Changing anticoagulants in midstream - what are the benefits and risks?

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(No Transcript)
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Introduction and ObjectivesIssues and challenges
in ACS
High Risk Patients with ACS EuroPCR 2008,
Barcelona, Spain

• Philippe Gabriel Steg
• INSERM U-698
• Hôpital Bichat Claude Bernard
• Université Paris VII Denis Diderot

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Disclosures
Speakers 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 ? Speakers Bureau
Boehringer-Ingelheim, BMS, GSK, Nycomed,
sanofi-aventis, Servier, ZLB-Behring ? I do
not have any potential conflict of interest
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The Landscape

• A changing pattern of care for all high-risk ACS

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Trends in Management of STEMI in the GRACE
Registry
Fox KAA et al. JAMA 20072971892-1900
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The Landscape

• A changing pattern of care for all high-risk ACS
• and outcomes which are improving

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In-Hospital and 6-Month Outcomes in Patients With
STEMI or LBBB
Fox KAA et al. JAMA 20072971892-1900.
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CRUSADE In-Hospital Outcomes Data from 2006

• Death 3.6
• (Re)-Infarction 1.8
• CHF 6.6
• Cardiogenic Shock 2.2
• Stroke 0.7
• RBC Transfusion 9.1

Excluding CABG-related transfusions CRUSADE
DATA January 1, 2006 December 31, 2006 (n
29,825)
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The Landscape

• A changing pattern of care for all high-risk ACS
• and outcomes which are improving
• A growing level of complexity

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Antithrombotics for ACSMore and More Choices
(and Combinations)
Fonda
Direct TIs
Lytics
Clopidogrel
GP IIb/IIIa inhibitors
LMWH
Heparin
Aspirin
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Choices Impacting Antithrombotic Therapy
Anticoagulants UFH LMWH Fonda Bival Antiplatele
ts ASA (dose) Clopidogrel (time/dose) IV
antiplatelets None Abcix Ept/Tiro
(timing) Cath strategy Early
Delayed Never
72 Different Combinations!
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Treatment of ACS is a Jungle !
Anticoagulant Rx UFH Enoxaparin Bivalirudin Fondap
arinux Warfarin ? Anti X ? Anti II
Timing
Antiplatelet Rx ASA Clopidogrel ? Prasugrel ? AZD
6140 GpIIb/IIIA IV blockers ? Cangrelor ? TRA
Revascularization PCIBMS DES CABG
Patient
Bleeding risk
Comorbidities
Risk of thrombotic event
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The Landscape

• A changing pattern of care for all high-risk ACS
• and outcomes which are improving
• A growing level of complexity
• Use and timing of interventions impact
  therapeutic choices

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The Landscape

• A changing pattern of care for all high-risk 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 !

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Objectives

• Know the current guidelines for the management of
  STEMI and NSTE ACS
• Understand their implications for patient
  management

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New Horizons for Patients with ST-Elevation
Myocardial Infarction

• Gregg W. Stone MD

Columbia University Medical Center Cardiovascular
Research Foundation
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Potential Conflicts of Interest
Speakers 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
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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
FACT
Ndrepepa et al. JACC 2008516907
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Impact of Major Bleed and MI after
Elective and Urgent PCI1-Year Mortality (N6,012)
With major bleed
8.8
5.7
With MI
Cumulative Mortality
Without major bleed
2.0
1.9
Without MI
Time from Randomization in Days
Stone GW. J Inv Cardiol 200416(suppl G)1217.
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Predictors of 1-year Mortality after
Elective and Urgent PCI
Variable Groups O.R. (95 CI) p-value
Creatinine clear. lt30 mL/min 7.21 (2.5320.51) lt0.0001
3060 mL/min 3.34 (1.925.78) lt0.0001
6090 mL/min 1.57 (0.962.57) lt0.0001
CHF Yes 4.38 (2.836.78) lt0.0001
Major Bleeding Yes 3.26 (1.785.96) 0.0001
MI _at_30day Yes 2.77 (1.624.75) 0.0002
Urg Revasc _at_30d Yes 2.77 (1.156.71) .024
Hx angina Yes 2.18 (1.253.81) 0.006
Prior MI Yes 1.81 (1.093.03) 0.023
Diabetes Yes 1.64 (1.102.44) 0.015
Stone GW. J Inv Cardiol 200416(suppl G)1217.
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1-year MortalityAll 6,012 Patients (ITT)
2.5
P value 0.16
1.9
Cumulative Deaths
Days
Lincoff AM et al. JAMA 2004292696703
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Impact of MI and Major Bleeding (non-CABG) in the
First 30 Days on Risk of Death Over 1 Year
1 yearEstimate
30
25
20
Mortality ()
15
10
5
0
0
30
60
90
120
150
180
210
240
270
300
330
360
390
Days from Randomization
Stone GW. ACC 2007
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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

