at rest for >20 min, hemodynamic instability, or recent syncope or presyncope should be strongly considered for immediate referral to an ED or to a specialized chest pain unit

Assess likelihood of CAD

Assess risk of adverse events

Adapted from Braunwald E, et al. Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.

STRIVETM

Likelihood of ACS Secondary to CAD“CONFIDENCE OF DIAGNOSIS”


High Intermediate Low

History Chest or left arm pain Chest or left arm Sx w/o intermediateSx as in prior angina pain; age >70 yr likelihood character-Known history of CAD Male sex; DM istics; recent cocaine

Exam Transient MR, Extracardiac Chest pain hypotension, vascular reproduced diaphoresis, disease by palpation

pulmonary edema, orrales

ECG New transient Fixed Q waves T-wave flattening orST-segment deviation Abnormal ST-seg inversion in leadsor T-wave inversion or T-waves not w/dominant R waveswith symptoms documented as new Normal ECG

Cardiac Elevated Normal NormalMarkers

STRIVETM

TIMI Risk Score for UA/NSTEMI:7 Independent Predictors

1. Age ≥65 y

2. ≥3 CAD risk factors (high cholesterol, family history, hypertension, diabetes, smoking)

3. Prior coronary stenosis ≥50%

4. Aspirin in last 7 days

5. ≥2 anginal events ≤24 h

6. ST-segment deviation

7. Elevated cardiac markers (CK-MB or troponin)

Antman EM, et al. JAMA. 2000;284:835-842.

Number of Predictors

0

5

10

15

20

25

30

35

40

45

0/1 2 3 4 5 6/7

% D

ea

th /

MI

/ R

ev

as

c

STRIVETM

Troponin I, C-Reactive Protein, and B-type Natriuretic Peptide as Determinants of 30-Day Mortality in Acute

Coronary Ischemia: A Multimarker Approach

Adapted with permission from Sabatine MS, et al. Circulation. 2002;105:1760-1763.

P=.014 P<.0001

67 150 155 78

30-D

ay M

ort

alit

y R

elat

ive

Ris

k

504 717 324 90

OPUS-TIMI 16

11.8

3.5

6

0

1

2

3

4

5

6

0 1 2 3

TACTICS-TIMI 18

12.1

5.7

13

0

2

4

6

8

10

12

14

0 1 2 3Elevated Cardiac Biomarkers (N)Elevated Cardiac Biomarkers (N)

n=67 n=150 n=155 n=78 n=504 n=717 n=324 n=90

STRIVETM

Future of Biomarkers in ACS: Toward a Multimarker Strategy

hs-CRP = high-sensitivity C-reactive protein; CD40L = CD 40 ligand; BNP = brain natriuretic peptide; NT = N-terminal; HbA1c = hemoglobin A1c; CrCl = creatinine clearance.

Adapted with permission from Morrow DA, Braunwald E. Circulation. 2003;108:250-252.

Myocyte Necrosis

Inflammation

Troponin

Accelerated Atherosclerosis

Vascular Damage

HemodynamicStress

hs-CRP, CD40L

HbA1c

Blood glucoseCrClMicroalbuminuria

Biomarker Profile in ACS

BNP, NT-proBNP

STRIVETM

Conservative Strategy

Invasive Strategy With GP IIb/IIIa Inhibitor

TRS = TIMI Risk Score.Adapted with permission from Cannon CP. Circulation. 2002;106:1588-1591.

Higher Risk +Troponin, STs, TRS 3, Recurrent Ischemia, CHF,Prior Revascularization

Lower Risk– ECG, – Markers,

TRS 0-2

Aspirin, Clopidogrel, Heparin/LMWH (IIa Enox)β-blocker, Nitrates

Evidence-Based Risk Stratification to Target Therapies in UA/NSTEMI

Long-term Medical Therapy (Aspirin, Clopidogrel, Statin, β-blocker, ACEI)

STRIVETM

ACC/AHA Guidelines for UA/NSTEMI

Bed rest with continuous ECG monitoring

Nitroglycerin started sublingual, then IV

Supplemental O2 for cyanosis or respiratory distress; confirm SaO2 >90%

Morphine sulfate IV for pain, anxiety, CHF

β-blocker started IV, then PO; calcium antagonist if β-blocker and/or nitrates contraindicated or insufficient

Add ACE inhibitor if hypertension persists


Anti-ischemic Therapy

STRIVETM

Definite ACSWith Cath and PCIor Higher Risk (IIa)

Lower-Risk ACS

Possible ACS

Aspirin+

IV heparin/LMWH*+

IV platelet GP IIb/IIIa inhibitor

clopidogrel

Aspirin+

SQ LMWH*or

IV heparin

clopidogrel

Aspirin

ACC/AHA Guidelines for UA/NSTEMIAntithrombotic Therapy Class I Recommendations*

*Class IIa: enoxaparin preferred over IV heparin.


STRIVETM

10.1

5.0*

Placebo158

ASA178

0

4

8

12

Pat

ien

ts (

%)

11.9

3.3*

Placebo118

ASA121

0

5

10

1512.9

6.2*

Placebo279

ASA276

0

5

10

15

Lewis HD Jr, et al. N Engl J Med.

1983;309:396-403.

Theroux P, et al. N Engl J Med.

1988;319:1105-1111.

Cairns JA, et al. N Engl J Med.

1985;313:1369-1375.

17.1

6.5*

Placebo397

ASA399

0

5

10

15

20

The RISC Group. Lancet.

1990;336:827-830.

Death or MI*P=.0005 *P=.012 *P=.008 *P<.0001

ASA in UA/NSTEMI

STRIVETMAdapted with permission from Yusuf S, et al. Circulation. 2003;107:966-972.

Pro

po

rtio

n E

ven

t-F

ree

RRR: 18% 95% CI, 0.70–0.95 P=.009

Clopidogrel

Placebo

CV Death, MI, or Stroke >30 Days–1 Year

Pro

po

rtio

n E

ven

t-F

ree

.90

.92

.94

.96

.98

1.00

Month 1 4 6 8 10 12Week 0 1 2 3 4

RRR: 21% 95% CI, 0.67–0.92 P=.003

Clopidogrel

Placebo

CV Death, MI, or Stroke First 30 Days

.90

.92

.94

.96

.98

1.00

No. at Risk5981 5481 4742 4004 3180 24185954 5390 4639 3929 3159 2388

Clopidogrel 6259 6145 6070 6026 5990Placebo 6303 6159 6048 5993 5965

No. at Risk

CURE Study: Event-Free Survival

RRR = relative risk reduction.

STRIVETMAdapted with permission from Yusuf S, et al. Circulation. 2003;107:966-972.

CURE: Efficacy of Very Early Clopidogrel Therapy in ACS Patients

Hours After Randomization

0.0

0.005

0.010

0.015

0.020

0.025

0 2 4 6 8 10 12 14 16 18 20 22 24

P=.003

Placebo+ Aspirin(n=6303)

Clopidogrel+ Aspirin(n=6259)

34%Relative RiskReduction

CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours

Cu

mu

lati

ve H

aza

rd R

ate

STRIVETM

*Other standard therapies were used as appropriate.

Peters RJ, et al. Circulation. 2003;108:1682-1687.

Clopidogrel + Aspirin*

Placebo + Aspirin*

Aspirin Dose

75-100 mg 1.9% 3.0%101-199 mg 2.8% 3.4%200-325 mg 3.7% 4.9%

CURE: Major Bleeding by Aspirin Dose Through Follow-up

STRIVETM

Unstable Angina/Non–ST-Segment Elevation

Myocardial Infarction (UA/NSTEMI)

Early Invasive Strategy, PCI/Drug-eluting Stents, Secondary Prevention

STRIVETM

Prior CABGHigh-risk findings on noninvasive stress testing

PCI within 6 monthsRecurrent angina/ischemia with CHF, S3, PE, rales, etc.

