Transcript No Slide Title

ACS-WRAP
Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA
Professor and Chairman
Emergency Medicine, Pennsylvania Hospital
University of Pennsylvania Health System
Philadelphia
Non-ST-Segment-Elevation ACS

Inclusive of unstable angina and NSTEMI

These are the same clinical syndrome, with
the only distinction being the objective
identification of myonecrosis with NSTEMI

Neither UA or NSTEMI are necessarily
associated with ischemic ECG changes
 Result from partial or intermittent obstruction
of epicardial vessels, or complete obstruction
of distal branches
 In contradistinction, STEMI is complete
obstruction of larger vessel, which is
associated with ECG changes
Non-ST-Segment-Elevation ACS

UA/NSTEMI typically result from fissure or
frank rupture of an atherosclerotic plaque
 Stimulates local activation of:
• platelets
• coagulation cascade
• complement


Platelet aggregate forms over site of plaque
injury . . . but remains unstable and subject to
shear forces from passing blood flow
No obstruction in situ, but downstream
embolization can occur
• perhaps resulting in ST↓ or troponin leak
Non-ST-Segment-Elevation ACS

Pharmacologic therapy in NSTE ACS is
therefore directed at this triad of abnormal
activity:
 Platelet activation—anti-activation and antiaggregation
• ASA and clopidogrel
• GPIs


Coagulation activation—anticoagulants
Complement activation—anti-inflammatories .
. . ? statins
Guidelines for NSTE-ACS diagnosis and
management

Very complex disease state with broad ranges
of risk and a multitude of therapeutic options

Many important and pertinent clinical studies

Information overload!

Need evidence-based guidelines to promote
consistency of care and resulting better
outcomes
Guidelines for NSTE-ACS diagnosis and
management

AHCPR guidelines 1994: first attempt

ACC/AHA Joint Task Force: Sep 2000
 Widely read, lots of interest
 Clear evidence scoring, sensible
recommendations, temporal sequencing
• “soup to nuts”

Recapitulation, interpretation, and
promulgation for upstream providers in Annals
of Emergency Medicine
Applying Classification of
Recommendations
Class I
Class IIa
Benefit >>> Risk
Benefit >> Risk
Additional studies
with focused
objectives needed
Procedure/
Treatment SHOULD
be performed/
administered
should
is recommended
is indicated
is useful/effective/
beneficial
Class IIb
Benefit ≥ Risk
Additional studies
with broad objectives
needed; Additional
registry data would be
IT IS REASONABLE to helpful
perform
procedure/administer Procedure/Treatment
treatment
MAY BE
CONSIDERED
is reasonable
can be useful/effective/
beneficial
is probably
recommended or
indicated
may/might be
considered
may/might be
reasonable
usefulness/effectiveness
is unknown
/unclear/uncertain or
not well established
Class III
Risk ≥ Benefit
No additional studies
needed
Procedure/Treatment
should NOT be performed/administered
SINCE IT IS NOT
HELPFUL AND MAY
BE HARMFUL
is not recommended
is not indicated
should not
is not useful/effective/
beneficial
may be harmful
“The Guidelines”
Weighing the Evidence

