Transcript Bleeding, Mortality, and Future Directions

High Risk Patients with ACS —
EuroPCR 2008, Barcelona, Spain
Introduction and Objectives
Issues and challenges in ACS
Philippe Gabriel Steg
INSERM U-698
Hôpital Bichat – Claude Bernard
Université Paris VII – Denis Diderot
Disclosures
Speaker’s name: Philippe Gabriel Steg
 I have the following potential conflicts of interest to report:
 Consulting/Advisory Board: AstraZeneca, Boehringer-Ingelheim,
BMS, GSK, MSD, Nycomed, sanofi-aventis, Servier, Takeda, The
Medicines Company
 Research Grant: sanofi-aventis
 Speaker’s Bureau: Boehringer-Ingelheim, BMS, GSK, Nycomed,
sanofi-aventis, Servier, ZLB-Behring
 I do not have any potential conflict of interest
The Landscape
• A changing pattern of care for all highrisk ACS
Trends in Management of STEMI in the
GRACE Registry
Fox KAA et al. JAMA 2007;297:1892-1900
The Landscape
• A changing pattern of care for all highrisk ACS
• …and outcomes which are improving
In-Hospital and 6-Month Outcomes in
Patients With STEMI or LBBB
Fox KAA et al. JAMA 2007;297:1892-1900.
CRUSADE In-Hospital Outcomes:
Data from 2006
Death
(Re)-Infarction
CHF
Cardiogenic Shock
Stroke
RBC Transfusion*
3.6%
1.8%
6.6%
2.2%
0.7%
9.1%
*Excluding CABG-related transfusions
CRUSADE DATA: January 1, 2006 – December 31, 2006
(n= 29,825)
The Landscape
• A changing pattern of care for all highrisk ACS
• …and outcomes which are improving
• A growing level of complexity
Antithrombotics for ACS
More and More Choices (and Combinations)
Fonda
Direct TIs
Lytics
Clopidogrel
GP IIb/IIIa inhibitors
LMWH
Heparin
Aspirin
Choices Impacting Antithrombotic Therapy
Anticoagulants:
Antiplatelets:
UFH
ASA (dose)
IV antiplatelets:
None
Cath strategy:
Early
LMWH
Fonda
Bival
Clopidogrel (time/dose)
Abcix Ept/Tiro (timing)
Delayed
72 Different Combinations!
Never
Treatment of ACS is a Jungle !
Antiplatelet Rx
ASA
Clopidogrel
? Prasugrel
? AZD 6140
GpIIb/IIIA IV
blockers
? Cangrelor
? TRA
Anticoagulant Rx
UFH
Enoxaparin
Bivalirudin
Fondaparinux
Warfarin
? Anti X
? Anti II
Timing
Revascularization
PCI
BMS
DES
CABG
Patient
Bleeding risk
Comorbidities
Risk of thrombotic event
The Landscape
• A changing pattern of care for all highrisk ACS
• …and outcomes which are improving
• A growing level of complexity
• Use and timing of interventions impact
therapeutic choices
The Landscape
• A changing pattern of care for all highrisk ACS
• …and outcomes which are improving
• A growing level of complexity
• Use and timing of interventions impact
therapeutic choices
• Fortunately, we have guidelines to
assist us !
Objectives
• Know the current guidelines for the
management of STEMI and NSTE ACS
• Understand their implications for patient
management
New Horizons for Patients
with ST-Elevation Myocardial
Infarction
Gregg W. Stone MD
Columbia University Medical Center
Cardiovascular Research Foundation
Potential Conflicts of Interest
Speaker’s name: Gregg W. Stone, MD
 I have the following potential conflicts of interest to report:
 Consulting
 Employment in industry
 Stockholder of a healthcare company
 Owner of a healthcare company
 Grant/Research Support: The Medicines Company and
Boston Scientific
 I do not have any potential conflict of interest
FACT
Major bleeding (with or without
blood product transfusions)
has emerged as a powerful
independent predictor of early
and late mortality in pts with
NSTEMI, STEMI and in those
undergoing PCI
Ndrepepa et al. JACC 2008;51:690–7
Impact of Major Bleed and MI
after Elective and Urgent PCI
Cumulative % Mortality
1-Year Mortality (N=6,012)
With major bleed 8.8%
With MI 5.7%
Without major bleed 2.0%
Without MI 1.9%
Time from Randomization in Days
Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.
Predictors of 1-year Mortality
after Elective and Urgent PCI
Variable
Groups
O.R.
(95% CI)
<30 mL/min
7.21
(2.53–20.51)
30–60 mL/min
3.34
(1.92–5.78)
60–90 mL/min
1.57
(0.96–2.57)
CHF
Yes
4.38
(2.83–6.78)
<0.0001
Major Bleeding
Yes
3.26
(1.78–5.96)
0.0001
MI @30day
Yes
2.77
(1.62–4.75)
0.0002
Urg Revasc @30d
Yes
2.77
(1.15–6.71)
.024
Hx angina
Yes
2.18
(1.25–3.81)
0.006
Prior MI
Yes
1.81
(1.09–3.03)
0.023
Diabetes
Yes
1.64
(1.10–2.44)
0.015
Creatinine clear.
Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.
p-value
<0.0001
1-year Mortality
All 6,012 Patients (ITT)
Cumulative Deaths
3.0
Heparin+GPllb/llla N=3008
Bivalirudin N=2994
2.5%
2.5
P value = 0.16
2.0
1.9%
1.5
1.0
0.5
0.0
0
60
120
180
240
Days
Lincoff AM et al. JAMA 2004;292:696–703
300
360
Impact of MI and Major Bleeding (non-CABG) in
the First 30 Days on Risk of Death Over 1 Year
1 year
Estimate
Both MI and Major Bleed (N=94)
Major Bleed only (without MI) (N=551)
MI only (without Major Bleed) (N=611)
No MI or Major Bleed (N=12,557)
30
28.9%
12.5%
8.6%
3.4%
Mortality (%)
25
20
15
10
5
0
0
30
60
90
120 150
180 210 240 270
Days from Randomization
Stone GW. ACC 2007
300 330 360
390
Influence of Major Bleeding and MI in the
First 30 Days on the Risk of Death within 30 Days
Of 13,819 enrolled pts, 704 (5.1%) had a MI, 644 (4.7%) had a
major bleed (non CABG), and 206 (1.5%) died within 30 days
Cox model adjusted for baseline predictors, with MI and major
bleeding (non-CABG) as time-updated covariates
HR ± 95% CI
HR (95% CI)
Attributable
deaths
P-value
Myocardial infarction
5.25 (3.72-7.43) <0.0001
Major bleeding without
or before transfusion
3.04 (1.66-5.55) <0.0001
42.0*
38.2**
Major bleeding after
transfusion
5.45 (3.54-8.38) <0.0001
*20.4% of all deaths
**18.5% of all deaths
Attributable deaths = N deaths
among pts with the time updated
event (attribute) X (adj. HR – 1)/adj. HR
Stone GW. ACC 2008
Influence of Major Bleeding and MI in the
First 30 Days on Risk of Death Over 1 Year
Of 13,819 enrolled pts, 524 (3.8%) died within 1 year
Cox model adjusted for baseline predictors, with MI and major
bleeding (non-CABG) as time-updated covariates
HR ± 95% CI
HR (95% CI)
Attributable
deaths
P-value
Myocardial infarction
2.51 (1.95-3.25) <0.0001
Major bleeding without
or before transfusion
2.00 (1.30-3.06) <0.0001
51.5*
66.5**
Major bleeding after
transfusion
3.93 (2.95-5.24) <0.0001
*9.8% of all deaths
**12.7% of all deaths
Attributable deaths = N deaths
among pts with the time updated
event (attribute) X (adj. HR – 1)/adj. HR
Mehran RM et al. Submitted
ACUITY: Early and Late Mortality
Landmark analysis
Mortality (%)
4
UFH/Enoxaparin + IIb/IIIa
Bivalirudin + IIb/IIIa
Bivalirudin alone
3
30 day
Estimate
(log rank)
1.4%
1.6%
1.6%
—
0.53
0.39
P
30d - 1 year P
Estimate (log rank)
3.1%
2.7%
2.3%
—
0.54
0.21
2
1
0
0
30
60
90
120 150
180 210 240 270
Days from Randomization
Stone GW. JAMA 2007;298:2497-506
300 330 360
390
Harmonizing Outcomes with Revascularization and Stents in AMI
≥3400* pts with STEMI with symptom onset ≤12 hours
Aspirin, thienopyridine
R
1:1
UFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Emergent angiography, followed by triage to…
CABG – Primary PCI – Medical Rx
3000 pts eligible for stent randomization
Bare metal stent
*To rand 3000 stent pts
R
1:3
TAXUS paclitaxel-eluting stent
Clinical FU at 30 days, 6 months,
1 year, and then yearly through 5 years
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI
R
1:1
Randomized
UFH +
GP IIb/IIIa
N=1802
9
15
Bivalirudin
Monotherapy
N=1800
• • • Withdrew • • •
• • • Lost to FU • • •
10
13
30 day FU*
N=1778
(98.7%)
N=1777
(98.7%)
ITT population
N=1802
N=1800
* Range ±7 days
Stone GW et al. In press.