Sustained VTST-segment depression

Hemodynamic instabilityElevated TnT or Tnl

Ejection fraction <.40Recurrent angina/ischemia

Class IAn early invasive strategy in patients with UA/NSTEMI and any of the following high-risk indicators (Level of Evidence: A)

Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374.

ACC/AHA Guidelines for UA/NSTEMI:Early Invasive Strategy

STRIVETM

0.1 0.5 1 2 5

Favors Invasive

Favors Conservative

Odds Ratio Death or MI

OR 0.82, P<.001

Trial (N)

TIMI IIIB (1473)

VANQWISH (920)

MATE (201)

FRISC II (2457)

TACTICS (2220)

RITA 3 (1810)

Total (N=9212)

Invasive Management of UA/NSTEMI Meta-analysis: Death/MI at End of Follow-up (mean 17.3 months)

11.6 13.8

32.9 30.3

14.4 12.2

10.4 14.1

7.3 9.5

10.6 12.9

VINO (131) 6.3 22.4

Inv (%) Cons (%)

12.2 14.4

Adapted with permission from Mehta S, et al. JAMA. 2005;293:2908-2917.

STRIVETM

Patients (N): 920 2874 7018

Adapted with permission from Cannon CP, Turpie AG. Circulation. 2003;107:2640-2645.

Optimal Strategy for UA/NSTEMI

Conservative Invasive

TIMI IIIB

MATEVANQWISH

FRISC II

TACTICS-TIMI 18

VINO

RITA-3

TRUCS

ISAR-COOL

ICTUS

STRIVETM

Benefit of Clopidogrel in PCI-CUREAccording to Timing of PCI

Lewis BS, et al. Am Heart J. 2005;150:1177-1184.

0.20

0.15

0.10

0.05

0.0

Cu

mu

lati

ve H

azar

d R

ates

0 100 200 300Days of Follow-up

<48 hrs after rand

RR:.53 (0.27-1.06)

Denotes medianTime to PCI

0.20

0.15

0.10

0.05

0.0

Cu

mu

lati

ve H

azar

d R

ates


PCI ≥ 48 hrs from rand and during initial hosp

RR:.72 (0.51-1.01)

Clopidogrel

Placebo

Cu

mu

lati

ve H

azar

d R

ates

PCI after hospitaldischarge

0.20

0.15

0.10

0.05

0.0


RR:.70 (0.48-1.02)

STRIVETM

Clopidogrel NoTrial Pretreatment Pretreatment

PCI-CURE 3.6 5.1

CREDO n/a n/a

PCI-CLARITY 4.0 6.1

Overall 3.7 5.5

Meta-analysis of Clopidogrel Pretreatment

CV Death or MI after PCI (%)

MI before PCI (%)

1.00.25 2.00.5

1.00.25 2.00.5OR (95% CI)

OR (95% CI)

OR: 0.67P=.005

FavorsPretreatment

FavorsNo Pretreatment

OR: 0.71P=.004

Adapted with permission from Sabatine MS, et al. JAMA. 2005;294:1224-1232.

Clopidogrel NoTrial Pretreatment Pretreatment

PCI-CURE 2.9 4.4

CREDO 6.0 7.1

PCI-CLARITY 3.3 5.4

Overall 3.9 5.5

STRIVETM

ACC/AHA/SCAI 2005 Guideline Update for PCIOral Antiplatelet Adjunctive Therapies

A loading dose of clopidogrel should be administered before PCI is performed

I IIa IIb III

A

Adapted from Smith SC Jr, et al. Available at: www.acc.org/clinical/guidelines/percutaneous/update/index_rev.pdf.

An oral loading dose of 300 mg, administered at least 6 hours before the procedure, has the best established evidence of efficacy

B

STRIVETM

ARMYDA-2 Trial: Design and Primary End Point

Primary composite of death, MI, or target vessel revasc at 30 days

P=.041

4

0%

2%

4%

6%

8%

10%

12%

14%

High Dose Standard Dose

12

High Loading Dose

of Clopidogrel600 mgPre-PCI

Standard Loading Dose of

Clopidogrel 300 mgPre-PCI

255 patients with stable CAD or NSTEMI prior to PCI

13% received GP IIb/IIIa inhibitors20% received drug-eluting stents

Randomized 4-8 Hours Pre-PCI

ARMYDA-2 = Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty.

Patti G, et al. Circulation. 2005;111:2099-2106.

STRIVETM

30-Day Death or Nonfatal MIRisk Ratio and 95% CI

Placebo BetterGP IIb/IIIa Inhibitor Better

Trial

Pooled 11.5%

PlaceboGP IIb/IIIa Inhibitor

10.7%29,855

n

0.92 (0.86, 0.995)P=.037

PRISM-PLUS 11.9% 10.2%1,915

PURSUIT 15.7% 14.2%9,461

PARAGON A 11.7% 11.3%2,282

7.1%PRISM 5.8%3,232

0.5 1.0 1.5

PARAGON B 11.4% 10.5%5,165

GUSTO-IV ACS

8.0% 8.7%7,800

GP IIb/IIIa Inhibition for Non–ST-Elevation ACS

Boersma E, et al. Lancet. 2002;359:189-198.

CI = confidence interval.

STRIVETM

GP IIb/IIIa Inhibitor During Medical Rx and After PCI: CAPTURE, PURSUIT, PRISM-PLUS

0%

2%

4%

6%

8%

10%

PCI

N=2754P=.001

N=12,296P=.001

+24 h +48 h +72 h +24 h +48 h

4.3%

2.9%

8.0%

4.9%

Dea

th o

r M

I

Medical Rx/Pre-PCI Post-PCI

Control

GP IIb/IIIa inhibitor

0

Adapted with permission from Boersma E, et al. Circulation. 1999;100:2045-2048.

STRIVETM

Benefits of GP IIb/IIIa by Troponin Status in Clinical Trials

Newby KL, et al. Circulation. 2001;103:2891-2896.

TnT-NegativeTnT-Positive

PARAGON-B

PRISM

CAPTURE

Combined

0.125 1 20.5 0.125 1 20.5GP IIb/IIIa

BetterGP IIb/IIIa

WorseGP IIb/IIIa

BetterGP IIb/IIIa

Worse

STRIVETM

ISAR-REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets

With and Without Elevated Troponin levels (>0.03 µg/L)

ISAR-REACT 2 = Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2.

Adapted with permission from Kastrati A, et al. JAMA. 2006;295:1531-1538.

20

15

10

5

0

0 5 10 15 20 25 30Days After Randomization

Cu

mu

lati

ve R

ate

of

Pri

mar

y E

nd

Po

int,

%

Placebo Group (n=1010)Abciximab Group (n=1012)

Troponin >0.03 µg/LLog-Rank P=.02

Troponin <0.03 µg/LLog-Rank P=.98

STRIVETM

ACC/AHA UA/NSTEMI 2002 Guideline Update:Platelet GP IIb/IIIa Inhibitors

Any GP IIb/IIIa inhibitor + ASA/heparin for all patients, if cath/PCI planned

I IIa IIb III

*High-risk: age >75 y; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST ; VT; positive cardiac markers.

