Transcript STRIVE Lecture 1 - Clinical Trial Results

STRIVE
TM
Learning Objectives
After taking part in this activity, participants should be able to:

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
STRIVE
TM
Learning Objectives (cont.)
After taking part in this activity, participants should be able to:

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
STRIVE
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Pathophysiology and
Epidemiology of
Acute Coronary Syndromes
STRIVE
TM
Atherothrombosis:
A Progressive Phenomenon
Atherosclerosis
Thrombosis
Unstable
angina
MI
A
C
S
Ischemic
stroke/TIA
Acute limb
ischemia
Cardiovascular
death
Adapted from Libby P. Circulation. 2001;104:365-372.
Libby P. Sci Am. 2002;286:46-55.
STRIVE
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Spectrum of CAD/ACS
No ST elevation
Stable
angina
Unstable
angina
NSTEMI
ST elevation
STEMI
ACUTE CORONARY SYNDROMES
CAD = coronary artery disease; NSTEMI = non-ST-segment elevation myocardial infarction;
STEMI = ST-segment elevation myocardial infarction.
Source (Photos): Davies MJ. Heart. 2000;83:361-366.
STRIVE
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Epidemiology of CAD/ACS
1.56 Million
Hospital Discharges for ACS
UA/NSTEMI
~1.23
Million
Discharges Per Year
STEMI
~0.33 Million
Discharges
Per Year
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 in
Wiviott S, et al. J Am Coll Cardiol. 2006;47;1553-1558.
STRIVE
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Evidence of Multiple “Vulnerable”
Plaques in ACS
Angiographic and angioscopic images of a 58-year-old man
with anterior myocardial infarction
Multiple
“vulnerable”
plaques
detected in
nonculprit
segments 1-7
Culprit lesion with
thrombus (red)
detected in #8
Reprinted with permission from Asakura M, et al. J Am Coll Cardiol. 2001;37:1284-1288.
Multiple
“vulnerable”
plaques
detected in
nonculprit
segments 9-12
STRIVE
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Overlap of Atherosclerotic Disease
Cerebrovascular
Disease
Coronary
Artery Disease
38% overlap in
2 vascular beds
Peripheral Arterial
Disease
Patients with 1 manifestation
often have coexistent disease in other vascular beds
Ness J, Aronow WS. J Am Geriatr Soc. 1999;47:1255-1256.
STRIVE
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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 College
of Cardiology; March 12, 2006; Atlanta, Ga.
STRIVE
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Baseline Prevalence of Polyvascular
Disease in the REACH Registry
Single Arterial Bed
Overall
CAD Alone
CVD Alone
PAD Alone
%
65.9
44.6
16.6
4.7
Polyvascular Disease
Overall
CAD + CVD
CAD + PAD
CVD + PAD
CAD + CVD + PAD
15.9
8.4
4.7
1.2
1.6
Multiple Risk Factors
18.3
0
10
20
30
40
50
60
70
Patients, %
Bhatt DL, et al; for the REACH Registry Investigators. JAMA. 2006;295:180-189.
STRIVE
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REACH 1-Year Results: Single vs Multiple and
Overlapping Atherothrombotic Locations:
The Example of CAD
30
26.9
25
23.3
CAD alone
CAD+CVD
CAD+PAD
CAD+CVD+PAD
20
%
20
15
13.3
10
7.4
6.4
5
1.5 2
2.9
4
3.7
3.6
1.4 1.6 1.4 1.8
0.9
4.8
3.1
1.3
0
CV Death
Nonfatal MI Nonfatal Stroke
Death/MI/
Stroke
Death/MI/
Stroke/Hosp*
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 College
of Cardiology; March 12, 2006; Atlanta, Ga.
STRIVE
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ACS Treatment Strategies
Reperfusion/Revascularization Therapy
Medical
therapy
Thrombolysis
CABG
PCI (with/
without stenting)
Antithrombotic Cotherapy
ASA
UFH
LMWH
Penta
DTI
GP IIb/
IIIa
ADP
antagonist
Acute and Long-term Medical Therapy
Nitrates
BBs
ACEIs
ARBs
CCBs
Statins
APT
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 = adenosine
diphosphate antagonist; BBs = beta blockers; ACEI = angiotensin converting enzyme inhibitors;
ARBs = angiotensin receptor blockers; CCBs = calcium channel blockers; APT = antiplatelet therapy.
STRIVE
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ST-Segment Elevation
Myocardial Infarction (STEMI) in
the Emergency Department
STRIVE
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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
Antman EM, et al. J Am Coll Cardiol. 2004;44:671-719.
STRIVE
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Options for Transport of Patients With STEMI
and Initial Reperfusion Treatment
Hospital fibrinolysis:
door-to-needle
within 30 min
Not PCI
capable
Onset of
symptoms of
STEMI
9-1-1
EMS
dispatch
EMS on-scene
• Encourage 12-lead ECGs
• Consider prehospital fibrinolytic
if capable and EMS-to-needle
within 30 min
GOALS
5
min
8
min
Patient EMS
Interhospital
transfer
PCI
capable
EMS Transport
Prehospital fibrinolysis
EMS-to-needle
within 30 min
Dispatch
1 min
Golden hr = 1st 60 min
EMS transport
EMS-to-balloon within 90 min
Patient self-transport
Hospital door-to-balloon
within 90 min
Total ischemic time: within 120 min
Adapted with permission from Antman EM, et al. Available at:
http://www.acc.org/clinical/guidelines/stemi/index.pdf.
Accessed September 1, 2006
STRIVE
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ER-TIMI 19: Time Saved to First r-PA Bolus with
Prehospital Administration
Data=Median Times (Q1-Q3)
Ambulance
arrival
ED arrival
Inhospital
lytic
63 min (48–89)
Control
31 min (24–37)
32 min saved
P<.0001*
Prehosp
First r-PA bolus
*Adjusted for any effect of site and interaction.
Adapted with permission from Morrow DA, et al. J Am Coll Cardiol. 2002;40:71-77.
STRIVE
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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.
STRIVE
TM
ACC/AHA 2004 STEMI Guidelines:
Acute Medical Therapy
General treatment
measures