Primary Outcome Measures (ITT)
Diff = -2.9% [-4.9, -0.8]
RR = 0.76 [0.63, 0.92]
Diff = -3.3% [-5.0, -1.6]
RR = 0.60 [0.46, 0.77]
Diff = 0.0% [-1.6, 1.5]
RR = 0.99 [0.76, 1.30]
PNI ≤ 0.0001
Psup = 0.005
PNI ≤ 0.0001
Psup ≤ 0.0001
Psup = 0.95
1 endpoint
1 endpoint
*Not related to CABG
**MACE = All cause death, reinfarction, ischemic TVR or stroke
30 Day Bleeding Endpoints*
UFH + GP IIb/IIIa Bivalirudin
P Value
(N=1802)
(N=1800)
Protocol Major, non CABG**
8.3%
4.9%
<0.0001
Protocol Major, All
10.8%
6.8%
<0.0001
Protocol Minor
15.4%
8.6%
<0.0001
Blood transfusion
3.5%
2.1%
0.009
TIMI Major
5.0%
3.1%
0.002
TIMI Minor
4.6%
2.8%
0.006
TIMI Major or Minor
9.6%
5.9%
<0.0001
GUSTO LT*** or Severe
0.6%
0.4%
0.49
GUSTO Moderate
5.0%
3.1%
0.002
GUSTO LT or Sev or Mod
5.6%
3.5%
0.002
*CEC adjudicated, except protocol minor;
**Primary endpoint; ***Life threatening
Thrombocytopenia
P = 0.002
P = 0.04
P = 0.02
<100,000 cells/mm3
<50,000 cells/mm3
Stone GW et al. In press.
<20,000 cells/mm3
30 Day MACE Components*
UFH + GP IIb/IIIa
(N=1802)
Bivalirudin
(N=1800)
P Value
3.1%
2.1%
0.047
- Cardiac
2.9%
1.8%
0.028
- Non cardiac
0.2%
0.3%
0.75
Reinfarction
1.8%
1.8%
0.90
- Q-wave
1.2%
1.4%
0.66
- Non Q-wave
0.7%
0.4%
0.37
1.9%
2.6%
0.18
- Ischemic TLR
1.8%
2.5%
0.13
- Ischemic remote TVR
0.3%
0.3%
1.0
0.6%
0.7%
0.68
Death
Ischemic TVR
Stroke
*CEC adjudicated
Stone GW et al. In press.
30 Day Mortality
Death (%)
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
3.1%
2.1%
HR [95%CI] =
0.66 [0.44, 1.00]
P=0.048
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
Time in Days
1800
1802
1758
1764
1751
1748
1746
1736
1742
1728
Stone GW et al. In press.
1729
1707
1666
1630
30 Day Mortality: Cardiac and Non Cardiac
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
Death (%)
HR [95%CI] =
0.62 [0.40, 0.96]
P=0.029
2.9%
Cardiac
1.8%
Non cardiac
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
0.3%
0.2%
Time in Days
1800
1802
1758
1764
1751
1748
1746
1736
1742
1728
Stone GW et al. In press.
1729
1707
1666
1630
30 Day Stent Thrombosis (N=3,124)
UFH +
Bivalirudin
P
GP IIb/IIIa
(N=1571) Value
(N=1553)
ARC 30d definite or
probable stent thrombosis*
1.9%
2.5%
0.30
- definite
1.4%
2.2%
0.09
- probable
0.5%
0.3%
0.24
- acute (≤24 hrs)
0.3%
1.3%
0.0007
- subacute (>24 hrs – 30d)
1.7%
1.2%
0.28
*Protocol definition of stent thrombosis, CEC adjudicated
30 Day Mortality: PCI Cohort
Heparin + GPIIb/IIIa inhibitor (n=1662)
Bivalirudin monotherapy (n=1678)
5
HR [95%CI] =
0.63 [0.40, 0.99]
Death (%)
4
P=0.049
3
2.8%
Cardiac
2
1.8%
1
Non cardiac
0.2%
0.1%
0
0
Number at risk
Bivalirudin
1678
Heparin + GPIIb/IIIa 1662
5
10
15
20
25
30
1620
1583
1563
1512
Time in days
1647
1631
1640
1615
1635
1604
1632
1598
Stone GW et al. In press.