A

A

B

Eptifibatide or tirofiban + ASA/heparin for high-risk* patients in whom early cath/PCI is not planned

Any GP IIb/IIIa inhibitor for patients already on ASA + heparin + clopidogrel, if cath/PCI is planned


STRIVETM

Anticoagulation in UA/NSTEMI 4 classes of anticoagulants are available

– Unfractionated heparin (UFH)– Low-molecular-weight heparins (LMWH)– Direct thrombin inhibitors– Factor Xa inhibitors

Current guidelines support use of UFH and LMWH, with enoxaparin preferred over UFH (Class IIa)

Recent studies suggest direct thrombin inhibitors (bivalirudin) and factor Xa inhibitors (fondaparinux) may be appropriate new options for anticoagulation

– Effective, lower risk of bleeding

STRIVETM

Meta-analysis: Enoxaparin vs UFH in UA/NSTEMIDeath or MI at 30 Days*

Trial Enox (%) UFH (%) Odds ratio [95% CI] Odds ratio (95% CI)

ESSENCE 5.8 7.5 0.76 [0.58, 1.01]

TIMI 11B 6.4 7.8 0.81 [0.60, 1.10]

INTERACT 4.6 8.1 0.55 [0.28, 1.08]

A to Z 7.3 6.9 1.06 [0.68, 1.67]

SYNERGY 12.6 14.8 0.84 [0.68, 1.05]

Overall 8.0 9.4 0.81 [0.70, 0.94]

Enoxaparin better UFH betterTest for heterogeneity: χ2 = 2.86, df = 4, P = .58 0.2 1.0 2.0

Petersen JL, et al. JAMA. 2004;292:89-96.

*No prerandomization therapy population.

STRIVETM

At least 2 of 3 required: Age 60 ST (transient) or (+) CK-MB or Troponin

IV Heparinn=4985

Primary end point: death or MI at 30 days

High-RiskACS Patients

Randomize(N=10,027)

Early invasive strategyOther therapy per ACC/AHA Guidelines

(ASA, -blocker, ACEI, clopidogrel, GP IIb/IIIa)

60 U/kg 12 U/kg/h (aPTT 50-70 sec)

1 mg/kg SC q12hr

SYNERGY: Study Design

Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54.

No prerandomizationtherapy population

Enoxaparinn=4993

STRIVETM

SYNERGY: Primary End Point

0 5 10 15 20 25 300.8

0.85

0.9

0.95

1.0

Fre

edo

m F

rom

Dea

th /

MI

Days From Randomization

UFH

Enoxaparin

HR 0.96 (0.87-1.06)

30-Day Death/MI

0.80.8 11 1.21.2

Hazard Ratio (95% CI)

Enoxaparin

Better

UFH

Better

Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54.Adapted with permission from www.clinicaltrialresults.org.

STRIVETM

SYNERGY: Bleeding Events at 30 DaysEnoxaparin UFH P value

(n=4993) (n=4983)

GUSTO severe bleeding 2.7 2.2 .08Any RBC transfusion 17.0 16.0 .16TIMI major bleeding:

Clinical 9.1 7.6 .008CABG-related 6.8 5.9 .08Non–CABG-related 2.4 1.8 .03Hb drop 15.2 12.5 <.001

12% of patients randomized to enoxaparin were switched to UFH4% of patients randomized to UFH were switched to enoxaparin

Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54.

STRIVETM

Moderate-to high-

riskACS

ACUITY Study Design:First Randomization

An

gio

gra

ph

y w

ith

in 7

2 h

Aspirin in all,Clopidogrel dosing

and timingper local practice

UFH or enox+ GP IIb/IIIa

n=4603

Bivalirudin+ GP IIb/IIIa

n=4604

Bivalirudinalone

n=4,612

R*

Moderate- to high-risk patients with UA or NSTEMIundergoing an invasive strategy (N=13,819)

Medicalmanagement

PCI

CABG

Stone GW, et al. Am Heart J. 2004;148:764-775.

*Stratified by preangiography thienopyridine use or administration.

STRIVETM

11.7%11.8% 1.01 (0.90-1.12)<.001

.93

0 1 2

Risk ratio±95% CI

Risk ratio±95% CI

Primaryend point

ACUITY: Primary End Point Measures*UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin + GP IIb/IIIa

Net clinical outcome

Ischemic composite

Major bleeding

Bivalirudin + GP IIb/IIIa betterBivalirudin + GP IIb/IIIa better UFH/Enox + GP IIb/IIIa betterUFH/Enox + GP IIb/IIIa better

Bival+ IIb/IIIa

UFH/Enox+ IIb/IIIa

RR (95% CI)P value

(noninferior)(superior)

7.3%7.7% 1.07 (0.92-1.23).015.39

5.7%5.3% 0.93 (0.78-1.10)<.001

.38

Up

per

bo

un

dar

y n

on

infe

rio

rity

Stone GW, et al. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 11-14, 2006; Atlanta, Georgia.Adapted with permission from www.clinicaltrialresults.org.

*ITT population

STRIVETM

0 1 2

ACUITY: Primary End Point Measures*

Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Risk ratio±95% CI

Risk ratio±95% CI

Primaryend point

Bivalalone

UFH/Enox+ IIb/IIIa

RR (95% CI)

Net clinical outcome

Ischemic composite

Major bleeding

Up

per

bo

un

dar

y n

on

infe

rio

rity

11.7%10.1% 0.86 (0.77-0.97)<.001.015

7.3%7.8% 1.08 (0.93-1.24).02.32

5.7%3.0% 0.53 (0.43-0.65)<.001<.001

P value(noninferior)

(superior)

UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin alone

*ITT population.

UFH = unfractionated heparin

Stone GW, et al. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 11-14, 2006; Atlanta, Georgia.Adapted with permission from www.clinicaltrialresults.org.

STRIVETM

Patients with NSTE ACS, chest discomfort < 24 hours2 of 3: age >60 y, ST-segment Δ, cardiac markers

Patients with NSTE ACS, chest discomfort < 24 hours2 of 3: age >60 y, ST-segment Δ, cardiac markers

Fondaparinux (n=10,057)2.5 mg SC once daily

OASIS-5: Study Design

ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per

local practiceRandomize

Enoxaparin (n=10,021)1 mg/kg SC twice daily

Primary: Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 days

Risk benefit: Death, MI, refractory ischemia, major bleeds 9 days

Hypothesis: First test noninferiority, then test superiority

Primary: Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 days

Risk benefit: Death, MI, refractory ischemia, major bleeds 9 days

Hypothesis: First test noninferiority, then test superiority

Outcomes

PCI <6 h: No additional UFHPCI >6 h: IV UFHWith IIb/IIIa, 65 U/kgWithout IIb/IIIa, 100 U/kg

PCI <6 h: IV Fonda 2.5 mgwithout IIb/IIIa, 0 with IIb/IIIaPCI >6 h: IV Fonda 2.5 mg withand 5.0 mg without IIb/IIIa

N=20,078

Yusuf S, et al. N Engl J Med. 2006;354:1464-1476.Adapted with permission from www.clinicaltrialresults.org.

STRIVETM

OASIS-5: Results

Death, MI, or Refractory Ischemia Through Day 9 Major Bleeding Through Day 9

0.06

0.05

0.04

0.03

0.02

0.01

0.00

Days

Cu

mu

lati

ve H

azar

d Hazard ratio, 1.01 (95% CI, 0.90-1.13)

Enoxaparin

Fondaparinux

0.04

0.03

0.02

0.01

0.00

Days

Cu

mu

lati

ve H

azar

d Hazard ratio, 0.52 (95% CI, 0.44-1.61)P<.001

Enoxaparin

Fondaparinux

Adapted with permission from Yusuf S, et al. N Engl J Med. 2006:354:1464-1476.

Event Fondaparinux Enoxaparin P

Mortality Day 30 2.9% 3.5% .02

Mortality 6 Months 5.8% 6.5% .05

30 Day and 6 Month Results

1 9 1 9

1.5% thrombus on catheter (in fonda group) if no UFH given

STRIVETM

Cell Division G1

M

G2

G0

CELL CYCLE

Resting

S

Sirolimus

XPaclitaxel

X

Drug-eluting Stents: Cell-Cycle Sites of Action for Sirolimus and Paclitaxel

STRIVETM

Drug-eluting Stents: Freedom From TLR

Time After Initial Procedure (months)

100

CYPHERBare-Metal Stent

93.6%

0 6 12 18 24 30 36Time After Initial Procedure

(months)

TAXUSBare-Metal Stent

90.6%

80.1%

0 6 12 18 24 30 36

76.8%

P<0.0001P<0.0001

TAXUS II, IV, V, VI(n=3,445)

RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS(n=1,748)

Schampaert et al. Circulation 2005;112;II-650.Stone et al. Circulation 2005;112;II-651.

