OPTIMAL UPSTREAM ANTITHROMBIN THERAPY
IN NSTE ACS PATIENTS MANAGED IN THE
CARDIAC CATH LAB: DOES IT MATTER WHICH
AGENT IS STARTED IN THE ED?
Charles V. Pollack, Jr., M.A., M.D., FACEP, FAAEM
Department of Emergency Medicine
Pennsylvania Hospital, Philadelphia
Steven V. Manoukian, Gregg W. Stone, Judd E. Hollander, Chadwick Miller, Deborah
B. Diercks, W. Frank Peacock, Gerard X. Brogan, Charles L. Emerman, Andra
Blomkalns, W. Brian Gibler, Ivan Rokos, David Larson, and James W. Hoekstra
NSTE ACS: Optimal Therapy, 2006
 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.
Hospital Care: 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
Braunwald et al, Circulation 2002;106:1893-1900
Acute Medication Use in High-Risk
NSTE Patients: CRUSADE
Within first 24 hours in patients without contraindications
100%
96%
90%
82%
% Use
80%
54%
60%
47%
40%
20%
0%
Aspirin
Beta
Blockers
Heparin
(LMW+UFH)
CRUSADE DATA: Quarter 4, 2004 – Quarter 3, 2005 (n=35,897)
GP llb-llla
Inhibitors
Clopidogrel
Hospital Care
Conservative vs. Invasive Strategies
I IIa IIb III
Early 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
Braunwald et al, Circulation 2002;106:1893-1900
Hospital Care
Conservative vs. Invasive Strategies
I IIa IIb III
Either strategy in low- to moderate-risk patients
without contraindications to revascularization
Early invasive strategy for patients with repeated
ACS presentations, without high-risk features or
ongoing ischemia
Braunwald et al, Circulation 2002;106:1893-1900
Invasive Cardiac Procedures: CRUSADE
(among patients without contraindications to cath)
100%
Median Times
82%
80%
% Use
65%
60%
51%
• Cath - 22 hrs
• PCI - 21 hrs
• CABG - 69 hrs
37%
40%
20%
12%
0%
Cath
Cath < 48
hr
CRUSADE data, unpublished, March 2006
PCI
PCI < 48
hr
CABG
ACUITY Study (ACC, March 2006)
UFH or
Enoxaparin
+ IIb/IIIa
Moderate
and
high risk
ACS
Aspirin in all
Clopidogrel
dosing and timing
per local practice
R*
Bivalirudin
+ IIb/IIIa
Bivalirudin
Alone
Angiography within 72h
Moderate and high risk unstable angina or NSTEMI
undergoing an invasive strategy (N = 13,819)
*Stratified by pre-angiography thienopyridine use or administration
ACUITY Design. Stone GW et al. AHJ 2004;148:764–75
Medical
management
PCI
CABG
Primary Endpoint Measures (ITT)
UFH/Enoxaparin + GPI vs. Bivalirudin Alone
30 day events (%)
UFH/Enoxaparin+GPI (N=4603)
PNI <0.0001
PSup = 0.015
11.7%
Bivalirudin alone (N=4612)
PNI = 0.011
PSup = 0.32
PNI <0.0001
PSup <0.0001
10.1%
7.3%
7.8%
5.7%
3.0%
Net clinical
outcome
Ischemic
composite
Major bleeding
ACUITY
 More than 99% of patients in ACUITY were taken to the
cath lab, at a median time of 19.6 hours after arrival.
 One-third of these patients were randomized to receive
bivalirudin monotherapy. The median time from
randomization to angiography/intervention was
approximately 5 hours.
 Because of their assessed ischemic risk, 64.1% of
patients enrolled in ACUITY were treated with either
UFH or enoxaparin prior to randomization. Consistently,
63.9% of patients randomized to bivalirudin monotherapy
were pretreated . . .
 40.5 % with UFH
 25.4 % with enoxaparin
Rationale and Hypothesis
 In contemporary practice, bivalirudin is not
ordinarily used outside the cardiac cath lab.
 Patients with NSTE ACS and high risk features
are typically administered an anticoagulant in
the ED as empiric therapy. Whether UFH or
enox is used in this setting is an issue of local
preference and policy.
 Hypothesis: The nature of upstream
anticoagulant therapy—UFH or enox—will not
affect outcomes of NSTE ACS patients who
subsequently receive bivalirudin in the cath lab.
ACUITY: Methodology
 Patients were excluded from the study if they
had received more than one dose of enox prior
to potential randomization.
 Patients who had received one dose of enox
were eligible for inclusion.
 Randomized therapy initiated 12h after enox dose
 Patients who had received UFH were eligible for
inclusion.
 30-minute wash-out period
ACUITY: Results
 Of 13,819 patients enrolled, 4,612* were
randomized to receive bivalirudin monotherapy.