Predictors of 30 Day Mortality
32 Candidate Baseline Variables*
Demographic: Age; sex; race; US vs. OUS; HTN, hyperlipidemia,
smoking, diabetes, diabetes on insulin, MI, PCI, CABG, CAD,
angina, CHF, major cardiac rhythm/rate disturbances, PVD
Medication use at home previous 5 days: aspirin, beta blocker,
thienopyridines, calcium channel blocker, ACE/ARB, diuretic
Time from symptom onset to hospital ER
Physical exam: BMI; KILLIP class
Baseline labs: Estimated CrCl, anemia, platelet count
Medications in hospital prior to angiography: Randomized
treatment (bivalirudin vs. heparin + GPI; pre-procedure heparin;
clopidogrel load
* Angiographic variables not yet available;
- treatment related variables not used
Time-updated covariate adjusted Cox model relating
single 30-day adverse events to 30-day mortality
Ischemic Events
Attributable
deaths*
C-stat
HR (95% CI)
P
Reinfarction
11.09 [5.44,22.59]
<0.001
9.1 [8.2,9.6]
0.83
Ischemic TVR
6.91 [3.36,14.18]
<0.001
7.7 [6.3,8.4]
0.83
Stent thrombosis, definite**
- any
10.71 [3.93,29.18]
<0.001
4.5 [3.7,4.8]
0.83
- acute (<24 hours)
5.88 [0.78,44.30]
0.09
0.8 [-0.3,1]
0.82
5.44 [1.67,17.69]
0.005
2.4 [1.2,2.8]
0.82
Stroke
* Of 93 total deaths; ** in 3,124 successfully stented pts
***Only 2 pts with acute stent thrombosis died within 30
days, 1 in each randomized group
Time-updated covariate adjusted Cox model relating
single 30-day adverse events to 30-day mortality
Bleeding Events
HR (95% CI)
P
Attributable
deaths*
C-stat
Major bleed (non-CABG)
4.43 [2.67, 7.33]
<0.001
20.1 [16.3,22.5] 0.85
Major bleed (all)
5.92 [3.73, 9.41]
<0.001
29.1 [25.6,31.3] 0.86
Transfusion
3.88 [2.09, 7.20]
<0.001
11.9 [8.4,13.8]
0.83
- <100,000 cells/mm3
3.89 [2.22, 6.84]
<0.001
11.1 [8.2,12.8]
0.78
- <50,000 cells/mm3
6.44 [2.93,14.18]
<0.001
5.9 [4.6,6.5]
0.78
- <20,000 cells/mm3
4.98 [1.20,20.66]
0.03
1.6 [0.3,1.9]
0.77
Thrombocytopenia**
* Of 93 total deaths; ** 88 deaths in 3550 patients
Attributable deaths = N deaths among pts with the time
updated event (attribute) X (adj. HR – 1)/adj. HR
Time-updated covariate adjusted Cox model
relating 30-day events to 30-day mortality
- Complete model with MACE components and major bleeding Risk Factor
HR [95% CI]
P-value
Reinfarction
9.75
<0.001
[2.72,34.91]
Major bleeding (non CABG)
4.66
<0.001
[2.84, 7.63]
Ischemic TVR
1.11
0.88
[0.29, 4.21]
2.64
Stroke
[0.71, 9.75]
0.01
0.1
1
10
Hazard Ratio [95% CI]
C-statistic = 0.87.
100
0.15
Time-updated covariate adjusted Cox model
relating 30-day events to 30-day mortality
- Complete model with MACE components and major bleeding Risk Factor
HR [95% CI]
P-value
Attributable
Deaths
9.75
<0.001
9.0*
Reinfarction
Incidence 69 (2.2%)
10 deaths with event
[2.72,34.91]
Major bleeding
(Non CABG)
Incidence 238 (6.8%)
26 deaths with event
0.01
0.1
4.66
[2.84, 7.63]
1
10
Hazard Ratio [95% CI]
100
<0.001
[6.3, 9.7]
20.4**
[16.8, 22.6]
*9.7% of 93 total deaths
**21.9% of 93 total deaths
C-statistic = 0.87. Attributable deaths = N deaths among pts
with the time updated event (attribute) X (adj. HR – 1)/adj. HR
Time-updated covariate adjusted Cox model
relating 30-day events to 30-day mortality
- Complete model in 3,124 pts with successfully implanted stents Risk Factor
HR [95% CI]
Stent thrombosis
(definite)
Incidence 57 (1.8%)
5 deaths with event
10.62
[3.96, 28.48]
Major bleeding
(non CABG)
Incidence 195 (6.2%)
18 deaths with event
0.01
0.1
6.22
[3.33, 11.60]
1
10
Hazard Ratio [95% CI]
100
P-value
<0.001
<0.001
Attributable
Deaths
4.5*
[3.7, 4.8]
15.1**
[12.6, 16.4]
*8.3% of 54 total deaths
**28.0% of 54 total deaths
C-statistic = 0.87. Attributable deaths = N deaths among pts
with the time updated event (attribute) X (adj. HR – 1)/adj. HR
Conclusions
1. Major bleeding is a powerful independent determinant
of mortality in ACS, STEMI, and in pts undergoing PCI,
at least as important as MI/reinfarction.
2. In high risk pts with STEMI undergoing primary PCI,
treatment with bivalirudin compared to heparin + GPI
results in a significant reduction in bleeding,
thrombocytopenia and transfusions, with similar rates
of reinfarction, stent thrombosis, iTVR and stroke.
3. This favorable balance of adverse events results in
lower 30-day mortality in primary PCI pts treated with
bivalirudin rather than heparin + GPI, representing a
new standard of care for pts with STEMI.
SWITCH
Changing Anticoagulants in Midstream
— What Are the Benefits and Risks?
Harvey White
Green Lane Cardiovascular Service and
Cardiovascular Research Unit
Auckland City Hospital; Auckland, New Zealand
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Potential conflicts of interest
Speaker’s name: Harvey D. White
 I have the following potential conflicts of interest to report:
 Research Grants: Sanofi Aventis, The Medicines company,
Eli Lilly, Roche,Schering Plough, Pfizer, Johnson and
Johnson, Astra Zenica, Merck Sharpe and Dohme and NIH
 Consulting Fees: The Medicines Company
 Employment in industry
 Stockholder of a healthcare company
 Owner of a healthcare company
 I do not have any potential conflict of interest
Background
► ACS patients
 87% of patients receive either UFH or Enox within 24
hours after admission1
 72% of patients in SYNERGY and 50 % of patients in
OASIS- 5 received prior antithrombin2,3
► Published studies and perceptions
 Patients in SYNERGY who crossed over between UFH
and Enox had an increase in bleeding complications2
 This activity occurred at various times through the study period:
At times in response to clinical or clinician perception
 Consistent therapy is better4
1
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
3
CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004;
OASIS -5; Yusuf et al, NEJM 2006; 4 Cohen et al, JACC 2006;
Switching
► Concern about switching antithrombins in
patients with ACS (lessons from SYNERGY)
► European guidelines
► Why should switching to bivalirudin
monotherapy be reasonable?
► Mechanistic rationale for switching
 SWITCH
 REPLACE 2
 ACUITY
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
ESC Non-STEACS Guidelines
►At PCI procedures, the initial anticoagulant
should also be maintained during the
procedure regardless of whether this
treatment is UFH (I-C), enoxaparin (IIb-B),
or bivalirudin (I-B)
EHJ 2007;28:1598-60
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
SWITCH
Definitions
► Switch: Protocol mandated change in
antithrombotic therapy at randomization
► Crossover : Post randomization change in
antithrombotic therapy due to physician
choice
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
ACUITY — SWITCH
►Hypothesis
 Bivalirudin improves bleeding outcomes
while preserving ischemic protection for ACS
patients even if the patients are switched
from either UFH or enoxaparin to bivalirudin
(monotherapy) at the time of presentation
►Is it better to switch to bivalirudin or
remain on consistent therapy?