90

80

70

60

100

90

80

70

60

STRIVETM

Drug-eluting Stents: Freedom From Cardiac Death

Time after Initial Procedure (months) Time after Initial Procedure (months)



60

70

80

90

100

60

70

80

90

100

CYPHERBare-Metal Stent

98.2%

97.8%

0 6 12 18 24 30 36

TAXUSBare-Metal Stent

98.0%

97.9%

0 6 12 18 24 30 36

P=0.61 P=0.81


STRIVETM

Drug-eluting Stents: Freedom From MI

Time after Initial Procedure (months) Time after Initial Procedure (months)



60

70

80

90

100

CYPHER®

Bare-Metal Stent

95.3%

00 66 1212 1818 2424 3030 3636

TAXUS®

Bare-Metal Stent

93.6%93.6%

93.4%93.4%

00 66 1212 1818 2424 3030 3636

95.2%

P=0.93 P=0.96

60

70

80

90

100


STRIVETM

Predictors of Stent Thrombosis in DES Era

• Premature discontinuation of antiplatelet therapy

• DES Platform– Polymer (inflammatory, thrombogenic)– Drug (cytotoxic)

• Mechanical/lesion-specific factors– Incomplete stent apposition– Lesion complexity (bifurcation, AMI, ISR)– Stent length

• Hypercoaguable conditions– Antiplatelet therapy ‘resistance’– High platelet reactivity and clot strength

Wenaweser P, et al. J Am Coll Cardiol. 2005;45:1748-1752.Gurbel PA, et al. J Am Coll Cardiol. 2005;46:1820-1826.Gurbel PA, et al. J Am Coll Cardiol. 2005;46:1827-1832.

STRIVETM

2229 patients after successful DES implantation

PES1167 pts

2223 stents

SAT4 (0.4%)

SAT10 (0.9%)

LST5 (0.5%)

LST10 (0.9%)

Total SES9 (0.9%)

Total PES20 (1.7%)

9.3 5.6 months Total DES 29/2229 (1.3%)

P=0.5

P=0.3

P=0.09

10.2 4.4 m 7.9 3.6 m

SES1062 pts

2272 stents

Milan/Siegburg Experience

Iakovou I, et al. JAMA. 2005;293:2126-2130.

STRIVETM

2.6% 3.2% 3.5%5.5%

29.0%

2.0%1.3%

8.7%

Unstableangina

PriorbrachyRx

Thrombus Diabetes Unprot.left main

Bifurcation Renalfailure

Prematureantiplatelet d/c

Several patient and lesion subgroups have a higher

stent thrombosis rate than identified in RCTs

Milan/Siegburg Experience

Stent thrombosis after DES (SES or PES) occurred

in 29/2229 pts (1.3%) at 9.3 ± 5.6 mos

Iakovou I, et al. JAMA. 2005;293:2126-2130.

STRIVETM

BASKET-LATE Trial: Study Design

Primary End Point: Composite cardiac death or nonfatal MI between months 7 and 18

Other End Points: - Thrombosis-related events:

- angiographically documented stent thrombosis

- cardiac death/target vessel MI- TVR

743 PCI patients from BASKET TrialNone had target vessel diameter ≥4mm, restenotic lesions, or MACE

during the on-clopidogrel phase.Concomitant medications: aspirin indefinitely

Pfisterer ME, et al. Presented at ACC, Atlanta, Ga. March 14, 2006; Presentation 422-11.Adapted with permission from www.clinicaltrialresults.org.

BMS Groupn=244

DES Groupn=499

STRIVETM

BASKET-LATE: Primary Composite End Point

Pfisterer ME, et al. ACC, Atlanta, Ga. March 14, 2006; Presentation 422-11.Adapted with permission from www.clinicaltrialresults.org.

Components of primary composite end point: nonfatal MI/cardiac death (%)

2.6

1.3

0

1

2

3

DES BMS

Additional end point of thrombosis-related events (%)

P=.23

4.9

1.3

0

1

2

3

4

5

6

DES BMS

Composite of cardiac death or nonfatal MI (%)P=.01

% P

atie

nts

4.1

1.21.3

0.00.0

1.0

2.0

3.0

4.0

5.0

MI Cardiac Death

DES BMS

P=.04

P=.09

% P

atie

nts

% P

atie

nts

STRIVETMBraunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374.

Long-Term Medical Therapy for UA/NSTEMI: Class I Recommendations

Aspirin 75 to 325 mg/d Clopidogrel 75 mg/d when aspirin is not tolerated Combination of aspirin and clopidogrel for 9 months

post-UA/NSTEMI

β-blocker

Lipid-lowering agent and diet in patients with LDL-C >130 mg/dL

Lipid-lowering agent if LDL-C after diet >100 mg/dL*

ACE inhibitor for patients with CHF, LV dysfunction (EF <.40), hypertension, or diabetes

*NCEP ATP III update indicates optional goal of LDL-C < 70 mg/dL.

STRIVETM

CTT Collaboration: Relation Between Proportional Reduction in Incidence of Major Vascular Events and

Absolute LDL-C Reduction at 1 Year

Cholesterol Treatment Trialists’ Collaborators. Lancet. 2005;366:1267-1268.

Pro

po

rtio

nal

Red

uct

ion

in E

ven

t R

ate

(SE

)50%

40%

30%

20%

10%

0%

-10%

0.5 1.0 1.5 2.0

Major vascular events

Reduction in LDL cholesterol (mmol/L)

STRIVETM

Trial Population Duration, y

Treatment Arms Primary End Point

PROVE IT-TIMI 22

Post-ACS (N=4162)

2 40 mg pravastatin vs 80 mg atorvastatin

Death, MI, UA requiring hospitalization (>30 d), stroke

A to Z Post-ACS (N=4497)

2 Placebo (4 mos) then 20 mg simvastatin vs 40 mg simvastatin (1 month) then 80 mg simvastatin

CV death, MI, readmission for ACS, stroke

TNT Stable CAD (N=10,001)

5 10 mg atorvastatin vs 80 mg atorvastatin

CHD death, non-procedure-related MI, resuscitation after cardiac arrest, stroke

IDEAL Stable CAD (N=8888)

5 20 mg simvastatin vs 80 mg atorvastatin

CHD death, MI, cardiac arrest with resuscitation

Cannon CP, et al. J Am Coll Cardiol. 2006;48:438-445.

Meta-Analysis of CV Outcomes Trials Comparing Intensive vs Moderate Statin TherapyTrial Design and Baseline Characteristics

STRIVETM

Meta-Analysis of CV Outcomes Trials Comparing Intensive vs Moderate Statin Therapy

Changes in LDL-C Levels

Adapted with permission from Cannon CP, et al. J Am Coll Cardiol. 2006;48:438-445.

Patients ACS Stable CAD Pooled

n 4162 4497 10001 8888 27548

25.2% 0% 0% 75.5% 28.2%

PROVE IT-TIMI 22

A-to-Z TNT IDEAL Pooled*

Baseline 108 113 152 122 130

Standard 97 101 101 104 101

Intensive 65 69 77 81 75

LD

L-C

(mg

/dL

)

160

140

120

100

80

60

40

Baseline

Standard

Intensive

Prior Statin Use

STRIVETM

Meta-Analysis of CV Outcomes Trials ComparingIntensive vs Moderate Statin TherapyReduction in Risk of Coronary Death or MI

Adapted with permission from Cannon CP, et al. J Am Coll Cardiol. 2006;48:438-445.