Weight of evidence grades:
= Data from many large, randomized trials
= Data from fewer, smaller randomized trials,
careful analyses of nonrandomized studies,
observational registries
= Expert consensus
NSTE ACS: Optimal Therapy, 2002-07
• Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA
guidelines for the management of patients with unstable angina
and non-ST-segment elevation myocardial infarction: a report of
the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee on the
Management of Patients with Unstable Angina). J Am Coll
Cardiol 2000;36:970-1062 (2002 update at www.acc.org;
summary in Circulation 2002;106:1893-1900)
• Pollack CV, Roe MT, Peterson ED: 2002 Update to the
ACC/AHA guidelines for the management of patients with
unstable angina and non-ST-segment elevation myocardial
infarction: Implications for emergency department practice. Ann
Emerg Med 2003;41:355-69.
NSTE ACS: Optimal Therapy, 8/6/07
• Anderson JL, Adams CD, Antman EM, et al. 2007
guidelines for the management of patients with unstable
angina/non-ST-segment-elevation myocardial infarction: a
report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines. J Am
Coll Cardiol 2007;50:e1-e157, and Circulation
2007;116:e148-e304, and at www.acc.org and at
www.americanheart.org.
• Pollack CV, Braunwald E: 2007 Update to the ACC/AHA
guidelines for the management of patients with unstable
angina and non-ST-segment elevation myocardial
infarction: Implications for emergency department practice.
Ann Emerg Med 2008, in press.
CRUSADE: A National
Quality Improvement Initiative
Can Rapid Risk Stratification of Unstable Angina Patients
Suppress ADverse Outcomes with Early Implementation
of the ACC/AHA Guidelines
2002-2007
The CRUSADE Experience
443 Participating Sites
205,528 Patients
WA
(5)
VT (1)
ND
(1)
MT
(0)
MI
WY
(0)
UT
(1)
CA
(34)
CO
(9)
MI
(20)
IA
(6)
NE
(3)
NV
(2)
NY
(34)
WI
(5)
SD
(3)
ID
(0)
NH (1)
MN
(3)
OR
(5)
IL
(17)
OH
(35)
IN
(7)
OK
(7)
NM
(1)
AR
(2)
MS
(6)
WV
(2)
TX
(13)
VA
(17)
NC
(14)
SC
(7)
AL
(9)
GA
(14)
LA
(6)
FL
(31)
AK
(0)
HI (0)
January 2007
Data on file, Duke Clinical Research Institute.
MA (10)
RI (1)
CT (7)
NJ (12)
DE (3)
KY
(8)
MO
(8)
KS
(3)
PA
(36)
TN
(9)
AZ
(8)
ME
(0)
MD (13)
DC (1)
Hospital Link Between Overall
Guidelines Adherence and Mortality
% In-Hosp Mortality
7
6
5.95
6.31
5.16 5.06
5
4.97
4.63
4.16 4.15
4
3
2
Every 10%  in guidelines adherence 
10%  in mortality (OR=0.90, 95% CI: 0.84-0.97)
1
0
<=25%
25 - 50%
50 - 75%
>=75%
Hospital Composite Quality Quartiles
Adjusted
Unadjusted
Peterson et al, JAMA 2006;295:1863-1912
Management Strategies: 2002 Guidelines
Conservative vs. Invasive Strategies
I IIa IIb III
Early (within 48h) invasive strategy in
high-risk patients with any of the
following:
- Recurrent ischemia, despite meds
- Elevated Troponin I or T
- New ST-segment depression
- New CHF symptoms
- High-risk stress test findings
- LV dysfunction (EF < 40%)
- Hemodynamic instability, sustained VT
- PCI within 6 months, prior CABG
Invasive Procedures 4Q 2006
(among patients without contraindications to cath)
Median Times
100%
• Cath - 22 hrs
• PCI - 21 hrs
• CABG - 69 hrs
83%
80%
67%
60%
53%
38%
40%
20%
12%
0%
Cath
Cath < 48 hr
PCI
PCI < 48 hr
CABG
Management Strategies: 2007
Early Invasive vs Selectively Invasive

Early invasive: diagnostic angiography with
intent to perform revascularization


cath anticipated within 4-24 hours
follows a foundation of risk-directed medical therapy

Selectively invasive (or early conservative):
invasive evaluation only if optimal medical
management fails

Note: from ED perspective, both strategies
involve risk-directed, evidence-based medical
therapy
Management Strategies: 2007
Early Invasive vs Selectively Invasive
I IIa IIb III
EIS is indicated in initially stabilized
UA/NSTEMI patients (without
contraindications) who have an elevated
risk for clinical events
EIS is indicated in UA/NSTEMI patients
(without contraindications) who have
refractory angina or hemodynamic or
electrical instability
SIS may be considered in initially
stabilized patients who have an elevated
risk for clinical events (including ↑Tn)
% Inhospital Mortality
Benefits of Early Catheterization
by Risk Group
12
10
8
6
4
2
0
Low Risk
Moderate Risk
Early Cath
High Risk
No Early Cath
- Bhatt AHA 2002
Medical Management: 2007 Guidelines
Anti-Ischemic Therapy: Independent of Strategy
I IIa IIb III
NTG
Morphine
Beta-Blockers: emphasis on oral dosing
Medical Management: 2002 Guidelines
Anti-Thrombotic Therapy
I IIa IIb III
Immediate aspirin
Clopidogrel, if aspirin contraindicated
Heparin (IV unfractionated, LMW) with
antiplatelet agents listed above
Enoxaparin preferred over UFH unless
CABG is planned within 24 hours
Medical Management: 2007 Guidelines
Anti-Thrombotic Therapy
I IIa IIb III
Immediate ASA
In EIS:

enoxaparin or UFH

bivalirudin* or fondaparinux
In SIS:

enoxaparin or UFH

fondaparinux
Medical Management: 2007 Guidelines
Anti-Thrombotic Therapy
Relevant new studies for antithrombotic therapy:
SYNERGY, JAMA 2004