 Of these:
 1,658 received no prior anticoagulant
 1,773 received UFH prior to randomization
 1,073 received enox prior to randomization
 97 received both UFH and enox and were excluded
from this analysis.
* 11 pts did not have complete data available
Patient Characteristics
BIV—no AT
(N=1,658)
UFH→BIV
(N=1,773)
Enox→BIV
(N=1,073)
Arrival to cath
[median, hrs]
18.82
16.85
23.67*
% to PCI
54.8%
59.7%
55.2%
% to CABG
9.8%
10.7%
12.0%
% to MM
35.5%
29.6%
32.8%
% pre-rand GPI
2.4%
9.6%*
6.8%*
* P value < 0.001
Ischemic Outcomes
BIV—no AT
(N=1,658)
UFH→BIV
(N=1,773)
Enox→BIV
(N=1,073)
30d death
1.4%
1.4%
2.4%
30d MI
4.8%
5.8%
5.5%
Unplanned revasc
2.1%
2.7%
2.3%
Composite
6.8%
8.3%
8.7%
All comparisons NS - before and after adjustment for baseline characteristics
Bleeding Outcomes
BIV—no AT
(N=1,658)
UFH→BIV
(N=1,773)
Enox→BIV
(N=1,073)
TIMI Major non-CABG
Bleed (%)
0.9%
1.0%
1.0%
Protocol Non-CABG
Major Bleed (%)
3.2%
2.9%
3.1%
Any TIMI non-CABG
Bleed (%)
3.7%
4.2%
4.3%
Protocol Non-CABG
Minor Bleed (%)
13.3%
11.3%
14.2%
Non-CABG
Transfusions (%)
1.6%
1.7%
1.4%
All comparisons NS - before and after adjustment for baseline characteristics
Net Clinical Outcome
BIV - no AT vs. UFH →BIV vs. Enox →BIV
30 day events (%)
BIV - No AT (N=1658)
UFH to BIV (N=1773)
10.4%
9.1%
Net Clinical Outcome
All comparisons NS
Enox to BIV (N=1073)
11.4%
Primary Outcomes: Summary by PreRandomization AT
BIV - no AT vs. UFH →BIV vs. Enox →BIV
30 day events (%)
BIV - No AT (N=1658)
UFH to BIV (N=1773)
Enox to BIV (N=1073)
11.4%
10.4%
9.1%
8.3% 8.7%
6.8%
3.2% 2.9% 3.1%
Net Clinical
Outcome
All comparisons NS
Composite
Ischemia
Major Bleeding
Outcomes in High-Risk Patients
Elevated Biomarker and/or ST-segment changes
BIV—no AT
UFH→BIV
Enox→BIV
N=989 (59.7%)
N=1,279 (72.1%)
N=827 (77.1%)
Composite ischemia
8.3%
9.1%
9.8%
Protocol Non-CABG
Major Bleed
3.6%
3.6%
3.7%
Protocol Non-CABG
Minor Bleed
13.8%
12.3%
14.6%
Non-CABG
Transfusions
1.6%
2.2%
1.8%
Net clinical outcome
10.9%
11.9%
13.1%
All comparisons NS
Primary Outcomes – High Risk Patients
BIV - no AT vs. UFH →BIV vs. Enox →BIV
30 day events (%)
BIV - No AT (N=989)
UFH to BIV (N=1279)
13.1%
11.9%
10.9%
8.3% 9.1%
Enox to BIV (N=827)
9.8%
3.6% 3.6% 3.7%
Net Clinical
Outcome
All comparisons NS
Composite
Ischemia
Major Bleeding
Caveats
 Further analysis of the ACUITY data will
ascertain the impact of duration of therapy with
bivalirudin on outcomes, as well as the
relationship between upstream GPI use and risk
as perceived in the ED. There will also be a
comprehensive economic analysis.
 The dose of bivalirudin used in ACUITY for precath management is not a labeled dose.
 The washout periods for prior AT therapy
mandated in the study may not be scrupulously
followed in contemporary practice.
Conclusions
 The efficacy and safety of bivalirudin in patients
with moderate and high risk NSTE ACS from the
ACUITY trial is not significantly influenced by
prior AT with UFH or enox.
 Prior UFH or enox does not significantly
compromise the net clinical outcomes achieved
in patients subsequently converted to bivalirudin
for interventional management.
Study Medications
 Anti-thrombin agents (started pre angiography)
UF Heparin
U/Kg
Enoxaparin
mg/Kg
Bivalirudin
mg/kg
Bolus
60
1.0 sc bid
0.1 iv
Infusion/h
121
PCI
CABG
Medical mgt
1
0.25 iv
ACT
200-250s
0.30 iv bolus2
0.75 iv bolus3
0.50 bolus iv
1.75/h infusion iv4
Per institution
Per institution
Per institution5
None6
None6
None6
Target aPTT 50-75 seconds
If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose
4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used
5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before
6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion
2