PROVE IT-TIMI 22

A-to-Z

TNT

IDEAL

Total

.66 1 1.5High-dose better High-dose worse

Odds Ratio (95% CI)

OR, 0.8495% CI, 0.77-0.91P=0.00003

OddsReduction

Event RatesNo./Total (%)

High Dose Std Dose

-17%147/2099

(7.0)172/2063

(8.3)

-15%205/2265

(9.1)235/2232

(10.5)

-21%334/4995

(6.7)418/5006

(8.3)

-12%411/4439

(9.3)463/4449

(10.4)

-16%1097/13798

(8.0)1288/13750

(9.4)

STRIVETM

Safety of Achieving Ultra-Low LDL

Event* 80-100 60-80 40-60 <40 P value

Myositis or Myalgia (AE)

1.6 3.1 3.2 2.8 NS

CK > 3x ULN 2.3 0.7 1.9 1.0 NS

CK > 10x ULN 0.3 0 0.3 0 NS

Rhabdomyolysis 0 0 0 0 NS

ALT > 3X ULN 3.1 3.0 3.2 3.6 NS

Wiviott et al. J Am Coll Cardiol. 2005;46:1411-1416.

LDL Level

STRIVETM

HOPE

HOPE: Adapted with permission from the Heart Outcomes Prevention Evaluation (HOPE) study investigators. N Engl J Med. 2000;342:145-153.

P<.001RRR = 22%

0

5

10

15

20

0 500 1000 1500

Follow-up (days)Pat

ien

ts R

each

ing

Co

mp

osi

te E

nd

Po

int

[MI,

Str

oke

, CV

Dea

th]

(%)

Ramipril

Placebo

CV

Dea

th, M

I, o

r C

ard

iac

Arr

est

(%)

Placebo annual event rate: 2.4%

Perindopril

Placebo

P=.0003RRR: 20%

Years

0 1 2 3 4 5

N = 12,218

14

12

10

8

6

4

2

EUROPA: Adapted with permission from Fox KM; EUROPA Investigators. Lancet. 2003;362:782-788.

PEACE: Adapted with permission from Braunwald E, et al; PEACE Trial Investigators.N Engl J Med. 2004;351:2058-2068.

0 1 2 3 4 5 6

30

25

20

15

10

5

0

No. at RiskTrandolapril 4158 4017 3752 3506 3079 1963 969Placebo 4132 3990 3719 3486 3027 1929 891

Placebo

Trandolapril

Inci

den

ce o

f P

rim

ary

En

d P

oin

t (%

)

Years After Randomization

EUROPA

PEACE

ACE Inhibitor Trials: Primary End Points

STRIVETM

CHARISMA Study: Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)†

† First occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death.*All patients received ASA 75-162 mg/day.§The number of patients followed beyond 30 months decreases rapidly tozero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo).

Adapted with permission from Bhatt DL, et al. N Eng J Med. 2006:354:1706-1717.

Cu

mu

lati

ve e

ven

t ra

te (

%)

0

2

4

6

8

Months since randomization 0 6 12 18 24 30

Placebo + ASA* 7.3%

Clopidogrel + ASA*6.8%

RRR: 7.1% [95% CI: -4.5%, 17.5%]P = 0.22

STRIVETM

CHARISMA Study: Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV

Death/Hospitalization)†

†First occurrence of MI, stroke, CV death, or hospitalization for UA, TIA, or revascularization.*All patients received ASA 75-162 mg/day.§The number of patients followed beyond 30 months decreases rapidly tozero and there are only 38 secondary efficacy events that occurred beyond this time (23 clopidogrel and 15 placebo).

Placebo + ASA*

17.9%

Clopidogrel + ASA*

16.7%

RRR: 7.7% [95% CI: 0.5%, 14.4%] P = 0.04

Cu

mu

lati

ve e

ven

t ra

te (

%)

0

5

10

15

20

Months since randomization§

0 6 12 18 24 30


STRIVETM

CHARISMA StudyOverall Population: Safety Results

*Adjudicated outcomes by intention to treat analysis.

ICH = intracranial hemorrhage.

Safety Outcome* – N (%)

Clopidogrel + ASA

(n=7802)

Placebo + ASA(n=7801)

RR (95% CI) P value

GUSTO Severe Bleeding

130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09

Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17

Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89

GUSTO Moderate Bleeding

164 (2.1) 101 (1.3) 1.62 (1.27, 2.10) <0.001

Bhatt DL, et al. N Engl J Med. 2006;354:1706-1717.

STRIVETM

CHARISMA Study: Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category

*A statistical test for interaction showed marginally significant heterogeneity (P=0.045) in treatment response for these pre-specified subgroups of patients.†166 patients did not meet any of the main inclusion criteria but were followed (intent-to-treat analysis).

Population RR (95% CI) P value

Qualifying CAD, CVD or PAD* 0.88 (0.77, 0.998) 0.046(n=12,153)

Multiple Risk Factors * 1.20 (0.91, 1.59) 0.20 (n=3,284)

Overall Population† 0.93 (0.83, 1.05) 0.22 (n=15,603)

0.6 0.8 1.41.2

Clopidogrel + ASA Better

Placebo + ASA Better

1.60.4


STRIVETM

CHARISMA: Clinical Implications In the acute setting, prior studies have shown the benefit of dual

antiplatelet therapy for 1 year post ACS or PCI

For stable patients, CHARISMA failed to demonstrate a reduction in CV death/MI/stroke with dual antiplatelet therapy

CHARISMA may suggest differential long-term effects of dual antiplatelet therapy by patient type:

– NOT Recommended for Primary Prevention– Potential benefit in Secondary Prevention (CAD, CVD, or PAD)

CV death/MI/stroke - 9 events prevented per 1000 patients treated

Balanced by 2 severe GUSTO bleeds per 1000 patients treated

These data and future trials will help physicians decide which non-acute/stable patients should receive long-term dual antiplatelet therapy

Bhatt DL, et al. N Engl J Med. 2006;354:1706-1717.

STRIVETM

Quality Improvement Programs and

Critical Pathways

STRIVETM

Why Develop Critical Pathways?

“A treatment gap between therapy that is dictated by evidence-based medicine and therapy that occurs in practice is not a deficit of knowledge; rather, it is a deficit of implementation.”

Sidney Smith, MDDirector, Center for Cardiovascular Science and Medicine, UNC School of Medicine

STRIVETM

Critical Pathways Standardized treatment protocols for the management of specific

disorders Developed to optimize and streamline patient care Prevent underutilization of medications, time in

ICU/hospital, costs Ensure quality-of-care measures (eg, door-to-drug times) Optimize patient triage Facilitate communication with specialists and PCP

post-discharge Enhance patient compliance and outcomes Minimize potential for medical errors Improve compliance with national standards (JCAHO)

Adapted from: Cannon CP, O’Gara PT. Critical Pathways in Cardiology. Lippincott Williams & Wilkins; 2001.

STRIVETM

Joint Commission on Accreditationof Healthcare Organizations (JCAHO)

1997: Launched ORYX™ to integrate use of outcomes and other performance measures into accreditation process

2001: Announced 4 initial core measurement areas for hospitals (2 of 4 required):

– Acute MI– Heart failure– Community-acquired pneumonia– Pregnancy

2004: New accreditation process (“Shared Visions–New Pathways”) introduced. Hospitals previously collecting 2 of 4 measure sets are now required to collect 3 of 4 measure sets

www.jcaho.org

STRIVETM

JCAHO Quality Measures in MI

Hospitals graded on: Antiplatelet therapy in AMI at arrival and discharge -blocker therapy at arrival and discharge ACE inhibitor therapy for LVSD Time to thrombolysis Time to PCI Adult smoking cessation counseling Inpatient mortality

www.jcaho.org

STRIVETM

Why a Hospital-Based System?