10,027 patients with high-risk NSTE ACS, randomized
to enox vs UFH, open-label, superiority
OASIS-5, NEJM 2006

20,078 patients with high-risk NSTE ACS, randomized
to fonda vs enox, double-blind, noninferiority
ACUITY, NEJM 2006

13,819 patients with moderate or high-risk NSTE ACS,
randomized to hep/GPI vs bival/GPI vs bival, openlabel, noninferiority
Anti-Aggregation Antiplatelet Tx: 2002
Platelet GP IIb/IIIa Inhibitors
I IIa IIb III
Any GP IIb/IIIa inhibitor + ASA/Heparin
for all patients, if cath/PCI planned
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
* High-risk: Age > 75; prolonged, ongoing CP; hemodynamic
instability; rest CP w/ ST ; VT; positive cardiac markers
Ant-Aggregation Antiplatelet Tx: 2002
Platelet GP IIb/IIIa Inhibitors
I IIa IIb III
Eptifibatide or tirofiban + ASA/Heparin
for patients without continuing
ischemia in whom PCI is not planned
Abciximab for patients in whom PCI is
not planned
Anti-Activation Antiplatelet Therapy: 2002
Clopidogrel
I IIa IIb III
Aspirin + clopidogrel, for up to 1 month*
Aspirin + clopidogrel, for up to 9 months*
Withhold clopidogrel for 5-7 days for CABG
* For patients managed with an early conservative strategy, and
those who are planned to undergo early PCI
Guidelines do not specify initial timing of using
clopidogrel when coronary anatomy is unknown
Advanced Antiplatelet Tx: 2007
I IIa IIb III
All patients receive ASA
EIS: upstream clopidogrel or IIb/IIIa
EIS: upstream IIb/IIIa should be smallmolecule
SIS: if medical management fails, add
IIb/IIIa or clopidogrel . . .
. . . upstream
Advanced Antiplatelet Tx: 2007
I IIa IIb III
SIS with recurrent ischemia on ASA,
clopidogrel, and anticoag: add IIb/IIIa
upstream
EIS: it is reasonable to give both
clopidogrel and IIb/IIIa upstream
EIS: can omit IIb/IIIa if bivalirudin is
anticoagulant + at least 300mg
clopidogrel given > 6h prior to cath
Anti-Activation Antiplatelet Tx: 2007
More on Clopidogrel
I IIa IIb III
Clopidogrel with full loading dose in
ASA-allergic patients
EIS: clopidogrel or IIb/IIIa administered
upstream
SIS: clopidogrel initiated “as soon as
possible” and continued for at least
one month . . .
. . . and preferably for one year
Antiplatelet Drug Targets
Platelet
Thrombin
PAR-1
Platelet
PAR-4
Clopidogrel
Prasugrel
Aspirin
ADP
Fibrinogen
P2Y1
GP IIIa
GP IIb
P2Y12
P2Y12
Thromboxane
A2
TXA2-R
GP IIb
GP IIIa
Epinephrine
Serotonin
Collagen
5HT2A
GP VI
GP Ia
Anionic
phospholipid
surfaces
Gp IIb/IIIa
inhibitors
CURE Primary Results
%
14
12
Death, MI, or Stroke
11.4%
Placebo
+ ASA
9.3%
10
8
Clopidogrel
+ ASA
6
4
20% RRR
P < 0.001
N = 12,562
2
0
0
3
6
9
Months of Follow-Up
N Engl J Med. 2001
12
Cumulative Hazard Rates
CURE: Ischemic Endpoints Were
Reduced within 24h of
Randomization
0.025
Placebo
+ ASA
0.020
33%
RRR
0.015
Clopidogrel
+ ASA
0.010
0.005
RR = 0.67
P = 0.003
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
Hours After Randomization
Adapted from Yusuf S, et al. Circulation. 2003;107:966-972.
ACUITY Composite Ischemia at 1-Year
UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone
1 yr KM estimate
Hazard ratio
±95% CI
Bival UFH/Enox
alone + IIb/IIIa
Biomarkers (CK/Trop)
Elevated (n=5072)
Normal (n=3402)
HR (95% CI)
Pint
17.7%
14.6%
16.4%
16.1%
1.14 (0.99-1.30)
0.95 (0.80-1.14)
0.11
16.2%
16.4%
17.2%
14.3%
0.97 (0.86-1.11)
1.20 (1.01-1.44)
0.07
19.8%
21.1%
9.0%
19.2%
20.7%
9.6%
1.09 (0.96-1.23)
1.04 (0.79-1.36)
0.97 (0.76-1.24)
0.67
Pre Thienopyridine
Yes (n=5751)
No (n=3305)
Actual Treatment
PCI (n=5179)
CABG (n=1040)
Medical (n=2994)
0
Bivalirudin alone better
ACUITY 1-Year Data as presented at ACC 2007.
1
2
UFH/Enox + IIb/IIIa better
P value
interaction
only between
subgroups
Clopidogrel Dosing and Duration of Therapy