Infarct size
limitation
Reperfusion
Antithrombotic
and antiplatelet
therapy





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
Antman EM, et al. Available at: http://www.acc.org/clinical/guidelines/stemi/index.pdf.
Accessed September 1, 2006.
STRIVE
TM
Primary PCI vs Thrombolysis in STEMI:
Quantitative Analysis (23 RCTs, N=7739)
25
Frequency (%)
20
Short-term
outcomes
(4-6 wk)
P<.000
1
P<.000
1
15
P=.000
2
P<.000
1
PCI
P=.032
10
Thrombolytic
therapy
5
0
P<.000
1
Death
Nonfatal
MI
Recurrent HemorIschemia rhagic
Stroke
Major
Bleed
Death,
Nonfatal
Reinfarction,
or Stroke
Adapted with permission from Keeley EC, et al. Lancet. 2003;361:13-20.
STRIVE
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Absolute Risk Difference in Death (%)
Mortality With 1° PCI vs Time Delay
15
Circle sizes = sample size of individual
study
10
Solid line = weighted meta-regression
P=.006
5
62 min
Favors PCI
Favors lysis
0
-5
0
20
40
60
80
100
PCI-related Time Delay (Door-to-Balloon minus Door-to-Needle)
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.
STRIVE
TM
Clinical Trials of Interhospital Transfer
for PCI vs Fibrinolysis
Mortality (%)
20
On-site fibrinolysis
Transfer for PCI
14
15
12.1
10
6.7 6.7
7
8.4
10
8.5
6.8
6.5
5
0
LIMI1 PRAGUE-12 AIR-PAMI3 PRAGUE-24 DANAMI5
(N=150)
(N=200)
(N=137)
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.
(N=850)
(N=1129)
STRIVE
TM
STEMI: Transfer for PCI
NRMI (1999-2002) 4278 Patients
Door-to-Balloon Time
% of Patients
<90 min
4.2
<2 h
16.2
2–4 h
55.4
>4 h
28.4
Nallamothu BK, et al. Circulation. 2005;111:761-767.
STRIVE
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Facilitated PCI,
Rescue PCI, and Adjunctive
Therapy for STEMI
STRIVE
TM
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.
STRIVE
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Meta-analysis of
17 Facilitated PCI Trials*
Event
Facilitated PCI (%)
PCI (%)
P
Death
5.0
3.0
.04
Reinfarction
Urgent TVR
Major bleeding
Stroke
3.0
4.0
7.0
1.1
2.0
1.0
5.0
0.3
.006
.010
.010
.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.
STRIVE
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Rescue Angioplasty Versus
Conservative Treatment
or Repeat Thrombolysis (REACT) Trial
427 STEMI patients with failed thrombolysis
ASA and thrombolytic therapy (60% rec’d streptokinase) within 6 h of chest pain onset,
<50% ST-segment resolution within 90 minutes
Repeated thrombolysis
with alteplase or reteplase
(n=142)
Rescue PCI
Angiography with or without
revascularization (n=144)
Conservative Treatment
Including IV UFH for 24 h
(n=141)
Primary End Point
Composite of death, reinfarction, stroke, or severe heart failure
within 6 months
Gershlick AH, et al. N Engl J Med. 2005;353:2758-2768.
STRIVE
TM
RESCUE PCI:
Probability of Event-free Survival
REACT Trial — Primary End Point
Primary End Point = death, recurrent MI, severe heart
failure, or cerebrovascular event within 6 months
1.00
Rescue PCI 84.6%
95% Cl, 78.7-90.5
0.90
0.80
Conservative therapy 70.1%
95% Cl, 62.5-77.7
0.70
Repeated thrombolysis 68.7
95% Cl, 61.1-76.4
P=.004
0.60
0.00
0
20
40
60
80
100 120 140
Days After Randomization
160
180
200
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.
STRIVE
TM
ExTRACT-TIMI 25: Protocol Design
STEMI < 6 h
Lytic eligible
ASA
Lytic choice by MD
(TNK, tPA, rPA, SK)
Double-blind, double-dummy
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
UFH (N = 10,223)
60 U / kg bolus (4000 U)
Inf 12 U / kg / h (1000 U / h)
Duration: at least 48 h
Cont’d at MD discretion
Day 30
1° Efficacy End Point: Death or Nonfatal MI
1° Safety End Point: TIMI Major Hemorrhage
ExTRACT = Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction
Antman EM et al. N Engl J Med. 2006;354:1477-1488.
Adapted with permission from http://www.clinicaltrialresults.com.
STRIVE
TM
Main Results From ExTRACT-TIMI 25
Main Secondary Endpoint:
Death, non-fatal re-MI, urgent
revascularization by 30 days
Primary End point:
Death or nonfatal re-MI by 30 days
UFH
12
9.9
12
14.5
11.7
ENOX
9
%
UFH
12.0 15
ENOX
9
RR = 0.83
6
p = 0.000003
%
3
3
0
0
0
5
RR = 0.81
6
10 15 20 25 30
Days
p = 0.000001
0
5
10 15 20 25 30
Days
• Major bleeding: 1.4% with UFH vs 2.1% with enoxaparin (P<.001)
• ICH: .7% for UFH vs .8% for enoxaparin (P=.14)
Adapted with permission from www.clinicaltrialresults.org.
Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:1477-1488.
STRIVE
TM
ExTRACT-TIMI 25:
Net Clinical Benefit at 30 Days
Prespecified Definitions
UFH (%) Enox (%) RRR (%)
Death or Nonfatal MI or
Nonfatal Disabling Stroke
12.3
10.1
18
12.8
11.0
14
12.2
10.1
17
P<.001
Death or Nonfatal MI or
Nonfatal Major Bleed
Death or Nonfatal MI or
Nonfatal ICH
P<.001
P<.001
0.8
0.9
Enoxaparin Better
1
RR
1.25
UFH Better
Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:1477-1488.
STRIVE
TM
ExTRACT-TIMI 25 PCI Cohort: Primary
End point Death or Nonfatal MI by 30 days
Death or MI (%)
15
UFH
13.8%
ENOX
10.7%
10
RR 0.77
P=0.001
5
0
0
5
10
15
Days
20
Gibson M. Presented at World Congress of Cardiology; September 4, 2006;
Barcelona, Spain. Adapted with permission from www.clinicaltrialresults.org.
25
30
STRIVE
TM
ExTRACT-TIMI 25 PCI Cohort: Safety
Event
ENOX
n=2,238
UFH
RR
P-Value
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
Minor Bleed
4.6%
4.0%
1.15 (0.88-1.51)
.31
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.
STRIVE
TM
OASIS-6 Trial: Study Design
12,092 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
Stratum 1 (No UFH)
n=5,658
Fondaparinux
n=2,823
Placebo
n=2,835
2.5 mg/day for up to 8 days
or hospital discharge