Patients

– Patient capture point

– Have patients/family attention: “teachable moment”

– Predictor of care in community

Hospital structure

– Standardized processes/protocols/orders/teams

– JCAHO (ORYX and “Shared Visions – New Pathways”)

Source: http://www.americanheart.org/getwiththeguidelines

STRIVETM

Practical Steps to Improve the Use of Practical Steps to Improve the Use of Evidence-Based Therapies for ACSEvidence-Based Therapies for ACS

Develop critical pathways Establish a multidisciplinary team approach (cardiology,

ED, primary care, nursing, laboratory) Identify local cardiology and ED “champions” Track adherence to ACC/AHA guidelines Develop educational materials to improve physicians’

knowledge of the guidelines Secure institution’s commitment to improved patient care Identify areas for continuous QI; provide QI tools Elicit ongoing quarterly feedback

Cannon CP, et al. Am Heart J. 2002;143:777-789.

STRIVETM

Adapted from Cannon CP, O’Gara PT. Critical Pathways in Cardiology. Lippincott Williams & Wilkins; 2001. Corbelli J, et al. Critical Pathways in Cardiology. 2003;2:71-87.

Critical Pathways Begin in Ambulance and Extend to Long-term, Office-based Care

EMS

ED

Inpatient

Discharge

Community

STRIVETM

EMS Reperfusion Checklist: Evaluation of the STEMI Patient

Step 1: Has patient experienced chest discomfort for > 15 min and < 12 h?

YES NO STOP

Step 2: Are there contraindications to fibrinolysis? If ANY of the following are CHECKED, fibrinolysis MAY be contraindicated.

Systolic BP greater than 180 mm Hg Diastolic BP greater than 110 mm Hg

Right vs left arm systolic BP difference greater than 15 mm Hg

History of structural central nervous system disease

Recent (< 6 wk) major trauma, surgery (including laser eye surgery), GI/GU bleed

Bleeding or clotting problem or on blood thinners

CPR greater than 10 min

Pregnant female

Serious systemic disease(eg, advanced/terminal cancer, severe liver or kidney disease)

Significant closed head/facial trauma within the previous 3 months

Step 3: Is patient at high risk such that PCI is preferable?

Heart rate greater than or equal to 100 bpmPulmonary edema (rales greater than halfway up)

Systolic BP less than 100 mm Hg

Systemic hypoperfusion (cool, clammy)

□ Yes □ No

□ Yes □ No□ Yes □ No□ Yes □ No

□ Yes □ No

□ Yes □ No□ Yes □ No

□ Yes □ No□ Yes □ No□ Yes □ No□ Yes □ No

□ Yes □ No

□ Yes □ No□ Yes □ No

□ Yes □ No

Adapted from Antman EM, et al. Available at: http://www.acc.org/clinical/guidelines/stemi/index.pdf.

STRIVETM

STEMI Critical Pathways

Corbelli J, et al. Critical Pathways in Cardiology. 2003;2:71-87.

ST-ELEVATION MI (STEMI): EMERGENCY DEPARTMENT ORDERS

ALLERGIES

DO NOT USE THESE UNSAFE ABBREVIATIONS“U” and “IU” should be unit, “Ug” should be mcg. “QD” should be daily. “QOD” should be every other day. “BIW” should be two times a week. “TIW” should be three times a week, “AU”, “AS”, “OS”, and “OD” should be written out in full. Correct Use of Leading and Trailing Zeros – Always Leading Never Trailing. .1 should be 0.1 and 1.0 should be 1

Initial Orders Check all that apply

DIAGNOSTICS Stat EKG, obtain old EKG record Repeat stat EKG 60 minutes after initial bolus of Retavase Start Acute Coronary Syndrome Lab Panel: CMP, CBC/diff, PT/INR/aPTT, CK + CK-MB (site specific), Troponin-I, Magnesium, hs-CRP, lipid profile (routine) Stat portable CXR Cardiac monitor and SaO2 monitors Other ______________________________________ ANTI-ISCHEMIC THERAPY Oxygen 2L/minute Nasal Cannula (titrate to keep pulse oximetry saturations > 94%) IV – 0.9 NS: Intermittent Infusion Device KVO ____ ml/hour Opiate: __________________________________ mg IV (suggest Morphine Sulfate)

Nitroglycerin Therapy (Hold if patient has taken Sildenafil (Viagra) within 24 hours) NTG 0.4mg SL every 5 minutes X 3 doses or until pain relief or systolic BP < 100 mm Hg NTG paste _______________________inch(es) topically X 1 IV- start NTG infusion at 10 mcg/minute, then titrate as per pharmacy protocol (use 100mg in 250 ml D 5W)

ANTI-THROMBOTIC THERAPY Aspirin 162 mg po (2 chewable 81 mg tablets)

Actual WEIGHT____________ kg Estimated lbs Actual HEIGHT ____________ cm Estimated ft

STRIVETM

STEMI Critical Pathways

Fibrinolysis Indications 3-hr symptom onset Delay in PCI (door-to-balloon >90 min) Contraindications to PCI: poor arterial access, renal failure, dye allergy

Reperfusion TherapyIndications: Chest pain <12 hours, EKG ST-elevations or new left bundle branch block

Primary PCI Indications >3-hr symptom onset Presence of cardiogenic shock, CHF, contraindications to fibrinolysis Stat cardiology consult/catheterization lab page

Assess for contraindications for fibrinolytic therapy:1. History of hemorrhagic stroke at any time; other stroke or cerebrovascular event within 1 year2. Known intracranial neoplasm3. Active internal bleeding4. Suspected aortic dissection (consider CT of chest)

Reteplase (Retavase) 10 units IV bolus, repeat 10 units IV bolus at 30 minutes

HEPARIN THERAPY: (administer simultaneously with Retavase): Unfractionated heparin: ___units IV bolus (1000 units/ml), then ___units/hour IV infusionNote: When using a fibrinolytic (eg, reteplase): Use Cardiac Unfractionated Heparin Nomogram on back of form

Eptifibatide (Integrilin) _____ml IV bolus, then ____ml/hr IV infusion (dosing nomogram on back of form) (Dose adjustment based on serum creatinine may be required.) Unfractionated heparin _____ units IV bolus (1000 units/ml), then ______units/hour IV infusion

STRIVETMSTRIVE Scientific Committee

Sample Critical Pathways Grid: UA/NSTEMI

STRIVETM

Sample Pocket Card (front)

STRIVETM

Sample Pocket Card (back)

STRIVETM

Smooth Transition From Acute to Long-Term Management

Adapted from the American Heart Association. Get With The Guidelines. 2001.

• Follow guidelines• Improve communications• Ensure compliance• Improve quality of care

and outcomes

Guidelines Primary CareSecondary Prevention

CardiologyAcute Care

STRIVETM

Discharge Protocols Enhance communication with

patient and between specialist(s) and primary care physicians1

Medications: aspirin, clopidogrel, ACE inhibitor, β-blocker, statin1

Diet, exercise, smoking cessation recommendations1

Patient symptom awareness, “Act in Time” protocol2

Wallet-/purse-sized copy of ECG3

Follow-up appointments1

1. American Heart Association Web site. Get With The Guidelines. Available at: http://www.americanheart.org/presenter.jhtml?identifier=1165.