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
White HD. In Press JACC
ACUITY – Primary Results
UFH/Enoxaparin + GPI vs. Bivalirudin Alone
30 day events (%)
UFH/Enoxaparin+GPI (N=4603)
PNI <0.0001
PSup = 0.015
Bivalirudin alone (N=4612)
PNI = 0.011
PSup = 0.32
PNI <0.0001
PSup <0.0001
11.7%
10.1%
7.3%
7.8%
5.7%
3.0%
Net clinical outcome
Ischemic composite
Major bleeding
ACUITY — Switch Analysis
►Study Methods
 Patients on prior antithrombin therapy
 Consistent: No switching from pre-randomization
antithrombin agent to randomized therapy:
 Enoxaparin →Enoxaparin or UFH → UFH
 Switch: Single switch to bivalirudin determined by
randomization code
 From Enoxaparin → Bivalirudin or UFH →
Bivalirudin
►Event rates at 30-days
 Net clinical outcome
 Ischemic composite
 Major bleeding
White HD, et al. J Am Coll Cardiol 2008;51:1734–41
ACUITY – Switch Consort
ACUITY
13819
Pts on Prior AT
N = 4215 ╪
CONSISTENT
SWITCH
UFH/Enox
N = 2137
Bivalirudin
N = 2078
UFH→UFH
N = 1294
Enox→Enox
N = 843
UFH→Biv
N = 1313
Enox→Biv
N = 765
╪ excludes Arm B and pts. with multiple crossovers, missing data
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Consistent vs. Switch
Comparing Consistent therapy on Enox + GPIIb/IIIa
Inhibition vs. Switch to Bivalirudin Alone
Consistent Enox + GPIIb/IIIa Inhibition (N = 843)
0.80 [0.60 – 1.81]
P=0.15
30 day events (%)
20
15
Switch to Bivalirudin alone (N = 765)
0.58 [0.35 – 0.96]
P=0.03
0.86 [0.60 – 1.25]
P=0.43
11.0%
8.9%
7.0%
10
6.1%
5.0%
2.9%
5
0
Net clinical outcome Ischemic composite Major bleeding
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
White HD, et al. J Am Coll Cardiol 2008;51:1734–41
ACUITY – Switch
Consistent vs. Switch High Risk
High Risk Patients
Comparing Consistent UFH/Enox vs Switch Bivalirudin
Consistent
Switch
UFH/Enox Bivalirudin
RR
N = 1581
N = 1496
Net Clinical Outcome
13.0%
10.6%
0.82 [0.67-0.99]
Ischemia
8.2%
7.7%
0.94 [0.74-1.20]
Major Bleeding
6.5%
3.5%
0.51 [0.39-0.75]
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
ACUITY – SWITCH
Consistent vs. Switch Patients Undergoing PCI
PCI Patients
Comparing Consistent UFH/Enox vs Switch Bivalirudin
Consistent
UFH/Enox
Switch
Bivalirudin
N = 1236
N = 1292
Net Clinical Outcome
13.2%
11.8%
0.90 [0.73 -1.10]
Ischemia
8.2%
9.0%
1.10 [0.85 -1.42]
Major Bleeding
6.7%
3.5%
0.52 [0.36-0.74]
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
RR
ACUITY: Switch
30 Days
Prior Antithrombin Therapy
Relative Risk ± 95% CI
RR (95% CI)
Composite
Ischemia
0.93 (0.75-1.16)
Major Bleeding
0.49 (0.36-0.66)
Net Clinical
Outcome
0.77 (0.65-0.92)
0
Switch to Bivalirudin Better
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
1
2
Consistent UFH/Enox + IIb/IIIa
Better
White HD, et al. J Am Coll Cardiol 2008;51:1734–41
ACUITY — Switch
30 Days
Naïve to Antithrombin Therapy
Relative Risk ± 95% CI
RR (95% CI)
Composite
Ischemia
1.11 (0.83-1.49)
Major Bleeding
0.52 (0.35-0.77)
Net Clinical
Outcome
0.85 (0.67-1.07)
0
Randomization to
Bivalirudin Better
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
1
2
Randomization to
UFH/Enox + IIb/IIIa Better
White HD, et al. J Am Coll Cardiol 2008;51:1734–41
ACUITY – Switch
ACUITY PCI: Switch from Prior Antithrombin
30-Day Results
1-Year Results
Risk Ratio
± 95% CI
Hazard Ratio
± 95% CI
RR (95% CI)
PCI
PCI
(n=2528)
Composite
ischemia
1.10 (0.85-1.42)
Major bleeding
0.52 (0.36-0.74)
(n=2528)
Mortality
PCI HIGH RISK*
0.93 (0.58-1.48)
PCI HIGH RISK*
(n=1988)
(n=1988)
Composite
ischemia
1.14 (0.86-1.52)
Major bleeding
0.56 (0.38-0.81)
0.1
HR (95% CI)
Switch to
Bivalirudin
better
1
10
Mortality
0.1
Switch to
Consistent UFH/Enox
Bivalirudin
+ IIb/IIIa better
better
* High risk = ↑Tn, CKMB or ECG Δ’s
0.99 (0.60-1.63)
1
10
Consistent UFH/Enox
+ IIb/IIIa better
White HD. In Press JACC
Naïve to Antithrombin Therapy
Randomized to Enox + GPIIb/IIIa Inhibition (N = 842)
30 day events (%)
Randomized to Bivalirudin (N = 1427)
20
0.83 [0.63 – 1.09
P=0.18
1.06 [0.76 – 1.49]
P=0.74
0.51 [0.33 – 0.78]
P<0.01
9.5%
15
8.0%
5.8%
10
6.2%
5.0%
2.5%
5
0
Net clinical
outcome
Ischemic
composite
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Major
bleeding
ACUITY – Switch Limitations
►Post-hoc subgroup analysis
►Pre-randomization use of anti-thrombin
was not stratified
►Timing and dose of last UFH and Enox
was not collected in the CRF
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
REPLACE-2: SWITCH Analysis
Overall population: Urgent or elective PCI patients
(N=6,002)1
Randomize
Bivalirudin
UFH
0.75 mg/kg bolus/1.75 mg/kg/h infusion
with “provisional” GP IIb/IIIa (n=2,994)1
65 U/kg with planned GP IIb/IIIa
(n=3,008)1
Naïve – no
prior AT
(n=2,345)2
Prior UFH
(n=287)2
Prior
LMWH
(n=258)2
Naïve – no
prior AT
(n=2,325)2
Prior UFH
(n=349)2
Prior
LMWH
(n=313)2
Protocol major/minor bleeding, TIMI bleeding, transfusion, mortality
AT=antithrombin.
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
1. Lincoff ML et al. JAMA. 2004;292:696-703.
2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
Protocol Major/Minor Bleeding by
SWITCH and Randomized Therapy

Regardless of prior heparin or not, patients administered bivalirudin had decreased
bleeding
There was a significant increase in major/minor protocol bleeding in patients
administered UFH with prior heparin therapy
Protocol major/minor bleed

33.8%
35%
34.8%
†
28.6%
30%
25%
20%
*
15.6%
15.3%
16.7%
15%
10%
5%
0%
Naïve→
Bivalirudin‡
(n=2,345)
UFH→
Bivalirudin
(n=287)
LMWH→
Bivalirudin
(n=258)
Naïve→
UFH +
GP IIb/IIIa‡
(n=2,325)
UFH→UFH LMWH→UFH
+ GP IIb/IIIa + GP IIb/IIIa
(n=349)
(n=313)
*P=NS for all 3-way comparisons versus bivalirudin alone; †P<.05 vs prior treatment with UFH or enoxaparin;
‡naïve=no prior AT therapy in preceding 48 hours.
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
TIMI Major/Minor Bleeding by
SWITCH and Randomized Therapy

TIMI major/minor bleed

Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of
TIMI bleeding
Patients administered UFH had higher rates of bleeding, with highest rates in
patients switching between heparins
6%
5.4%
5%
4.3%
3.5%
4%
3%
2%
*
1.9%
1.9%
1.4%
1%
0%
Naïve→
Bivalirudin†
(n=2,345)
UFH→
Bivalirudin
(n=287)
LMWH →
Bivalirudin
(n=258)
Naïve→UFH UFH→UFH
+ GP IIb/IIIa† + GP IIb/IIIa
(n=349)
(n=2,325)
LMWH→UFH
+ GP IIb/IIIa
(n=313)
*P=NS for all 3-way comparisons versus bivalirudin alone; †naïve=no prior AT therapy in preceding 48 hours.