Stratum 2 (UFH)
n=6,434
Fondaparinux
n=3,213
UFH
n=3,221
2.5 mg/day for up to 8 days
or hospital discharge
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
Yusuf S, et al. JAMA. 2006;295:1519-1530.
Adapted with permission from www.clinicaltrialresults.org.
STRIVE
TM
OASIS-6 Trial: Results
Reduction in Death/MI at 30 days:
Stratum 1 (No UFH indicated)
P<.05
14
14%
Primary End Point:
Death/Reinfarction (%)
14.8
15%
13.4
10%
8%
4%
9.7
9%
8.9
2%
7.4
0%
6%
3%
P=.008
P=.003
P=.008
0%
9 days
Fondaparinux (n=6036)
3-6 months
Control (n=6056)
Fondaparinux
Placebo
Reduction in Death/MI: Stratum 2
14%
(UFH Indicated)
12%
P=NS
10%
30 days
11.2
6%
11.2
12%
Frequency
12%
8.3
8%
8.7
p=0.
97
6%
4%
2%
Yusuf S, et al. JAMA. 2006;295:1519-1530.
Adapted with permission from www.clinicaltrialresults.org
0%
Fondaparinux
UFH
STRIVE
TM
CLARITY–TIMI 28: Study Design
Double-blind, randomized, placebo-controlled trial in
3491 patients, aged 18-75 yrs, with STEMI <12 hours
Fibrinolytic, ASA, Heparin
Randomized
Clopidogrel
300 mg + 75 mg qd
Placebo
Study
Drug
Coronary Angiogram
(2-8 days)
Open-label
clopidogrel
per MD in
both groups
Primary end point:
Occluded artery
(TIMI flow grade 0/1)
or death/MI
by time of angio
30-day clinical follow-up
CLARITY-TIMI 28 = CLopidogrel as Adjunctive ReperfusIon TherapY – Thrombolysis In
Myocardial Infarction.
Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.
STRIVE
TM
CLARITY–TIMI 28: End Points
CV Death, MI, RI  Urg Revasc
25
36%
21.7
15
Odds Reduction
Placebo
20
15
20%
Endpoint (%)
Occluded Artery or Death/MI (%)
Primary End Point Occluded
Artery (or Death/MI Through
Angio/HD)
15.0
10
10
Clopidogrel
Odds Ratio: 0.80
(95% CI, 0.65-0.97)
P=.03
5
5
0
0
n=1752
n=1739
Clopidogrel
Placebo
0
Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.
5
10
15
20
25
30
Days
STRIVE
TM
COMMIT/CCS-2: Study Design
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)
Mean treatment and follow-up: 16 days
COMMIT = ClOpidogrel & Metoprolol in Myocardial Infarction Trial.
COMMIT Collaborative Group. Lancet. 2005;366:1607-1621.
STRIVE
TM
COMMIT: Effect of Clopidogrel
on Death, Re-MI, or Stroke
Placebo + ASA: 1846
deaths (8.1%)
Placebo + ASA: 2311
events (10.1%)
9
8
7
Clopidogrel + ASA:
2125 events (9.3%)
Clopidogrel + ASA:
1728 deaths (7.5%)
6
6
5
4
9% (SE3) relative risk
reduction (2P=.002)
3
Mortality (%)
Event (%)
7
5
4
3
7% (SE3) relative
risk reduction
(2P=.03)
2
2
1
0
0
7
14
21
28
Days Since Randomization (up to 28 days)
1
0
0
7
14
21
28
Days Since Randomization (up to 28 days)
COMMIT = ClOpidogrel & Metoprolol in Myocardial Infarction Trial.
COMMIT Collaborative Group. Lancet. 2005;366:1607-1621.
STRIVE
TM
2004 ACC/AHA STEMI Guidelines
Secondary Prevention Goals
Preventive Measure
Goal
Smoking →
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.
STRIVE
TM
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)
STRIVE
TM
Unstable Angina/
Non–ST-Segment Elevation
Myocardial Infarction
(UA/NSTEMI)
Risk Stratification and Medical Management
STRIVE
TM
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.
STRIVE
TM
Likelihood of ACS Secondary to CAD
“CONFIDENCE OF DIAGNOSIS”
High
Intermediate
Low
History
Chest or left arm pain
Sx as in prior angina
Known history of CAD
Chest or left arm
pain; age >70 yr
Male sex; DM
Sx w/o intermediate
likelihood characteristics; recent cocaine
Exam
Transient MR,
hypotension,
diaphoresis,
pulmonary edema, or
rales
Extracardiac
vascular
disease
Chest pain
reproduced
by palpation
ECG
New transient
ST-segment deviation
or T-wave inversion
with symptoms
Fixed Q waves
Abnormal ST-seg
or T-waves not
documented as new
T-wave flattening or
inversion in leads
w/dominant R waves
Normal ECG
Cardiac
Markers
Elevated
Normal
Normal
Adapted from Braunwald E, et al. Available at:
http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.
STRIVE
TM
TIMI Risk Score for UA/NSTEMI:
7 Independent Predictors
45
2. ≥3 CAD risk factors (high
40
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
% Death / MI / Revasc
1. Age ≥65 y
35
30
25
20
15
10
5
7. Elevated cardiac markers
(CK-MB or troponin)
0
0/1
2
3
4
5
6/7
Number of Predictors
Antman EM, et al. JAMA. 2000;284:835-842.
STRIVE
TM
30-Day Mortality Relative Risk
Troponin I, C-Reactive Protein, and B-type Natriuretic
Peptide as Determinants of 30-Day Mortality in Acute
Coronary Ischemia: A Multimarker Approach
OPUS-TIMI 16
6
6
8
3
2
1
0
4
1
n=150
150
5.7
6
1.8
n=67
67
P<.0001
10
3.5
4
13
14
12
P=.014
5
TACTICS-TIMI 18
n=155
155
n=78
78
0
1
2
3
Elevated Cardiac Biomarkers (N)
2
0
1
n=504
504
2.1
n=717
717
n=324
324
n=90
90
0
1
2
3
Elevated Cardiac Biomarkers (N)
Adapted with permission from Sabatine MS, et al. Circulation. 2002;105:1760-1763.
STRIVE
TM
Future of Biomarkers in ACS:
Toward a Multimarker Strategy
Myocyte Necrosis
Troponin
Hemodynamic
Stress
Inflammation
hs-CRP, CD40L
BNP, NT-proBNP
HbA1c
Accelerated
Blood glucose Atherosclerosis
Vascular
Damage
CrCl
Microalbuminuria
Biomarker Profile in ACS
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.
STRIVE
TM
Evidence-Based Risk Stratification
to Target Therapies in UA/NSTEMI
Aspirin, Clopidogrel, Heparin/LMWH (IIa Enox)
β-blocker, Nitrates
Higher Risk
+Troponin, STs, TRS 3,
Recurrent Ischemia, CHF,
Prior Revascularization
Lower Risk
– ECG, – Markers,
TRS 0-2
Invasive Strategy With
GP IIb/IIIa Inhibitor
Conservative
Strategy
Long-term Medical Therapy
(Aspirin, Clopidogrel, Statin, β-blocker, ACEI)
TRS = TIMI Risk Score.
Adapted with permission from Cannon CP. Circulation. 2002;106:1588-1591.
STRIVE
TM
ACC/AHA Guidelines for UA/NSTEMI
Anti-ischemic Therapy