2. Act in Time to Heart Attack Signs Campaign. Available at: http://www.nhlbi.nih.gov/actintime/index.htm.

3. Greenberg DI, et al. J Cardiovasc Manag. 2004;15:16-18.

STRIVETMSTRIVE Scientific Committee

Sample Cardiac Discharge Checklist UA/NSTEMI

STRIVETM

Sample Letter to Patient’s PCP at Discharge for UA/NSTEMIDear Dr. ________________:Your patient, (name), has been discharged on (date) following treatment for ____ days with a diagnosis of acute coronary syndromes (unstable angina ___ or non-ST-segment elevation myocardial infarction ___). Risk stratification at discharge was _______________________. The patient underwent the following procedures: PCI _____ CABG _____The following medications have been prescribed post-discharge:Aspirin + clopidogrel:Aspirin at a dose of _____ mg/dClopidogrel at a dose of 75 mg/dNitrates (________________) at a dose of ______ mg/dBeta-blocker (________________) at a dose of ______ mg/dACE inhibitor (________________) at a dose of ______ mg/dCalcium channel blocker (________________) at a dose of ______ mg/dLipid-lowering agent(s)(__________________) at a dose of ______ mg/dOther: ________________________________________________________________The following counseling concerning risk modification was provided:______________________Follow-up is strongly recommended in these areas: ___________________________________If you have questions, please contact me at: telephone_______________voice mail ____________ email_______________________________Sincerely,

(Hospital discharge report attached)

STRIVETM

What Is the EvidenceThat Critical Pathways Work?

UCLA Cardiac Hospitalization Atherosclerosis Management Program (CHAMP)

ACC Guidelines Applied in Practice (GAP) initiative

AHA “Get With The Guidelines” program

CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines)

STRIVETM

CHAMP Study: UCLA

Designed to determine whether physician/patient compliance with preventive therapies can be improved through a hospital-initiated program

Tracked initiation of aspirin, β-blocker, ACE inhibitor, statins Used preprinted orders, guidelines, lectures, discharge forms Population: patients with symptomatic atherosclerosis treated at

university-associated teaching hospital Methods: no specific algorithms used before CHAMP (1992-1993) National guidelines (ACC/AHA, NCEP ATP I and ATP II) used in

CHAMP (1994-1995) Evaluation: treatment rates and clinical outcomes pre-CHAMP

and CHAMP in patients hospitalized for acute MI

Fonarow GC, Gawlinski A. Am J Cardiol. 2000;85(3A):10A-17A.

Cardiac Hospitalization Atherosclerosis Management Program

STRIVETM

Discharge Medications at UCLA Compared With 1437 NRMI Hospitals

0

20

40

60

80

100

Aspirin β-blockers ACEI Statins

68

92 9194 96

12

6872

78

85

52

6470

75

88 8990 91

98/99 Post-CHAMP (UCLA)00/01 Post-CHAMP (UCLA)

92/93 Pre-CHAMP (UCLA)94/95 Post-CHAMP (UCLA)96/97 Post-CHAMP (UCLA)

Fonarow GC, et al. Am J Cardiol. 2001;87:819-822.

[NRMI Hospitals 00/01 (n=154,602)]Nat’l Benchmark

Uti

lizat

ion

Rat

e (%

)CHAMP Over an 8-Year Period: Rapid and Sustained

Improvement, Superior to National Benchmarks

3742

65

77

STRIVETMAdapted from Mehta RH, et al. JAMA. 2002;287:1269-1276.

0

20

40

60

80

100

At Admission At Discharge

Pre-GAPPost-GAP

Asp

irin

Usa

ge

(%)

81 87 8492

P=.02 P=.002

ACC’s Guidelines Applied in Practice (GAP) Initiative: Impact on Aspirin Usage

at Admission and Discharge

STRIVETMAdapted with permission from Mehta RH, et al. JAMA. 2002;287:1269-1276.

Qu

alit

y

Ad

he

ren

ce

(%

)

Preintervention

No Tool Use

Tool Use

Postintervention

0

20

40

60

80

100

Aspirin β-Blocker LDL-CNo. of Ideal

Patients

81 8693

6573 77

64 64

82

343 308 96 213 174 71 131 165 87

P=.004P=.001

Early Quality Indicators and Standard Admission Orders

GAP Initiative: Adherence Improves With Tool Use

STRIVETM

GAP Initiative: Changes in Mortality Before and After GAP Project

Eagle KA, et al. J Am Coll Cardiol. 2005;46:1242-1248.

0

5

10

15

20

25

30

35

40

45

In-hospitalMortality

30-dMortality

1-yrMortality

% Baseline

Post-GAP P=.017

P=.001

P=.004

STRIVETM

AHA “Get With The Guidelines” Program

Components Training materials for hospital staff Patient education materials Assistance in creating multidisciplinary team Secondary prevention guidelines CME workshops Sample materials (care maps, discharge

protocols, discharge forms)

American Heart Association Web site. Get With The Guidelines. Available at: http://www.americanheart.org/presenter.jhtml?identifier=1165.

STRIVETM

Clinical/Lab: 8 clicks

Clinical/Lab: 8 clicks

Interactively checks patient’s data with the AHA Guidelines

Interactively checks patient’s data with the AHA Guidelines

Discharge meds and interventions: 7 clicks

Discharge meds and interventions: 7 clicks

Demographics: 6 clicks

Demographics: 6 clicks

AHA Tool: Simple One-Page, Online Form

American Heart Association Web site. Get With The Guidelines. Available at: http://www.americanheart.org/presenter.jhtml?identifier=1165.

STRIVETM

Rehab/Exercise

Baseline 4-6 Months 9-12 Months Benchmark*

Intervention

0

20

40

60

80

100

SmokingCounsel

LDL-C BPControl

Pro

po

rtio

n o

f P

ati

ents

*Benchmarks established by CMS AND NRMI.Reprinted with permission from the American Heart Association Web site. Get With The Guidelines. Available at: http://www.americanheart.org/presenter.jhtml?identifier=1165.

Get With The Guidelines 12-Month Pilot Results: 85 New England Hospitals

N=1709

STRIVETM

CRUSADE Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early

Implementation of the ACC/AHA Guidelines

Nationwide quality improvement (QI) initiative– Up to 600 participating hospitals

Collaborative effort between emergency medicine, cardiology, hospital QI, academia, and industry

Focused on improving the care of NSTEMI ACS patients

Adapted from CRUSADE Overview 2004. Available at: http://www.crusadeqi.com.© 2005 Duke Clinical Research Institute. Used with permission.

STRIVETM

CRUSADE: Inclusion Criteria Ischemic symptoms lasting >10 minutes within previous 24

hours and at least one of the following:

– Positive cardiac markers CK-MB or Tnl/TnT above ULN Positive bedside troponin assay

– ST-segment ECG changes ST-segment depression >0.5 mm Transient ST-segment elevation 0.6–1 mm (lasting

<10 mins)

Transfer patients (with any of the above) must arrive at CRUSADE hospital within 24 hours of symptoms

© 2005 Duke Clinical Research Institute. Used with permission. Available at http://www.crusadeqi.com.

STRIVETM

Goals for CRUSADE

Aspirin– Clopidogrel

-Blocker Heparin (UFH or LMWH) GP IIb/IIIa Inhibitor

– Cath/PCI

Aspirin Clopidogrel -Blocker ACE Inhibitor Statin/Lipid Lowering Smoking Cessation Cardiac Rehabilitation

Acute Therapy Discharge Therapy

2002 ACC/AHA Guidelines Update. Adapted from 2005 CRUSADE 2nd Quarter Results. Available at: http://www.crusadeqi.com.© 2005 Duke Clinical Research Institute. Used with permission.

Improve Adherence to ACC/AHA Guidelines Improve Patient Outcomes

STRIVETM

Hospital Presentation Characteristics in CRUSADE:

July 1, 2005–June 30, 2006 (n=31,665) Qualifying criteriaST-segment depression 28%Transient ST-segment elevation 5%Positive cardiac markers 93%

Baseline cardiac markers DrawnPositive

CK-MB 82%75%TnT/TnI 99%91%

Presenting characteristics Tachycardia 23%Hypotension 4%Signs of CHF 23%Adapted from 2006 CRUSADE Results.