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
SWITCH
Major Bleeding %
15%
13%
p = 0.39
10%
7%
5%
0%
3%
n = 30
n = 30
n = 31
GPI (0 - 4 hr)
GPII (4 - 8 hr)
GPIII (8 - 12 hr)
Time from last enoxaparin dose
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Waksman et al. J Invasive Cardiol 2006;18:370
HORIZONS AMI Switching Data
UFH pre-procedure was administered to 65.8% of
bivalirudin pts and 76.3% of heparin + GPIIb/IIIa pts
30-Day MACE
10%
Pint=0.08
8%
7.2%
5.6%
6%
5.2%
4.6%
4%
2%
RR [95%CI]=
0.81 [0.58,1.14]
RR [95%CI]=
1.39 [0.85,2.28]
0%
30-Day Major Bleeding
Bivalirudin with "provisional" GP IIb/IIIa
Heparin + GP IIb/IIIa
10%
8.5%
Pint=0.47
7.5%
8%
6%
4.8%
5.2%
4%
2%
RR [95%CI]=
0.57 [0.42,0.77]
RR [95%CI]=
0.69 [0.43,1.12]
UFH pretreatment
(n=2,553)
No UFH
pretreatment
(n=1,042)
0%
UFH pretreatment
(n=2,553)
No UFH
pretreatment
(n=1,042)
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
How to Switch
From UFH to Bivalirudin
• Discontinue UFH for 30 minutes before
starting bivalirudin
From LMWH to Bivalirudin
•
Discontinue LMWH for 8 hours before
starting bivalirudin
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Conclusions
►Switching to bivalirudin is safe
 Switching from any heparin to bivalirudin
monotherapy is not associated with an
increased risk for ischemic events
►Furthermore
 Switch to bivalirudin provides patients the
50% bleeding advantage of bivalirudin
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
The Role and Implications of Bleeding in ACS
Role of Bleeding Reduction in ACS
Impact on Outcomes and Costs
Keith A A Fox
Edinburgh Centre for Cardiovascular Science
Potential conflicts of interest
Speaker’s name: Keith A A Fox
 I have the following potential conflicts of interest to report:
 Consulting
 Research grants/speaker honoraria: sanofi-aventis, BristolMyers Squibb, and GlaxoSmithKline
 Stockholder of a healthcare company
 Owner of a healthcare company
 Other(s)
 I do not have any potential conflict of interest
.
Bleeding in ACS
►
How common is major bleeding in ACS?
► What are the risk factors for bleeding?
► The impact of anti-thrombotic therapy?
► What are the consequences of bleeding?
• Net clinical outcome
• Costs
Factors Contributing to the Balance of Risks
Reduced Thrombotic
and Embolic Events
Anticoagulants
Anti-platelets
Anti-thrombins
ACE / ARB
Hypertension &
lipid control
Smoking cessation
Cerebral and Systemic
Bleeding Events
Anticoagulants
Anti-platelets
Anti-thrombins
Renal dysfunction
Poor hypertension
control
Hierarchy of Bleeding Risk
A consistent definition
of bleeding is required
Fatal bleed
Intra-cerebral bleed
Life-threatening bleed
Bleed with hemodynamic disturbance
or requiring transfusion
or prolonging hospital stay
Minor bleeds
TIMI “ Major Bleed”: >5gm Hb drop or 5U transfusion or ICH
GUSTO “ severe/life threatening”: ICH or
hemodynamic compromise requiring treatment
Major Bleeding in ACS: GRACE Registry
6
Patients %
5
4.7
4
3.9
3
2
2.3
4.8
Overall ACS
Unstable angina
Non-ST MI
ST-MI
1
0
Major bleeding
Definition
of bleeding:
• Life threatening bleeding requiring a transfusion of 2+ units
• Bleeding resulting in an absolute decrease in hematocrit of ≥ 10%
• Bleeding resulting in death
n= 24,045 patients
European Heart Journal (2003) 24, 1815–1823
Multivariate Risk (Non-ST MI)
Major Bleeding (1)
Hosomer-Lemeshow p value 0.70, C statistic 0.73
Odds Ratio
(95% CI)
Thrombolytic +
IIb/IIIa
4.19
1.68-10.0
IIb/IIIa
1.86
1.43-2.43
History of Bleeding
2.18
1.17-4.08
Renal Insufficiency
1.53
1.13-2.08
Moscucci et al Eur Heart J 2003
Multivariate Risk (Non-ST MI)
Major Bleeding
Hosomer-Lemeshow p value 0.70, C statistic 0.73
Odds Ratio
(95% CI)
Age (10yr)
1.22
1.10-1.35
Female
1.36
1.07-1.73
Inotropes (iv)
1.88
1.35-2.62
Renal Insufficiency
2.01
1.38-2.91
Diuretics
1.91
1.46-2.49
Mean Arterial Pressure
(20mm )
1.04
1.14-1.27
Moscucci et al Eur Heart J 2003
GUSTO I Predictors of Bleeding
Variable
Odds Ratio
95% CI
2
Patients treated
in US
1.76
(1.08, 2.85)
521
Age (60 v 50y)
1.30
(1.26, 1.35)
222
Weight (75 v
85kg)
1.23
(1.18, 1.28)
164
Female
1.42
(1.31, 1.53)
73
African Ancestry
1.33
(1.12, 1.57)
10
Berkowitz, Circulation 1997;95:2508-2516 12
The Role and Implications of Bleeding in ACS
Bleeding and Outcome?
Bleeding and Outcomes in ACS
Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity
N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT
1.00
0.95
0.90
None
Mild
Moderate
Severe
0.85
0.80
0.75
0.70
0
5
10
15
Days to Death
Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6.
20
25
30
log rank p-value for all four categories <0.0001
log-rank p-value for no bleeding vs. mild bleeding = 0.02
log-rank p-value for mild vs. moderate bleeding <0.0001
log-rank p-value for moderate vs. severe <0.001
6-month Death/MI (Adjusted)
According to Severity of Bleeding
1.3
GUSTO Mild
2.0
GUSTO Moderate
5.1
GUSTO Severe
1.0
5.0
Odds ratio
Rao SV, et. al., ACC 2005
30 Day Death According to Bleeding
10 12 14
2
4
6
8
Bleeding
No Bleeding
0
Cumulative Events, %
OASIS Registry, OASIS-2, CURE
0
5
10
15
20
25
30
32879
420
32769
410
32710
408
Days
No. at Risk
No Bleeding 33676
Bleeding
470
J Eikelboom et al Circulation 2006
33419
459
33157
440
32990
430
The Role and Implications of Bleeding in ACS
The impact of renal dysfunction
SYNERGY: Clinical Outcomes and Procedures
Creatinine Clearance (CrCl)
CrCl < 30
CrCl 30-60
CrCl  60
N=156
N=2732
N=7011
Death/MI
24.4%
17.3%
12.7%
<0.0001
Death
15.4%
5.7%
1.8%
<0.0001
Cardiac Cath
80.1%
88.8%
93.7%
<0.0001
PCI
35.0%
42.4%
51.5%
<0.0001
CSBG
17.1%
20.0%
20.2%
0.84
7.7%
3.7%
1.8%
<0.0001
p-value
30-Day Outcomes
In-Hospital
Bleeding
GUSTO Severe
P-value from logistic regression with CrCl as continuous variable
* in-hospital
The Role and Implications of Bleeding in ACS
Increased Risks Associated with
Transfusion
CRUSADE Bleeding Risks
Transfusion by Age
% RBC Transfusion
20
14.9% overall
10.3% non-CABG
14.1
15
9.7
10
5
18.5
17.9
10.3
4.5
0
<65 yrs
Through Q2 2004 (n=74,271)
-- Yang, J Am Coll Cardiol 2005;46:1490-5
65-75 yrs
Non-CABG
> 75 yrs
Overall
Transfusion and 30-day Mortality
3.8
Adjusted for transfusion
propensity
3.5
Adjusted for baseline
characteristics
3.9
Adjusted for baseline
characteristics, bleeding
propensity, transfusion
propensity, & nadir HCT
0.1
1.0
10
Odds Ratio
Cox model, transfusion = time-dependent covariate
-- Rao SV, et. al., JAMA 2004
The Role and Implications of Bleeding in ACS
Does Prevention of Bleeding
Improve Long-term Outcome?