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
Adapted from Braunwald E, et al. Available at:
http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.
STRIVE
TM
ACC/AHA Guidelines for UA/NSTEMI
Antithrombotic Therapy Class I Recommendations*
Definite ACS
With Cath and PCI
or Higher Risk (IIa)
Aspirin
+
IV heparin/LMWH*
+
IV platelet
GP IIb/IIIa
inhibitor
Lower-Risk
ACS
Possible
ACS
Aspirin
+
SQ LMWH*
or
IV heparin
Aspirin
clopidogrel
clopidogrel
*Class IIa: enoxaparin preferred over IV heparin.
Adapted from Braunwald E, et al. Available at:
http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.
STRIVE
TM
ASA in UA/NSTEMI
Death or MI
*P=.0005
12
*P=.012
15
10.1
*P=.008
15
12.9
*P<.0001
20
17.1
11.9
Patients (%)
15
10
8
10
5.0*
4
6.2*
5
0
ASA
178
Lewis HD Jr, et al.
N Engl J Med.
1983;309:396-403.
6.5*
5
0
Placebo
158
10
3.3*
0
0
Placebo
279
ASA
276
Cairns JA, et al.
N Engl J Med.
1985;313:1369-1375.
5
Placebo
118
ASA
121
Theroux P, et al.
N Engl J Med.
1988;319:1105-1111.
Placebo
397
ASA
399
The RISC Group.
Lancet.
1990;336:827-830.
STRIVE
TM
CURE Study: Event-Free Survival
CV Death, MI, or Stroke
First 30 Days
1.00
Proportion Event-Free
Proportion Event-Free
1.00
Clopidogrel
.98
.96
Placebo
.94
RRR: 21%
95% CI, 0.67–0.92
P=.003
.92
Clopidogrel
.98
.96
Placebo
.94
RRR: 18%
95% CI, 0.70–0.95
P=.009
.92
.90
.90
Week
CV Death, MI, or Stroke
>30 Days–1 Year
0
1
2
3
No. at Risk
Clopidogrel 6259 6145
6070 6026
Placebo
6303 6159
6048 5993
4
5990
5965
Month
1
5981
5954
4
6
8
10
12
No. at Risk
5481 4742 4004 3180 2418
5390 4639 3929 3159 2388
RRR = relative risk reduction.
Adapted with permission from Yusuf S, et al. Circulation. 2003;107:966-972.
STRIVE
TM
Cumulative Hazard Rate
CURE: Efficacy of Very Early
Clopidogrel Therapy in ACS Patients
CV Death, MI, Stroke, Severe Ischemia
Within First 24 Hours
0.025
34%
0.020
Relative
Risk
Reduction
Placebo
+ Aspirin
(n=6303)
0.015
0.010
P=.003
Clopidogrel
+ Aspirin
(n=6259)
0.005
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
Hours After Randomization
Adapted with permission from Yusuf S, et al. Circulation. 2003;107:966-972.
STRIVE
TM
CURE: Major Bleeding by Aspirin
Dose Through Follow-up
Aspirin
Dose
75-100 mg
101-199 mg
200-325 mg
Placebo Clopidogrel
+ Aspirin* + Aspirin*
1.9%
2.8%
3.7%
3.0%
3.4%
4.9%
*Other standard therapies were used as appropriate.
Peters RJ, et al. Circulation. 2003;108:1682-1687.
STRIVE
TM
Unstable Angina/
Non–ST-Segment Elevation
Myocardial Infarction
(UA/NSTEMI)
Early Invasive Strategy, PCI/Drug-eluting
Stents, Secondary Prevention
STRIVE
TM
ACC/AHA Guidelines for UA/NSTEMI:
Early Invasive Strategy
Class I
An early invasive strategy in patients with UA/NSTEMI and any of
the following high-risk indicators (Level of Evidence: A)
Recurrent angina/ischemia
Ejection fraction <.40
Elevated TnT or Tnl
Hemodynamic instability
ST-segment depression
Sustained VT
Recurrent angina/ischemia
PCI within 6 months
with CHF, S3, PE, rales, etc.
High-risk findings on
Prior CABG
noninvasive stress testing
Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374.
STRIVE
TM
Invasive Management of UA/NSTEMI Meta-analysis: 
Death/MI at End of Follow-up (mean 17.3 months)
Trial (N)
Odds Ratio
Death or MI
Inv (%) Cons (%)
TIMI IIIB (1473)
11.6
13.8
VANQWISH (920)
MATE (201)
32.9
14.4
30.3
12.2
FRISC II (2457)
10.4
14.1
TACTICS (2220)
VINO (131)
7.3
6.3
9.5
22.4
RITA 3 (1810)
10.6
12.9
Total (N=9212)
12.2
14.4
0.1
OR 0.82, P<.001
0.5
1
Favors
Invasive
Adapted with permission from Mehta S, et al. JAMA. 2005;293:2908-2917.
2
5
Favors
Conservative
STRIVE
TM
Optimal Strategy for UA/NSTEMI
ISAR-COOL
RITA-3
VANQWISH
ICTUS
VINO
MATE
TRUCS
TIMI IIIB
TACTICSTIMI 18
FRISC II
Conservative
Patients (N): 920
Invasive
2874
7018
Adapted with permission from Cannon CP, Turpie AG. Circulation. 2003;107:2640-2645.
STRIVE
TM
Benefit of Clopidogrel in PCI-CURE
According to Timing of PCI
PCI ≥ 48 hrs from rand and
during initial hosp
<48 hrs after rand
0.15
0.10
0.05
0.20
0.20
0.15
Placebo
0.10
Clopidogrel
0.05
0.0
0
100 200 300
Days of Follow-up
0.15
0.10
0.05
RR:.72 (0.51-1.01)
RR:.53 (0.27-1.06)
0.0
Cumulative Hazard Rates
Denotes median
Time to PCI
Cumulative Hazard Rates
Cumulative Hazard Rates
0.20
PCI after hospital
discharge
RR:.70 (0.48-1.02)
0.0
0
100 200 300
Days of Follow-up
Lewis BS, et al. Am Heart J. 2005;150:1177-1184.
0
100 200 300
Days of Follow-up
STRIVE
TM
Meta-analysis of Clopidogrel Pretreatment
MI before PCI (%)
Clopidogrel
Trial
Pretreatment
PCI-CURE
3.6
CREDO
n/a
PCI-CLARITY
4.0
Overall
3.7
No
Pretreatment
5.1
n/a
6.1
5.5
0.25
Favors Favors
Pretreatment No Pretreatment
OR: 0.67
P=.005
0.5
CV Death or MI after PCI (%)
Clopidogrel
Trial
Pretreatment
PCI-CURE
2.9
CREDO
6.0
PCI-CLARITY
3.3
Overall
3.9
1.0
OR (95% CI)
No
Pretreatment
4.4
7.1
5.4
5.5
0.25
2.0
OR: 0.71
P=.004
0.5
1.0
OR (95% CI)
Adapted with permission from Sabatine MS, et al. JAMA. 2005;294:1224-1232.
2.0
STRIVE
TM
ACC/AHA/SCAI 2005 Guideline Update for PCI
Oral Antiplatelet Adjunctive Therapies
I IIa IIb III
A
A loading dose of clopidogrel should be
administered before PCI is performed
B
An oral loading dose of 300 mg,
administered at least 6 hours before the
procedure, has the best established
evidence of efficacy
Adapted from Smith SC Jr, et al. Available at:
www.acc.org/clinical/guidelines/percutaneous/update/index_rev.pdf.
STRIVE
TM
ARMYDA-2 Trial: Design and Primary End Point
255 patients with stable CAD or
NSTEMI prior to PCI
13% received GP IIb/IIIa inhibitors
20% received drug-eluting stents
Primary composite of death, MI,
or target vessel revasc at 30 days
14%
P=.041
12
12%
Randomized 4-8
Hours Pre-PCI
10%
8%
High Loading
Dose
of Clopidogrel
600 mg
Pre-PCI
Standard
Loading
Dose of
Clopidogrel
300 mg
Pre-PCI
6%
4%
4
2%
0%
High Dose
Standard Dose
ARMYDA-2 = Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty.
Patti G, et al. Circulation. 2005;111:2099-2106.
STRIVE
TM
GP IIb/IIIa Inhibition for
Non–ST-Elevation ACS
Trial
n
30-Day Death or Nonfatal MI
Risk Ratio and 95% CI
GP IIb/IIIa
Placebo Inhibitor
3,232
7.1%
5.8%
PRISM-PLUS 1,915
11.9%
10.2%
PARAGON A 2,282
11.7%
11.3%
PURSUIT
9,461
15.7%
14.2%
PARAGON B 5,165
11.4%
10.5%
8.0%
8.7%
11.5%
10.7%
PRISM
GUSTO-IV
ACS
Pooled
7,800
29,855
0.92 (0.86, 0.995)
P=.037
0.5GP IIb/IIIa Inhibitor1.0 Placebo Better 1.5
Better
CI = confidence interval.
Boersma E, et al. Lancet. 2002;359:189-198.
STRIVE
TM
GP IIb/IIIa Inhibitor During Medical Rx and After
PCI: CAPTURE, PURSUIT, PRISM-PLUS
Medical Rx/Pre-PCI
10%
N=12,296
P=.001
Death or MI
8%
Post-PCI
Control
GP IIb/IIIa inhibitor
N=2754
P=.001
8.0%
6%
4.9%
4.3%
4%
2.9%
2%
0%
0
+24 h
+48 h
+72 h
+24 h
+48 h
PCI
Adapted with permission from Boersma E, et al. Circulation. 1999;100:2045-2048.
STRIVE
TM
Benefits of GP IIb/IIIa by Troponin
Status in Clinical Trials
TnT-Positive
TnT-Negative
PARAGON-B
PRISM
CAPTURE
Combined
0.125 0.5
GP IIb/IIIa
Better
1
2
GP IIb/IIIa
Worse
Newby KL, et al. Circulation. 2001;103:2891-2896.
0.125 0.5
GP IIb/IIIa
Better
1
2
GP IIb/IIIa
Worse
STRIVE
TM
ISAR-REACT 2:
Cumulative Incidence of Death, MI, or Urgent TVR in Subsets
With and Without Elevated Troponin levels (>0.03 µg/L)
Placebo Group (n=1010)
Abciximab Group (n=1012)
Cumulative Rate of
Primary End Point, %
20
Troponin >0.03 µg/L
Log-Rank P=.02
15
10
Troponin <0.03 µg/L
Log-Rank P=.98
5
0
0
5
10
15
20
25
Days After Randomization
30
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.
STRIVE
TM
ACC/AHA UA/NSTEMI 2002 Guideline Update:
Platelet GP IIb/IIIa Inhibitors
I IIa IIb III
Any GP IIb/IIIa inhibitor + ASA/heparin for
all patients, if cath/PCI planned
A
A
Eptifibatide or tirofiban + ASA/heparin for
high-risk* patients in whom early cath/PCI
is not planned
B
Any GP IIb/IIIa inhibitor for patients
already on ASA + heparin + clopidogrel,
if cath/PCI is planned
*High-risk: age >75 y; prolonged, ongoing CP; hemodynamic instability;
rest CP w/ ST ; VT; positive cardiac markers.
Adapted from Braunwald E, et al. Available at:
http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.
STRIVE
TM
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
STRIVE
TM
Meta-analysis: Enoxaparin vs UFH in UA/NSTEMI
Death or MI at 30 Days*
Trial
Enox (%) UFH (%)
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]
Test for heterogeneity: χ2 = 2.86, df = 4, P = .58
Odds ratio (95% CI)
0.2
1.0
Enoxaparin better
2.0
UFH better
*No prerandomization therapy population.
Petersen JL, et al. JAMA. 2004;292:89-96.
STRIVE
TM
SYNERGY: Study Design
High-Risk
ACS Patients
At least 2 of 3 required:
 Age  60
 ST  (transient) or 
Enoxaparin
n=4993
1 mg/kg SC q12hr
Randomize
(N=10,027)
 (+) CK-MB or Troponin
IV Heparin
n=4985
60 U/kg  12 U/kg/h
(aPTT 50-70 sec)
Early invasive strategy
Other therapy per ACC/AHA Guidelines
(ASA, -blocker, ACEI, clopidogrel, GP IIb/IIIa)
No
prerandomization
therapy
population
Primary end point: death or MI at 30 days
Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54.
STRIVE
TM
SYNERGY: Primary End Point
1.0
Freedom From Death / MI
Hazard Ratio (95% CI)
0.95
30-Day Death/MI
n
n
0.9
HR 0.96 (0.87-1.06)
0.85
0.8
Enoxaparin
Enoxaparin
Better
UFH
1
UFH
1.2
Better
0.8
0
5
10
15
20
25
30
Days From Randomization
Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54.
Adapted with permission from www.clinicaltrialresults.org.
STRIVE
TM
SYNERGY: Bleeding Events at 30 Days
Enoxaparin UFH
(n=4993)
GUSTO severe bleeding 2.7
Any RBC transfusion
17.0
TIMI major bleeding:
Clinical
9.1
CABG-related
6.8
Non–CABG-related
2.4
Hb drop
15.2
P value
(n=4983)
2.2
16.0
.08
.16
7.6
5.9
1.8
12.5
.008
.08
.03
<.001
12% of patients randomized to enoxaparin were switched to UFH
4% of patients randomized to UFH were switched to enoxaparin
Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54.
STRIVE
TM
ACUITY Study Design:
First Randomization
UFH or enox
+ GP IIb/IIIa
n=4603
Moderateto highrisk
ACS
Aspirin in all,
Clopidogrel dosing
and timing
per local practice
R*
Bivalirudin
+ GP IIb/IIIa
n=4604
Bivalirudin
alone
n=4,612
Angiography within 72 h
Moderate- to high-risk patients with UA or NSTEMI
undergoing an invasive strategy (N=13,819)
Medical
management
PCI
CABG
*Stratified by preangiography thienopyridine use or administration.
Stone GW, et al. Am Heart J. 2004;148:764-775.
STRIVE
TM
ACUITY: Primary End Point Measures*
UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin + GP IIb/IIIa
Risk ratio
±95% CI
Bival UFH/Enox
RR (95% CI)
+ IIb/IIIa + IIb/IIIa
Upper boundary noninferiority
Primary
end point
Net clinical
outcome
Ischemic
composite
Major bleeding
0
Bivalirudin + GP IIb/IIIa better
1
P value
(noninferior)
(superior)
11.8%
11.7% 1.01 (0.90-1.12)
<.001
.93
7.7%
7.3% 1.07 (0.92-1.23)
.015
.39
5.3%
5.7% 0.93 (0.78-1.10)
<.001
.38
2
UFH/Enox + GP IIb/IIIa better
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
STRIVE
TM
ACUITY: Primary End Point Measures*
UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin alone
Risk ratio
±95% CI
Bival UFH/Enox
RR (95% CI)
alone + IIb/IIIa
Upper boundary noninferiority
Primary
end point
Net clinical
outcome
Ischemic
composite
Major bleeding
P value
(noninferior)
(superior)
10.1%
11.7% 0.86 (0.77-0.97)
<.001
.015
7.8%
7.3% 1.08 (0.93-1.24)
.02
.32
3.0%
5.7% 0.53 (0.43-0.65)
<.001
<.001
*ITT population.
0
Bivalirudin alone better
1
2
UFH = unfractionated heparin
UFH/Enox + IIb/IIIa better
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.
STRIVE
TM
OASIS-5: Study Design
Patients with NSTE ACS, chest discomfort < 24 hours
2 of 3: age >60 y, ST-segment Δ,  cardiac markers
Fondaparinux (n=10,057)
2.5 mg SC once daily
Randomize
N=20,078
ASA, Clop, GP IIb/IIIa,
planned Cath/PCI as per
local practice
Enoxaparin (n=10,021)
1 mg/kg SC twice daily
PCI <6 h: No additional UFH
PCI >6 h: IV UFH
With IIb/IIIa, 65 U/kg
Without IIb/IIIa, 100 U/kg
PCI <6 h: IV Fonda 2.5 mg
without IIb/IIIa, 0 with IIb/IIIa
PCI >6 h: IV Fonda 2.5 mg with
and 5.0 mg without IIb/IIIa
Outcomes
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
Yusuf S, et al. N Engl J Med. 2006;354:1464-1476.
Adapted with permission from www.clinicaltrialresults.org.
STRIVE
TM
OASIS-5: Results
Major Bleeding Through Day 9
0.06
Hazard ratio, 1.01 (95% CI, 0.90-1.13)
Cumulative Hazard
Cumulative Hazard
Death, MI, or Refractory Ischemia Through Day 9
0.05
Fondaparinux
0.04
0.03
0.02
Enoxaparin
0.01
0.00
1
Days
9
0.04
Hazard ratio, 0.52 (95% CI, 0.44-1.61)
P<.001
0.03
Enoxaparin
0.02
Fondaparinux
0.01
0.00
1
9
Days
30 Day and 6 Month Results
Event