Available at: http://www.crusadeqi.com.© 2006 Duke Clinical Research Institute. Used with permission.

STRIVETM

Baseline Characteristics:CRUSADE vs ACS Clinical Trials

Variable PURSUIT CURE SYNERGY CRUSADE(n = 9461) (n = 12,562) (n = 9975) (n = 180,842)

Mean age ± SD (yrs)63 ± 11 63 ± 12 67 ± 11 67 ± 14

Female sex (%) 36 39 34 40

Diabetes mellitus (%) 23 23 29 33

Prior MI (%) 32 25 28 30

Prior CHF (%) 11 8 9 18

Prior PCI (%) 13 18* 20 21

Prior CABG (%) 12 18* 17 19

ST depression (%) 50 42 55 34

N Engl J Med. 1998;339:436-43.N Engl J Med. 2001;345:494-502.JAMA. 2004:292:45-54.CRUSADE cumulative through June 30, 2006.

N Engl J Med. 1998;339:436-43.N Engl J Med. 2001;345:494-502.JAMA. 2004:292:45-54.CRUSADE cumulative through June 30, 2006.

STRIVETM

CRUSADE: Trends in Acute Therapy Adherence

Adapted from 2006 CRUSADE Results. Available at: http://www.crusadeqi.com.© 2006 Duke Clinical Research Institute. Used with permission.

96%90%

84%

46%

97%93% 88%

50%

0%

25%

50%

75%

100%

Antiplatelet β-Blocker Heparin GP IIb/IIIaInhibitor

Quarter 3-05 Quarter 4-05 Quarter 1-06 Quarter 2-06

Quarter 3, 2005, through Quarter 2, 2006.

STRIVETM

CRUSADE Data: July 1, 2005-June 30, 2006 (n=31,665)

CRUSADE: Invasive Cardiac Procedures July 1, 2005 – June 30, 2006 (n=31,665)

(Among Patients Without Contraindications to Cath)


83%

67%

53%

38%

12%

0%

20%

40%

60%

80%

100%

Cath Cath<48 hr

PCI PCI <48 hr CABG

STRIVETM

CRUSADE: Trends in Discharge Therapy Adherence

Quarter 3, 2005, through Quarter 2, 2006


94%

72%

91%

64%

89%

74%

94%

66%

88%95%

0%

25%

50%

75%

100%

Aspirin Clopidogrel β-Blocker ACE Inhibitor Lipid- Lowering

Agent


STRIVETM

CRUSADE: Trends in Discharge Recommendations Adherence

84%81%

62%

84%

62%

92%

0%

25%

50%

75%

100%

Smoking CessationCounseling

Dietary Modification Cardiac RehabilitationReferral


Quarter 3, 2005, through Quarter 2, 2006. Adapted from 2006 CRUSADE Results. Available at: http://www.crusadeqi.com.© 2006 Duke Clinical Research Institute. Used with permission.

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CRUSADE: Overall Guideline Adherence Trends Over Time

Available at www.crusadeqi.com © 2006 Duke Clinical Research Institute. Used with permission.

Quarter 1 2002

Quarter 12003

Quarter 12004

Quarter 12005

Quarter 22006

68.1%73.0%

78.0%80.8% 83.2%

0%

25%

50%

75%

100%

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Performance Matters! Association Between Hospital Guideline

Adherence and In-hospital Mortality in CRUSADE

Adapted with permission from Peterson ED, et al. JAMA.2006;295:1912-1920.

NSTE ACS = non-ST-segment elevation ACS; NSTEMI = non-ST-segment elevation MI.

8

7

6

5

4

3

2

1

01 2 3 4

In-H

osp

ital

Mo

rtal

ity

, %

Hospital Composite GuidelineAdherence Quartiles

NSTE ACS 8

7

6

5

4

3

2

1

01 2 3 4

In-H

osp

ital

Mo

rtal

ity

, %

Hospital Composite GuidelineAdherence Quartiles

NSTEMI

CRUSADE = Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines.

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NRMI. Available at: http://www.nrmi.org/index.html. Get With The Guidelines. Available at: http://www.americanheart.org. ACC National Cardiovascular Data Registry. Available at: http://www.acc.org/ncdr/index.htm. GRACE. Available at: http://www.umassmed.edu/outcomes/grace. CRUSADE. Available at: http://www.crusadeqi.com.REACH. Available at: http://www.REACHregistry.org

Importance of Data-Collection Registries Track adherence to guidelines Support local quality-improvement programs Compare practice patterns/outcomes with national benchmarks Comply with regulatory requirements Provide research data Major data-collection registries

– NRMI– AHA “Get With The Guidelines” Patient Management Tool– ACC National Cardiovascular Data Registry– GRACE– CRUSADE– REACH

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CRUSADE: Latest Results in NSTEMI ACS in US: Conclusions

Care for NSTEMI ACS is improving:– Continued progress in adherence to ACC/AHA Guidelines for

both acute and discharge treatments

– More early cath, leading to earlier discharge

Yet opportunities for improvement persist– Largest gaps: acute GP IIb/IIIa, D/C ACE, clopidogrel

– “Right dosing” to reduce adverse events

And can lead to even better patient outcomes!

Available at www.crusadeqi.com.© 2005 Duke Clinical Research Institute. Used with permission.

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Conclusions Gap between knowledge of guidelines

and practice

Several studies show:– Critical pathways interventions improve

care and improve patient outcomes

Need local champions, implementation plan, and action!

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Your Hospital Needs You As Champions!

Introduction to Breakout Session

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Breakout Session Identify a spokesperson/“team leader” for your group

Identify a “Champion” who will lead critical pathways implementation at hospital (spokesperson at workshop may or may not be the “Champion”)

Review sample pathways in your binder and copies of your own pathways if you have them with you

Faculty will circulate and respond to questions during the breakout sessions

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Breakout Session The session will be divided into 3 time periods

– Review pathways (15 min.)– Identify barriers to implementation (15 min.)– Develop a plan of action (15 min.)

At the end of each period, spokesperson will report progress to the main group

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Breakout Objective #1 (15 minutes)

Review the sample critical pathways and tools (last tab in your binder and on the flash drive)

If you already have ACS critical pathways for STEMI and UA/NSTEMI: Identify and discuss updates that can be made to your existing pathways

If you do not have ACS critical pathways for STEMI and/or UA/NSTEMI: Review the samples and begin planning customized critical pathways for your institution

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Breakout Objective #2

Identify barriers to implementing critical

pathways at your hospital and list potential

solutions to overcoming them

(15 minutes)

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Breakout Objective #3

Develop a short-term and long-term plan

to implement your new or updated

ACS critical pathways

(15 minutes)

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Concluding Remarks

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Conclusions Guidelines for both UA/NSTEMI and STEMI have had

updates in antithrombotic therapies and interventions

Major gap exists between physicians’ knowledge of guidelines and therapies received by patients

Studies show that critical pathways interventions (eg, GAP, CHAMP, GTWG, CRUSADE)– Improve care– Are associated with improved outcomes

Participation in national data registries enables multidisciplinary hospital teams to monitor and refine critical pathways and improve outcomes

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Revised ACC/AHA GuidelinesComing Soon…

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Success is Up to You Important to identify/recruit a “Champion” (should be

first order of business when you return to the hospital if not established this evening)

Begin to assemble multidisciplinary team for pathways development/implementation

Establish specific goals with time frames (eg, modify template or existing pathways to include new ACC/AHA Guidelines)

Schedule regular meetings to discuss progress

Begin to implement the new or revised ACS Critical Pathways -- set a time goal)

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Documents

STRIVE TM. STRIVE TM Learning Objectives Apply the current ACC/AHA guidelines for management of STEMI and UA/NSTEMI patients to the development of critical