1-Year Mortality
Multivariate Logistic Model
Predictor
Odds
Ratio
95%Confidence
Interval
CrCl <30 ml/min
7.9
2.7-22.4
CrCl 30-60
ml/min
3.8
2.2-6.6
CrCl 60-90
ml/min
1.7
1.0-2.7
Major Bleed
3.67
2.1-6.5
<0.001
Non-Q MI
2.58
1.5-4.4
0.004
Diabetes
1.74
1.3-2.6
0.005
p-value
<0.001
Influence of Major Bleeding and MI in the First
30 Days on Risk of Death Over 1 Year
Of 13,819 enrolled pts, 524 (3.8%) died within 1 year
Cox model adjusted for baseline predictors, with MI and major
bleeding (non-CABG) as time-updated covariates
HR ± 95% CI
HR (95% CI)
P-value
Myocardial infarction
2.51 (1.95-3.25) <0.0001
Major bleeding without or
before transfusion
2.00 (1.30-3.06) <0.0001
Attributable
deaths
51.5*
66.5**
Major bleeding after
transfusion
3.93 (2.95-5.24) <0.0001
*9.8% of all deaths
**12.7% of all deaths
Mehran RM et al. Submitted
Attributable deaths = N deaths
among pts with the time updated
event (attribute) X (adj. HR – 1)/adj. HR
Predictors of Major Bleeding
Results: The ACUITY Trial — PCI Population
Risk ratio ± 95% CI
RR (95% CI)
P-value
Age >75 (vs. 55-75)
1.56 (1.19-2.04)
0.0009
Anemia
1.89 (1.48-2.41)
<0.0001
CrCl <60mL/min
1.68 (1.29-2.18)
<0.0001
Diabetes
1.30 (1.03-1.63)
0.0248
Female gender
2.08 (1.68-2.57)
<0.0001
High-risk (ST / biomarkers)
1.42 (1.06-1.90)
0.0178
Hypertension
1.33 (1.03-1.70)
0.0287
No prior PCI
1.47 (1.15-1.88)
0.0019
Prior antithrombotic therapy
1.23 (0.98-1.55)
0.0768
Heparin(s) + GPI (vs. Bivalirudin)
2.08 (1.56-2.76)
<0.0001
0
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
1
2
3
Major Bleeding at 30 Days
UFH/Enox versus Fondaparinux
OASIS 5 & 6
0.03
0.02
Fondaparinux
0.01
HR 0.67
95% CI 0.59-0.76
P<0.00001
0.0
Cumulative Hazard
0.04
UFH/Enoxaparin
0
5
10
15
Days
20
25
30
Mortality: Day 30
OASIS 5
0.02
Fondaparinux
0.01
HR 0.83
95% CI 0.71-0.97
P=0.022
0.0
Cumulative Hazard
0.03
Enoxaparin
0
3
Yusuf et al NEJM 2006
6
9
12
15
Days
18
21
24
27
30
Relative Impact of MI, Refractory Ischemia
or Bleeding on Mortality
OASIS 5
Crude Odds Ratio for Death
(95% CI)
30 Days
30 to 180 Days
180 Days
Nonfatal MI
9.9 (8.0-12.3)
2.3 (1.6-3.3)
5.7 (4.7-6.9)
Refractory
Ischemia
4.1 (3.0-5.7)
1.4 (0.8-2.4)
2.7 (2.0-3.6)
Major Bleeds
6.6 (5.2-8.3)
2.2 (1.6-3.2)
4.2 (3.5-5.1)
Minor Bleeds
3.0 (2.1-4.3)
1.6 (1.0-2.5)
2.2 (1.7-3.0)
The Role and Implications of Bleeding in ACS
Minimizing the Risks of Bleeding?
Excessive Dosing of Anticoagulants by Age
70
64.5
% Excessive Dose
60
50
37
40
33.1
28.7
30
20
38.5
16.5
12.5 12.5
8.5
10
0
LMW Heparin
UF Heparin
< 65 yrs
65-75 yrs
GP IIb/IIIa
>75 yrs
Dosing Combinations and Transfusions
% RBC Transfusions
Heparin + GP IIb-IIIa Inhibitors*
20
18
16
14
12
10
8
6
4
2
0
18.5
9
4.1
Both Right
1 Excessive
Both Excessive
* Among patients receiving both Heparin (UFH or LMWH) and GP IIb-IIIa Inhibitors
Bleeding and Resource Use
Predictors of Total Costs
14,000
$12,409
12,000
10,000
8,000
$7,188
$
6,000
4,000
$5,255
$3,370
$2,488
$2,164
2,000
$2,436
$1,336
$1,158
0
Mod/Sev
Bld
UA
Cath
PCI
CABG
N=1235 pts from GUSTO IIb
Rao SV, et. al. AHJ 2008.
Pacemaker
IABP
ICU day
Non-ICU
day
Model C-index=0.87
Adjusted for patient characteristics
Conclusions
► In ACS bleeding is important as it is a harbinger of
adverse outcomes, including death

Major bleeding and recurrent MI have a similar risk of death
► Older age, chronic kidney disease, female gender,
anemia, diabetes: consistently associated with bleeding
and blood transfusion
► Major bleeding is associated with adverse outcomes and
increased costs
► Both ESC and ACC/AHA Guidelines in ACS highlight the
importance of bleeding reduction in ACS care
The Science and Medicine of ACS
Translating Advances in NSTEMI
and STEMI into Real World
Institutional Practice
Harold L. Dauerman, MD
Director, Cardiovascular Catheterization
Laboratories
Professor of Medicine
University of Vermont
Fletcher Allen Health Care
Potential conflicts of interest
Speaker’s name: Harold L. Dauerman, MD
 I have the following potential conflicts of interest to report:
 Consulting: The Medicines Company, Abbott Vascular
 Employment in industry
 Stockholder of a healthcare company
 Owner of a healthcare company
 Other(s)
 I do not have any potential conflict of interest
University of Vermont Post-PCI Bleeding
and Vascular Complication Rates
Bleeding Complication, %
4
Introduction of
Bivalirudin to Cath Lab
3.5
3
NNE Rate: 2.0% in 2006
2.5
2
1.5
1
0.5
Introduction of
Upstream Bivalirudin
0
2001
2002
2003
2004
2005
2006
2007
Any Transfusion, RPH or Repair = Bleeding Complication
Incorporation of Bivalirudin in Cath Lab for
NSTEMI in 2003—A Cautious Beginning
25%
33%
42%
Bivalirudin
GP IIb/IIIa Inhibitor
UFH alone
Signs of Hope Since 2004
4
Major Vascular Complications, %*
3.5
P < 0.001 for temporal trend
3.37
3.2
3
2.51
2.5
2.11
2
1.96
1.5
1
0.5
0
2002
2003
2004
2005
Arterial injury and/or arterial injury related bleeding
N= 36,631 Patients Undergoing PCI, NNE Registry
Dauerman, Applegate and Cohen, JACC 2007
2006
How We Introduced Upstream and
Downstream Bivalirudin: The UVMC Time Line
 2003: Put bivalirudin on the cath lab shelf as an option
for NSTEMI
 2007: Educational programs for fellows, floor staff and
attendings
 We did not remove GPI option
 We did NOT involve community hospitals in this
decision. They can do whatever they want as long as
they transfer and don’t overdose patients.