Fondaparinux Enoxaparin
P
Mortality Day 30
2.9%
3.5%
.02
Mortality 6 Months
5.8%
6.5%
.05
1.5% thrombus on catheter (in fonda group) if no UFH given
Adapted with permission from Yusuf S, et al. N Engl J Med. 2006:354:1464-1476.
STRIVE
TM
Drug-eluting Stents: Cell-Cycle Sites of
Action for Sirolimus and Paclitaxel
Resting
Cell
Division
Paclitaxel
X
M
G0
G1
Sirolimus
X
CELL
CYCLE
G2
S
STRIVE
TM
Drug-eluting Stents: Freedom From TLR
RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS
(n=1,748)
100
100
TAXUS II, IV, V, VI
(n=3,445)
93.6%
90.6%
90
90
80.1%
76.8%
80
80
P<0.0001
P<0.0001
70
70
Bare-Metal Stent
TAXUS
Bare-Metal Stent
CYPHER
60
60
0
6
12
18
24
30
36
Time After Initial Procedure (months)
Schampaert et al. Circulation 2005;112;II-650.
Stone et al. Circulation 2005;112;II-651.
0
6
12
18
24
30
36
Time After Initial Procedure
(months)
STRIVE
TM
Drug-eluting Stents: Freedom From Cardiac Death
RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS
(n=1,748)
98.2%
100
TAXUS II, IV, V, VI
(n=3,445)
98.0%
100
97.8%
90
97.9%
90
P=0.61
P=0.81
80
80
70
70
60
Bare-Metal Stent
CYPHER
0
6
12
18
24
30
36
Time after Initial Procedure (months)
Schampaert et al. Circulation 2005;112;II-650.
Stone et al. Circulation 2005;112;II-651.
60
Bare-Metal Stent
TAXUS
0
6
12
18
24
30
36
Time after Initial Procedure (months)
STRIVE
TM
Drug-eluting Stents: Freedom From MI
RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS
(n=1,748)
100
95.3%
95.2%
90
P=0.93
80
70
TAXUS II, IV, V, VI
(n=3,445)
100
93.6%
93.4%
90
P=0.96
80
70
Bare-Metal Stent
CYPHER®
Bare-Metal Stent
TAXUS®
60
60
0
6
12
18
24
30
36
Time after Initial Procedure (months)
Schampaert et al. Circulation 2005;112;II-650.
Stone et al. Circulation 2005;112;II-651.
0
6
12
18
24
30
36
Time after Initial Procedure (months)
STRIVE
TM
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.
STRIVE
TM
Milan/Siegburg Experience
2229 patients after successful DES implantation
PES
1167 pts
2223 stents
SES
1062 pts
2272 stents
SAT
4 (0.4%)
P=0.5
SAT
10 (0.9%)
LST
5 (0.5%)
P=0.3
LST
10 (0.9%)
10.2  4.4 m
9.3  5.6 months
Total DES 29/2229 (1.3%)
Total SES
9 (0.9%)
Iakovou I, et al. JAMA. 2005;293:2126-2130.
P=0.09
7.9  3.6 m
Total PES
20 (1.7%)
STRIVE
TM
Milan/Siegburg Experience
Stent thrombosis after DES (SES or PES) occurred
in 29/2229 pts (1.3%) at 9.3 ± 5.6 mos
Several patient and lesion
subgroups have a higher
stent thrombosis rate than
identified in RCTs
1.3%
Unstable
angina
2.0%
Thrombus
2.6%
Diabetes
3.2%
Unprot.
left main
Iakovou I, et al. JAMA. 2005;293:2126-2130.
3.5%
Bifurcation
29.0%
5.5%
Renal
failure
8.7%
Prior
brachyRx
Premature
antiplatelet d/c
STRIVE
TM
BASKET-LATE Trial: Study Design
743 PCI patients from BASKET Trial
None had target vessel diameter ≥4mm, restenotic lesions, or MACE
during the on-clopidogrel phase.
Concomitant medications: aspirin indefinitely
DES Group
n=499