Attributable deaths
HR 95 CI
P-value
HR (95 CI)
Myocardial infarction 5.25 (3.72-7.43) lt0.0001
Major bleeding without or before transfusion 3.04 (1.66-5.55) lt0.0001
Major bleeding after transfusion 5.45 (3.54-8.38) lt0.0001
42.0
38.2
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
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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
Attributable deaths
HR 95 CI
P-value
HR (95 CI)
Myocardial infarction 2.51 (1.95-3.25) lt0.0001
Major bleeding without or before transfusion 2.00 (1.30-3.06) lt0.0001
Major bleeding after transfusion 3.93 (2.95-5.24) lt0.0001
51.5
66.5
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
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ACUITY Early and Late MortalityLandmark analysis
4
3
Mortality ()
2
1
0
0
30
60
90
120
150
180
210
240
270
300
330
360
390
Days from Randomization
Stone GW. JAMA 20072982497-506
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Harmonizing Outcomes with Revascularization and
Stents in AMI
3400 pts with STEMI with symptom onset 12 hours
Clinical FU at 30 days, 6 months, 1 year, and
then yearly through 5 years
To rand 3000 stent pts
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Harmonizing Outcomes with Revascularization and
Stents in AMI
3602 pts with STEMI
UFH GP IIb/IIIa N1802
Bivalirudin Monotherapy N1800
Randomized
Withdrew Lost to FU
9 15
10 13
N1778 (98.7)
N1777 (98.7)
30 day FU
ITT population
N1802
N1800
Range 7 days
Stone GW et al. In press.
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Primary Outcome Measures (ITT)
Diff 0.0 -1.6, 1.5 RR 0.99 0.76, 1.30
Psup 0.95
Diff -3.3 -5.0, -1.6 RR 0.60 0.46,
0.77 PNI 0.0001 Psup 0.0001
Diff -2.9 -4.9, -0.8 RR 0.76 0.63, 0.92
PNI 0.0001 Psup 0.005
1? endpoint
1? endpoint
Not related to CABG MACE All cause death,
reinfarction, ischemic TVR or stroke
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30 Day Bleeding Endpoints
UFH GP IIb/IIIa (N1802) Bivalirudin (N1800) P Value
Protocol Major, non CABG 8.3 4.9 lt0.0001
Protocol Major, All 10.8 6.8 lt0.0001
Protocol Minor 15.4 8.6 lt0.0001
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 lt0.0001
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
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Thrombocytopenia
P 0.002
P 0.04
P 0.02
lt100,000 cells/mm3
lt20,000 cells/mm3
lt50,000 cells/mm3
Stone GW et al. In press.
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30 Day MACE Components
UFH GP IIb/IIIa (N1802) Bivalirudin (N1800) P Value
Death 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
Ischemic TVR 1.9 2.6 0.18
- Ischemic TLR 1.8 2.5 0.13
- Ischemic remote TVR 0.3 0.3 1.0
Stroke 0.6 0.7 0.68
CEC adjudicated
Stone GW et al. In press.
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30 Day Mortality
3.1
Death ()
2.1
HR 95CI 0.66 0.44, 1.00 P0.048
Time in Days
Number at risk Bivalirudin 1800 1758 1751 1746 17
42 1729 1666 Heparin GPIIb/IIIa
1802 1764 1748 1736 1728 1707 1630
Stone GW et al. In press.