 2008: A standardized STEMI bivalirudin approach
 For upstream AMI utilization, bivalirudin ordered from
pharmacy
 In collaboration with ED (EDICT for ACS Strategy)
Non ST-Elevation Myocardial Infarction
NSTEMI
Transfers, Upstream
Strategies, and
Results of Clinical Trials
What We Really Do With Transfers?
September 24, 2007 email from me
To:
Cc:
Subject:
Sullivan, Claudia A.
Ades, Philip A.
Transfer of John XXXXX, DOB 11/08/25
81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT.
ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical
Center.
Class I transfer. Change to bivalirudin on arrival. DNR—reverse
POLST (wants a cath, but no CABG). Echo today, cath tomorrow
(or today if unstable).
Thanks,
Harry
Protocol Major/Minor Bleed by
SWITCH and Randomized Therapy
33.8%
Protocol major/minor bleed
35%
28.6%
30%
34.8%
†
25%
20%
15.6%
15%
*
15.3%
16.7%
10%
5%
0%
Naïve→
Bivalirudin‡
(n=2,345)
UFH→
Bivalirudin
(n=287)
LMWH→
Bivalirudin
(n=258)
Naïve→ UFH +
GP IIb/IIIa‡
(n=2,325)
UFH→UFH LMWH→UFH
+ GP IIb/IIIa + GP IIb/IIIa
(n=349)
(n=313)
*P=NS for all 3-way comparisons versus bivalirudin alone; †P<.05 vs prior treatment with UFH or enoxaparin;
‡naïve=no prior AT therapy in preceding 48 hours.
Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
Transfer to Cardiology Floor
► Enoxaparin held—wait 8
►
►
►
►
►
hours from community
hospital last dose.
Then, start upstream
bivalirudin
Patient pain free—1st
case next A.M
DES, no eptifibatide,
closure device, 150 mg
clopidogrel
Ambulate at 6 hours
D/C following 0900 A.M.
If Patient is not Clopidogrel Exposed,
Do We Use Bivalirudin? Definitions?
UFH/Enoxaparin + IIb/IIIa (N=1722)
UFH/Enoxaparin + IIb/IIIa (N=811)
Bivalirudin Alone (N=1789)
Bivalirudin Alone (N=804)
RR [95%CI]
0.81 (0.68-0.96)
RR [95%CI]
0.96 (0.77-1.20)
RR [95%CI]
0.50 (0.37-0.67)
RR [95%CI]
1.07 (0.83-1.39)
13.8%
11.8%
RR [95%CI]
1.37 (1.00-1.88)
RR [95%CI]
0.61 (0.39-0.97)
12.7%
11.1%
10.3%
8.4%
8.1%
7.5%
7.2%
5.7%
3.5%
3.6%
Net clinical
outcomes
Ischemic
composite
Major bleeding
Thienopyridine Exposed
Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16
Net clinical
outcomes
Ischemic
composite
Major bleeding
Not Thienopyridine Exposed
Timing of Clopidogrel Administration and
30-Day Risk of Ischemic Outcomes
Risk ratio (RR) ±95% CI for the triple ischemic endpoint
(death, MI, unplanned revascularization)
Pre-PCI clopidogrel
N=3429, RR 0.92 [95% CI 0.74,1.15]
Peri-PCI Clopidogrel
N=1044, RR 1.26 [95% CI 0.82,1.92]
pinteraction = 0.35
Post-PCI Clopidgrel
(> 30 minutes After PCI)
N=519 RR 1.48 [95% CI 0.89, 2.47]
No Clopidogrel
N=88 RR 2.62 [95% CI 0.89, 7.72]
0
Bivalirudin alone better
S. Steinhubl TCT 2007
1
2
3
4
5
6
Heparin + GPIIb/IIIa better
7
8
Does Periprocedural Infarct Increase With
Upstream and Downstream Bivalirudin? No!
2005
2007
Bival 61%
N=373
Bival 91%
Any Transfusion (%)
2.0
1.0
NS
Death (%)
3.0
1.0
0.08
Urgent revascularization (%)
2.0
1.0
NS
MI, 50% CK-MB Rise (%)
4.0
1.0
0.02
Mechanical Complication (%)
8.0
6.0
NS
ACS PCI Outcomes
P value
N=361
Submitted, TCT 2008
Clopidogrel preload in approx 60% of PCI patients
CK-MB on all patients the day after PCI (University of Vermont data)
ST-Elevation Myocardial Infarction
STEMI
Switching, Clopidogrel and
Stent Thrombosis
The Standard of Care for STEMI PCI in 2005:
National Registry of Myocardial Infarction-5
Primary PCI for STEMI N= 7,629
Bivalirudin PCI
N=320 (4%)
Bivalirudin and GPIIbIIIa PCI
N=177 (55%)
Clopidogrel
N=171 (97%)
Clopidogrel
Prior to PCI
N=41 (24%)
Prior to PCI
N=37 (21%)
Not Prior to PCI
N= 140 (79%)
No Bivalirudin PCI
N= 7,309
Bivalirudin Alone
N=143 (45%)
Clopidogrel
N=137 (96%)
Prior to PCI
N=31 (23%)
Abciximab N=64 (36%)
Eptifibatide N=93 (52%)
Tirofiban N=1 (1%)
Unkown N=19 (11%)
AbciximabN=8 (22%)
EptifibatideN=27 (73%)
TirofibanN=1 (3%)
Unknown N=1 (2%)
AbciximabN=56 (40%)
EptifibatideN=66 (47%)
TirofibanN=0 (0%)
Unknown N=18 (13%)
Clopidogrel Prior
to PCI
N=1466 (21%)
GP IIbIIIa Inhibitor use
N=6,873 (94%)
Prior to PCI
N=2,489 (36%)
Not Prior to PCI
N= 4,384 (64%)
Abciximab N=2,283 (33%)
Eptifibatide N=3,551 (52%)
Tirofiban N=154 (2%)
Unknown N= 885 (13%)
AbciximabN=622 (25%)
EptifibatideN=1621 (65%)
TirofibanN=99 (4%)
Unknown N=147 (6%)
Dauerman and French, Coronary Artery Disease, 2006
Clopidogrel
N=6878 (94%)
AbciximabN=1661 (38%)
EptifibatideN=1930 (44%)
TirofibanN=55 (1%)
Unknown N=738 (17%)
Implementation of HORIZONS AMI PCI
Pharmacologic Aspects of Management
 Unfractionated heparin
 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250
secs; terminated at procedure end unless prolonged antithrombin
needed
 Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY)
 Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT;
terminated at procedure end unless prolonged antithrombin needed
(0.25 mg/kg/hr infusion)
 Glycoprotein IIb/IIIa inhibitors
 Routine use in UFH arm; recommended only for giant thrombus or
refractory no reflow in bivalirudin arm
 Abciximab or double bolus eptifibatide as per investigator discretion –
dosing per FDA label, renal adjusted; continued for 12 (abciximab) or
12-18 (eptifibatide)
* If pre randomization UFH administered, ACT is checked first
** If pre randomization UFH administered, started 30’ after last bolus
Primary PCI for STEMI: Community Hospital Algorithm
ASA, Clopidogrel and UFH and then Switch to Bivalirudin at UVM
27 miles, on interstate highway
Time from ED Presentation at NWMC to Open Artery at FAHC:
88 Minutes
Do I Have to Load Bivalirudin in the ED or Can I Start in
the Cath Lab? The HORIZONS AMI Switching Perspective
UFH + GP
IIb/IIIa
(N=1802)
UFH pre randomization
Bivalirudin
(N=1800)
65.6%
65.6%
98.9%
4.1%
 Bivalirudin
0.4%
96.9%
 Peak ACT
264 [228, 320]
357 [300, 402]
94.5%*
7.2%*
-
4.4%
 Abciximab
49.9%
4.0%
 Eptifibatide
44.4%
3.1%
0.2%
0.1%
Antithrombin in CCL
 UFH
GP IIb/IIIa in CCL
 Bail-out per protocol**
 Tirofiban
G Stone TCT 2007
*97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after
PCI. CCL = cardiac catheterization laboratory
Bivalirudin Improves Mortality in STEMI
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
Death (%)
3.1%
2.1%
HR [95%CI] =
0.66 [0.44, 1.00]
P=0.048
Time in Days
G Stone TCT 2007
The UVM STEMI Order Sheet
One Pathway for Primary PCI and ED Collaboration
TESTS AND MEDICATIONS
EKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required.