BMS Group
n=244
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
Pfisterer ME, et al. Presented at ACC, Atlanta, Ga. March 14, 2006; Presentation 422-11.
Adapted with permission from www.clinicaltrialresults.org.
STRIVE
TM
BASKET-LATE: Primary Composite End Point
Composite of cardiac death or nonfatal MI (%)
P=.01
6
4.9
P=.04
5.0
4
4.1
4.0
3
2
1.3
1
0
DES
BMS
% Patients
Additional end point of thrombosis-related
events (%)
3
2.6
P=.23
% Patients
% Patients
5
Components of primary composite end point:
nonfatal MI/cardiac death (%)
3.0
P=.09
2.0
1.3
1.2
1.0
0.0
0.0
MI
DES
Cardiac Death
BMS
2
1.3
1
0
DES
BMS
Pfisterer ME, et al. ACC, Atlanta, Ga. March 14, 2006; Presentation 422-11.
Adapted with permission from www.clinicaltrialresults.org.
STRIVE
TM
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.
Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374.
STRIVE
TM
Proportional Reduction in Event Rate (SE)
CTT Collaboration: Relation Between Proportional
Reduction in Incidence of Major Vascular Events and
Absolute LDL-C Reduction at 1 Year
50%
Major vascular events
40%
30%
20%
10%
0%
0.5
-10%
1.0
1.5
2.0
Reduction in LDL cholesterol (mmol/L)
Cholesterol Treatment Trialists’ Collaborators. Lancet. 2005;366:1267-1268.
STRIVE
TM
Meta-Analysis of CV Outcomes Trials Comparing
Intensive vs Moderate Statin Therapy
Trial Design and Baseline Characteristics
Trial
Population
Duration,
y
Treatment Arms
PROVE ITTIMI 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, nonprocedure-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.
Primary End Point
STRIVE
TM
Meta-Analysis of CV Outcomes Trials
Comparing Intensive vs Moderate Statin Therapy
Changes in LDL-C Levels
Patients
ACS
n
Prior Statin Use
160
Stable CAD
Pooled
4162
4497
10001
8888
27548
25.2%
0%
0%
75.5%
28.2%
LDL-C(mg/dL)
140
Baseline
Standard
Intensive
120
100
80
60
40
PROVE ITTIMI 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
Adapted with permission from Cannon CP, et al. J Am Coll Cardiol. 2006;48:438-445.
STRIVE
TM
Meta-Analysis of CV Outcomes Trials Comparing
Intensive vs Moderate Statin Therapy
Reduction in Risk of Coronary Death or MI
Odds
Reduction
Odds Ratio (95% CI)
Event Rates
No./Total (%)
High Dose
Std Dose
PROVE ITTIMI 22
-17%
147/2099
(7.0)
172/2063
(8.3)
A-to-Z
-15%
205/2265
(9.1)
235/2232
(10.5)
TNT
-21%
334/4995
(6.7)
418/5006
(8.3)
IDEAL
-12%
411/4439
(9.3)
463/4449
(10.4)
-16%
1097/13798
(8.0)
1288/13750
(9.4)
Total
OR, 0.84
95% CI, 0.77-0.91
P=0.00003
.66
1
1.5
High-dose better High-dose worse
Adapted with permission from Cannon CP, et al. J Am Coll Cardiol. 2006;48:438-445.
STRIVE
TM
Safety of Achieving Ultra-Low LDL
LDL Level
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
0
0
0
0
NS
3.1
3.0
3.2
3.6
NS
Rhabdomyolysis
ALT > 3X ULN
Wiviott et al. J Am Coll Cardiol. 2005;46:1411-1416.
STRIVE
TM
Incidence of Primary End Point (%)
20
HOPE
Placebo
15
Ramipril
10
RRR = 22%
P<.001
5
0
0
500
1000
1500
Follow-up (days)
CV Death, MI, or Cardiac Arrest (%)
Patients Reaching Composite End Point
[MI, Stroke, CV Death] (%)
ACE Inhibitor Trials: Primary End Points
14
EUROPA
12
Placebo annual event rate: 2.4%
Placebo
10
8
Perindopril
6
4
RRR: 20%
P=.0003
2
0
1
2
3
Years
4
5
N = 12,218
PEACE
30
Placebo
25
Trandolapril
20
HOPE: Adapted with permission from the Heart
Outcomes Prevention Evaluation (HOPE) study
investigators. N Engl J Med. 2000;342:145-153.
EUROPA: Adapted with permission from Fox KM;
EUROPA Investigators. Lancet. 2003;362:782-788.
15
10
PEACE: Adapted with permission from Braunwald
E, et al; PEACE Trial Investigators.
N Engl J Med. 2004;351:2058-2068.
5
0
0
1
2
3
4
5
Years After Randomization
No. at Risk
Trandolapril 4158 4017 3752 3506 3079 1963
Placebo
4132 3990 3719 3486 3027 1929
6
969
891
STRIVE
TM
CHARISMA Study: Overall Population: Primary
Efficacy Outcome (MI, Stroke, or CV Death)†
Placebo + ASA*
7.3%
Cumulative event rate (%)
8
Clopidogrel + ASA*
6.8%
6
4
RRR: 7.1% [95% CI: -4.5%, 17.5%]
P = 0.22
2
0
0
6
12
18
24
Months since randomization
30
† 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 to
zero 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.
STRIVE
TM
CHARISMA Study: Overall Population: Principal
Secondary Efficacy Outcome (MI/Stroke/CV
†
Placebo + ASA
Death/Hospitalization)
20
*
Cumulative event rate (%)
17.9%
Clopidogrel + ASA*
16.7%
15
10
RRR: 7.7% [95% CI: 0.5%, 14.4%]
P = 0.04
5
0
0
6
12
18
24
Months since randomization§
30
†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 to
zero and there are only 38 secondary efficacy events that occurred beyond
this time (23 clopidogrel and 15 placebo).
Adapted with permission from Bhatt DL, et al. N Eng J Med. 2006:354:1706-1717.
STRIVE
TM
CHARISMA Study
Overall Population: Safety Results
Clopidogrel +
ASA
(n=7802)
Placebo + ASA
(n=7801)
RR (95% CI)
P value
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
Safety Outcome* –
N (%)
GUSTO Severe
Bleeding
*Adjudicated outcomes by intention to treat analysis.
ICH = intracranial hemorrhage.
Bhatt DL, et al. N Engl J Med. 2006;354:1706-1717.
STRIVE
TM
CHARISMA Study: Primary Efficacy Results
(MI/Stroke/CV Death) by Pre-Specified Entry Category
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
0.93 (0.83, 1.05)
0.22
(n=3,284)
Overall Population†
(n=15,603)
0.4
0.6 0.8
Clopidogrel + ASA
Better
1.2
1.4 1.6
Placebo + ASA
Better
*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).
Adapted with permission from Bhatt DL, et al. N Eng J Med. 2006:354:1706-1717.
STRIVE
TM
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)
n CV death/MI/stroke - 9 events prevented per 1000 patients
treated
n 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.
STRIVE
TM
Quality Improvement
Programs and
Critical Pathways
STRIVE
TM
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, MD
Director, Center for Cardiovascular Science
and Medicine, UNC School of Medicine
STRIVE
TM
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.
STRIVE
TM
Joint Commission on Accreditation
of 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
STRIVE
TM
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
STRIVE
TM
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
STRIVE
TM
Practical Steps to Improve the Use of
Evidence-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.
STRIVE
TM
Critical Pathways Begin in Ambulance and
Extend to Long-term, Office-based Care
EMS
ED
Community
Inpatient
Discharge
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.
STRIVE
TM
EMS Reperfusion Checklist: Evaluation of the STEMI Patient
Step 1:
Has patient experienced chest discomfort for > 15 min and < 12 h?
YES
Step 2:
STOP
NO
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
Significant closed head/facial trauma within the previous 3 months
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)
Step 3:
□ Yes □ No
□ Yes □ No
□ Yes □ No
□ Yes □ No
□ Yes □ No
□ Yes □ No
□ Yes □ No
□ Yes □ No
□ Yes □ No
□ Yes □ No
□ Yes □ No
Is patient at high risk such that PCI is preferable?
Heart rate greater than or equal to 100 bpm
Pulmonary 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
Adapted from Antman
EM, et al. Available
at:
http://www.acc.org/cli
nical/guidelines/stemi/
index.pdf.
STRIVE
TM
STEMI Critical Pathways
ST-ELEVATION MI (STEMI): EMERGENCY DEPARTMENT ORDERS
ALLERGIES
 Actual
 Estimated
 Actual
 Estimated
WEIGHT____________  kg
 lbs
HEIGHT ____________  cm
 ft
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)
Corbelli J, et al. Critical Pathways in Cardiology. 2003;2:71-87.
STRIVE
TM
STEMI Critical Pathways
Reperfusion Therapy
Indications: Chest pain <12 hours, EKG ST-elevations or new left bundle branch block
Fibrinolysis Indications