ordinarily given with ASA (established in CURE)

labeled loading dose 300mg
 Many cardiologists prefer 600mg for faster onset of
action, no apparent additional safety concerns

labeled maintenance dose 75mg
 Some cardiologists prefer 150mg for first month after
stenting
CURRENT (OASIS-7) trial currently studying 600 vs
300, 150 vs 75 (first month), and low- vs high-dose ASA
 Results in 2009?

Clopidogrel Dosing and Duration of Therapy
duration of therapy after ACS, whether or nor PCI
performed with BMS, with 75-162mg ASA
 75mg daily for at least 1 month (I-A)
 preferably 12 months (I-B)

duration of therapy after ACS and PCI performed with
DES, with 162-325mg ASA for at least 3 months after
sirolimus-eluting stent and 6 months after paclitaxeleluting stent . . . then indefinitely thereafter
 75mg daily for at least 12 months (I-B)

CHARISMA showed no net benefit from long-term
clopidogrel therapy to patients with cardiac risk factors
but no objectively demonstrated CAD

Optimal Management of NSTE ACS:
ED to Cardiology — A Functional Model
 Chest Pain or ACS Committee
 Meets quarterly or PRN

PRN means after . . .
•
•
•
•
Pertinent, “practice-changing” new study published
ACC / AHA / TCT meetings
M & M or sentinel event
New guidelines published
Optimal Management of NSTE ACS
ED to Cardiology — A Functional Model
 Chest Pain or ACS Committee comprised of:
 Emergency physicians
 Interventional cardiologists
 Medical cardiologists
 Hospitalists
 CT surgeons
 ED nursing
 Cath lab nursing
 CCU nursing
 Lab
 Imaging
Optimal Management of NSTE ACS
ED to Cardiology — A Functional Model

Chest Pain or ACS Committee discusses:








Protocols and standing orders
Practice variations versus evidence
Time to catheterization predictability
Reduction of medical errors in ACS care
DTB times
QI issues (CRUSADE / NRMI / ACTION)
Transfers in, transfers out
New data: How should it impact our protocols?
Optimal Management of NSTE ACS
ED to Cardiology — Summary and Game Plan

ED physicians should be using optimal, evidencebased, guideline-consistent medical therapy for
NSTE ACS

ED physicians must work with their colleagues in
cardiology to develop pathways and approaches
(EDICT for ACS) for proper use of antithrombotic and
antiplatelet therapy at all levels

ED physicians should facilitate early invasive
management of ACS whenever feasible and
appropriate

ED physicians should address issues related to
bleeding risk as well as ischemic risk.

A seamless transition of care is most likely to result in
good outcomes.
Conclusion: NSTE ACS
We should be using optimal medical therapy for
NSTE ACS in the ED, just as in the CCU or the
cath lab.
There must be cross-disciplinary collaboration
(EM, CD, IM, HM, CTS, nursing throughout all
levels of care) to develop pathways for proper use
of antithrombotic and antiplatelet therapy at all
levels, to facilitate early invasive management
whenever feasible, and to address issues related
to bleeding risk as well as ischemic risk.