LABORATORY:
7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFT’s, CK, CK-MB and TnI sent immediately
on arrival: STAT
8. Other labs:
MEDICATIONS: Weight: __kg
Estimated / Actual (Circle one)
Check patient not allergic to aspirin
9. Aspirin Non- Enteric Coated 325 mg PO Daily
10. Clopidogrel 600 mg PO x one
11. Bivalirudin bolus 0.75 mg/kg IV, then infusion 1.75 mg/kg/hr (STAT from
Pharmacy)
12. Saline Lock with routine flushes every 8 hours
OPTIONAL:
13. Nitroglycerin infusion: 400 mcg/ml infusion at _______ mcg/kg/min IV
Titrate to chest pain, keep systolic BP >90.
14. Lopressor 5 mg IVP x 1 if HR > 80 and SBP > 140
The Bivalirudin Strategy for STEMI PCI
ASA, clopidogrel 600 po x 1, bivalirudin and stent
What About The Stent Thrombosis Risk?
UFH + GP IIb/IIIa
Bivalirudin
(N=1553)
(N=1571)
P
Value
1.9%
2.5%
0.33
Definite
1.4%
2.2%
0.11
Probable
0.5%
0.3%
0.26
Acute
(≤24 hrs)
0.3%
1.3%
0.0009
Subacute
(>24 hrs – 30d)
1.7%
1.2%
0.30
ARC definite or
probable*
G Stone TCT 2007
*Protocol definition of stent thrombosis, CEC adjudicated
Risk Stratification For STEMI Stent Thrombosis
The Importance of Thrombus Burden
Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583
Large thrombus burden (LTB), defined as thrombus burden > 2 vessel
diameters: Approx 25% of STEMI
Drug Eluting Stent Thrombosis and Large Thrombus
Burden: Modifying Strategy In Highest Risk Patients
15
Cumulative IRA-ST Rate (%)
 Large Thrombus
LTB vs. STB, p<0.001
12
 Burden> 5 fold
 Increased Risk of
LTB
9
8.2%
5.8%
30 Day Stent
Thrombosis
6
3.2%
Total Population
2.7%
2.1%
3
3.2%
STB
1.1% 1.4%
0
0.5%
0 1
0.7%
0.7%
3
6
1.3%
9
12
15
18
Months of follow-up
Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583
21
24
Thrombectomy
Prolonged Bivalirudin
GPI
ACUITY and Large Thrombus Data
The Rationale for Selective Adjunctive GPI
ACUITY
Heparin
+ IIb/IIIa
(N=222)
Bivalirudin
+ IIb/IIIa
(N=241)
Bivalirudin
alone
(N=249)
P value
3-way
Any thrombotic
complication post
PCI
8.6%
3.7%
5.6%
0.09
Final TIMI flow 3
90.5%
93.7%
90.7%
0.37
Final blush grade 3
81.5%
79.0%
79.5%
0.78
* New or ↑ thrombus, abrupt closure, no reflow, or distal embolization
G. Stone AHA 2006
Projecting What Happens if You Use GPI in 25%
of Your Bivalirudin STEMI Patients
9
8
8.3
Bival +
UFH + GPI
8.3
P < 0.001
Major Bleeding, %
7
Still P < 0.001
6
5
4.9
5.2
4
3
2
1
0
HORIZONS 7%
Assumes Bival + GPI bleeding rate of 6.8%
UVM Implemented
HORIZONS—25%
Incorporation of HORIZONS AMI and Large
Thrombus Data—STEMI Algorithm
► ED STEMI—25% of Patients
► ASA/clopidogrel 600 mg po
►
►
►
►
►
load and bivalirudin
Bolus and infusion of
eptifibatide after wiring
vessel shows Large
Thrombus Burden
Angiojet and Bare Metal
Stent
150 mg clopidogrel and 18
hours of eptifibatide
No ambulation until
eptifibatide off (18 hours)
D/C on Day 3 post MI
STEMI:
Within 24 Hours CP
PCI Capability or
< 60 minute Transfer Time
UFH or Bivalirudin:
GPI Optional: Avoid if High Bleed Risk
B Blockers ONLY if HTN
Clopidogrel
600 po
90 minutes
To Open
Artery
ASA
325 po
ASA/Clopidogrel
Statin
Groin Closure
Cardiac Rehab
Lopressor 12.5 bid
UFH (60 U/Kg)
Beta Blockers only if HTN
Clopidogrel
300 po
Emergent Transfer
Primary PCI with Stenting:
GPI/Thrombectomy if Large Thrombus
or as Bailout; Otherwise, Bivalirudin Alone
Continue bivalirudin for
2 hours after PCI
No PCI Capability and
> 60 minute Transfer Time
If Reperfusion Fails,
Emergent PCI with stent
Lytic
Contraindicated
Rescue
PCI:
Class I
Indication
TNK and UFH
Transfer
If no CP and less than 50%
ST Elevations, PCI at 12-24
Hours with Stent
The NSTEMI
Paradigm
of 4-48 Hours
Transfer from
Community ER
To PCI Site
Conclusions
Key Implementation Points
► Bivalirudin can be safely instituted across the spectrum of
PCI patients, including those with NSTE-ACS and STEMI.
► Clopidogrel 600 mg po load may be done in ED or
immediately after PCI.
► Community referring hospitals may use antithrombotic
therapy of choice—then switch to bivalirudin on arrival to PCI
institution.
► STEMI requires an algorithm for care and bivalirudin is the
baseline strategy. But, bivalirudin may be instituted in the ED
or the cath lab, depending upon local issues.
► Enhanced management of large thrombus burden should be
considered especially during the most “vulnerable” 2 hours
after PCI.
Questions for the Panel
► Does a consistent, unified upstream strategy for anticoagulation
across the STEMI and NSTE-ACS risk spectrum make sense?
When does it? When doesn’t it?
► Given that bleeding appears to be a driver of MACE events,
including mortality, in ACS and STEMI, and since switching to
bivalirudin appears to decrease bleeding, should this switching
strategy be promulgated in patients undergoing PCI?
► What are the best ways, from an institutional/process-of-care
perspective, to establish a consistent antithrombotic strategy for
this patient population?
► Other issues? We’ll answer your questions!