3-hr symptom onset
Delay in PCI (door-to-balloon >90 min)
Contraindications to PCI: poor arterial access, renal failure, dye allergy
Assess for contraindications for fibrinolytic therapy:
1. History of hemorrhagic stroke at any time; other stroke or cerebrovascular event within 1 year
2. Known intracranial neoplasm
3. Active internal bleeding
4. 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 infusion
Note: When using a fibrinolytic (eg, reteplase): Use Cardiac Unfractionated Heparin Nomogram on back of form
Primary PCI Indications



>3-hr symptom onset
Presence of cardiogenic shock, CHF, contraindications to fibrinolysis
 Stat cardiology consult/catheterization lab page
 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
STRIVE
TM
Sample Critical Pathways Grid: UA/NSTEMI
STRIVE Scientific Committee
STRIVE
TM
Sample Pocket Card (front)
STRIVE
TM
Sample Pocket Card (back)
STRIVE
TM
Smooth Transition From Acute
to Long-Term Management
Cardiology
Acute Care
Guidelines
•
•
•
•
Primary Care
Secondary
Prevention
Follow guidelines
Improve communications
Ensure compliance
Improve quality of care
and outcomes
Adapted from the American Heart Association. Get With The Guidelines. 2001.
STRIVE
TM
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.
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Sample Cardiac Discharge Checklist UA/NSTEMI
STRIVE Scientific Committee
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Sample Letter to Patient’s PCP at Discharge for UA/NSTEMI
Dear 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/d
Clopidogrel at a dose of 75 mg/d
Nitrates (________________) at a dose of ______ mg/d
Beta-blocker (________________) at a dose of ______ mg/d
ACE inhibitor (________________) at a dose of ______ mg/d
Calcium channel blocker (________________) at a dose of ______ mg/d
Lipid-lowering agent(s)(__________________) at a dose of ______ mg/d
Other: ________________________________________________________________
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)
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What Is the Evidence
That 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)
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CHAMP Study: UCLA
Cardiac Hospitalization Atherosclerosis Management Program

Designed to determine whether physician/patient compliance
with preventive therapies can be improved through a hospitalinitiated 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.
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CHAMP Over an 8-Year Period: Rapid and Sustained
Improvement, Superior to National Benchmarks
92/93 Pre-CHAMP (UCLA)
94/95 Post-CHAMP (UCLA)
96/97 Post-CHAMP (UCLA)
96
92 9194
100
Utilization Rate (%)
98/99 Post-CHAMP (UCLA)
00/01 Post-CHAMP (UCLA)
Nat’l Benchmark [NRMI Hospitals 00/01 (n=154,602)]
85
77
80
88 89 90
68
68
72
78
75
65
60
64
70
52
42
40
20
0
91
37
12
Aspirin
β-blockers
ACEI
Statins
Discharge Medications at UCLA
Compared With 1437 NRMI Hospitals
Fonarow GC, et al. Am J Cardiol. 2001;87:819-822.
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ACC’s Guidelines Applied in Practice (GAP)
Initiative: Impact on Aspirin Usage
at Admission and Discharge
Aspirin Usage (%)
100
P=.002
P=.02
80
81
87
84
92
Pre-GAP
Post-GAP
60
40
20
0
At Admission
At Discharge
Adapted from Mehta RH, et al. JAMA. 2002;287:1269-1276.
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GAP Initiative: Adherence Improves
With Tool Use
Early Quality Indicators and Standard Admission Orders
P=.001
100
Quality
Adherence (%)
81
86
P=.004
93
80
Preintervention
65
73
82
77
64 64
60
Postintervention
No Tool Use
Tool Use
40
20
0
No. of Ideal
Patients
343 308 96
213 174 71
131 165 87
Aspirin
β-Blocker
LDL-C
Adapted with permission from Mehta RH, et al. JAMA. 2002;287:1269-1276.
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%
GAP Initiative: Changes in Mortality
Before and After GAP Project
45
40
35
30
25
20
15
10
5
0
P=.004
P=.001
Baseline
Post-GAP
P=.017
In-hospital
Mortality
30-d
Mortality
Eagle KA, et al. J Am Coll Cardiol. 2005;46:1242-1248.
1-yr
Mortality
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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.
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AHA Tool: Simple One-Page, Online Form
Demographics:
6 clicks
Clinical/Lab:
8 clicks
Discharge
meds and
interventions:
7 clicks
American Heart Association Web site. Get With The Guidelines.
Available at: http://www.americanheart.org/presenter.jhtml?identifier=1165.
Interactively
checks patient’s
data with the
AHA Guidelines
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Get With The Guidelines 12-Month Pilot
Results: 85 New England Hospitals
Baseline
4-6 Months
9-12 Months
Benchmark*
Proportion of Patients
100
80
60
40
N=1709
20
0
Smoking
Counsel
LDL-C
BP
Control
Intervention
Rehab/
Exercise
*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.
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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.
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CRUSADE: Inclusion Criteria

Ischemic symptoms lasting >10 minutes within previous
24 hours and at least one of the following:
– Positive cardiac markers
n CK-MB or Tnl/TnT above ULN
n Positive bedside troponin assay
– ST-segment ECG changes
n ST-segment depression >0.5 mm
n 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.
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Goals for CRUSADE
Improve Adherence to ACC/AHA Guidelines
Improve Patient Outcomes
Acute Therapy




Aspirin
– Clopidogrel
-Blocker
Heparin (UFH or LMWH)
GP IIb/IIIa Inhibitor
– Cath/PCI
Discharge Therapy







Aspirin
Clopidogrel
-Blocker
ACE Inhibitor
Statin/Lipid Lowering
Smoking Cessation
Cardiac Rehabilitation
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.
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Hospital Presentation
Characteristics in CRUSADE:
July 1, 2005–June 30, 2006 (n=31,665)

Qualifying criteria
ST-segment depression
Transient ST-segment elevation
Positive cardiac markers
28%
5%
93%

Baseline cardiac markers
CK-MB
TnT/TnI
Drawn
82%
99%

Presenting characteristics
Tachycardia
Hypotension
Signs of CHF
23%
4%
23%
Adapted from 2006 CRUSADE Results.
Available at: http://www.crusadeqi.com.
© 2006 Duke Clinical Research Institute. Used with permission.
Positive
75%
91%
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Baseline Characteristics:
CRUSADE vs ACS Clinical Trials
Variable
PURSUIT
CURE
(n = 9461)
(n = 12,562)
(n = 9975)
(n = 180,842)
63 ± 12
39
23
25
8
18*
18*
42
67 ± 11
34
29
28
9
20
17
55
67 ± 14
40
33
30
18
21
19
34
Mean age ± SD (yrs)63 ± 11
Female sex (%)
36
Diabetes mellitus (%) 23
Prior MI (%)
32
Prior CHF (%)
11
Prior PCI (%)
13
Prior CABG (%)
12
ST depression (%)
50
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.
SYNERGY CRUSADE
STRIVE
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CRUSADE:
Trends in Acute Therapy Adherence
100%
96%
97%
90%
93%
84%
88%
75%
46%
50%
50%
25%
0%
Antiplatelet
Quarter 3-05
β-Blocker
Quarter 4-05
Heparin
Quarter 1-06
GP IIb/IIIa
Inhibitor
Quarter 2-06
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: Invasive Cardiac Procedures
July 1, 2005 – June 30, 2006 (n=31,665)
(Among Patients Without Contraindications to Cath)
100%
83%
80%
67%
60%
53%
38%
40%
20%
12%
0%
Cath
Cath
<48 hr
PCI
PCI <48 hr
CABG
CRUSADE Data: July 1, 2005-June 30, 2006 (n=31,665)
Adapted from 2006 CRUSADE Results.
Available at: http://www.crusadeqi.com.
© 2006 Duke Clinical Research Institute. Used with permission.
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CRUSADE: Trends in
Discharge Therapy Adherence
100%
94%
95%
91%
89%
74%
72%
75%
94%
64%
88%
66%
50%
25%
0%
Aspirin
Clopidogrel
Quarter 3-05
β-Blocker
Quarter 4-05
ACE Inhibitor
Quarter 1-06
LipidLowering
Agent
Quarter 1-06
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: Trends in Discharge
Recommendations Adherence
100%
84%
92%
84%
81%
75%
62%
62%
50%
25%
0%
Smoking Cessation
Counseling
Quarter 3-06
Dietary Modification Cardiac Rehabilitation
Referral
Quarter 4-06
Quarter 1-06
Quarter 2-06
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
100%
78.0%
75% 68.1%
80.8%
83.2%
73.0%
50%
25%
0%
Quarter 1
2002
Quarter 1
2003
Quarter 1
2004
Available at www.crusadeqi.com
© 2006 Duke Clinical Research Institute. Used with permission.
Quarter 1
2005
Quarter 2
2006
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Performance Matters!
Association Between Hospital Guideline
Adherence and In-hospital Mortality in CRUSADE
NSTE ACS
7
6
5
4
3
2
1
0
1
2
3
4
Hospital Composite Guideline
Adherence Quartiles
NSTEMI
8
In-Hospital Mortality, %
In-Hospital Mortality, %
8
7
6
5
4
3
2
1
0
1
2
3
4
Hospital Composite Guideline
Adherence Quartiles
NSTE ACS = non-ST-segment elevation ACS; NSTEMI = non-ST-segment elevation MI.
CRUSADE = Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse
Outcomes With Early Implementation of the ACC/AHA Guidelines.
Adapted with permission from Peterson ED, et al. JAMA.2006;295:1912-1920.
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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
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
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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!
STRIVE
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Your Hospital Needs You
As Champions!
Introduction to Breakout Session
STRIVE
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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
STRIVE
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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
STRIVE
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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
STRIVE
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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)
STRIVE
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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
STRIVE
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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
STRIVE
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Revised ACC/AHA Guidelines
Coming Soon…
STRIVE
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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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