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30 Day Mortality Cardiac and Non Cardiac
HR 95CI 0.62 0.40, 0.96 P0.029
2.9
Death ()
Cardiac
1.8
Non cardiac
0.3
0.2
Time in Days
Number at risk Bivalirudin 1800 1758 1751 1746 17
42 1729 1666 Heparin GPIIb/IIIa
1802 1764 1748 1736 1728 1707 1630
Stone GW et al. In press.
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30 Day Stent Thrombosis (N3,124)
UFH GP IIb/IIIa (N1553) Bivalirudin (N1571) P Value
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 (gt24 hrs 30d) 1.7 1.2 0.28
Protocol definition of stent thrombosis, CEC
adjudicated
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30 Day Mortality PCI Cohort
HR 95CI 0.63 0.40, 0.99 P0.049
2.8
Death ()
Cardiac
1.8
Non cardiac
0.2
0.1
Time in days
Number at risk Bivalirudin 1678 1647 1640 1635 16
32 1620 1563 Heparin GPIIb/IIIa
1662 1631 1615 1604 1598 1583 1512
Stone GW et al. In press.
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Predictors of 30 Day Mortality32 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
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Time-updated covariate adjusted Cox model
relating single 30-day adverse events to 30-day
mortality
Attributable
Ischemic Events HR (95 CI) P deaths C-stat Rein
farction 11.09 5.44,22.59 lt0.001 9.1
8.2,9.6 0.83 Ischemic TVR 6.91 3.36,14.18
lt0.001 7.7 6.3,8.4 0.83 Stent thrombosis,
definite - any 10.71 3.93,29.18 lt0.001
4.5 3.7,4.8 0.83 - acute (lt24 hours) 5.88
0.78,44.30 0.09 0.8 -0.3,1 0.82 Stroke
5.44 1.67,17.69 0.005 2.4 1.2,2.8 0.82
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
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Time-updated covariate adjusted Cox model
relating single 30-day adverse events to 30-day
mortality
Attributable
Bleeding Events HR (95 CI) P deaths C-stat Majo
r bleed (non-CABG) 4.43 2.67, 7.33 lt0.001
20.1 16.3,22.5 0.85 Major bleed (all) 5.92
3.73, 9.41 lt0.001 29.1 25.6,31.3
0.86 Transfusion 3.88 2.09, 7.20 lt0.001
11.9 8.4,13.8 0.83 Thrombocytopenia -
lt100,000 cells/mm3 3.89 2.22, 6.84 lt0.001
11.1 8.2,12.8 0.78 - lt50,000 cells/mm3
6.44 2.93,14.18 lt0.001 5.9 4.6,6.5 0.78
- lt20,000 cells/mm3 4.98 1.20,20.66 0.03 1.6
0.3,1.9 0.77
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
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Time-updated covariate adjusted Cox model
relating 30-day events to 30-day mortality-
Complete model with MACE components and major
bleeding -
HR 95 CI
P-value
Risk Factor
Reinfarction
9.75 2.72,34.91
lt0.001
Major bleeding (non CABG)
4.66 2.84, 7.63
lt0.001
Ischemic TVR
1.11 0.29, 4.21
0.88
Stroke
2.64 0.71, 9.75
0.15
C-statistic 0.87.
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Time-updated covariate adjusted Cox model
relating 30-day events to 30-day mortality-
Complete model with MACE components and major
bleeding -
Attributable Deaths
HR 95 CI
P-value
Risk Factor
Reinfarction Incidence 69 (2.2) 10 deaths with
event
9.75 2.72,34.91
9.0 6.3, 9.7
lt0.001
Major bleeding (Non CABG) Incidence 238 (6.8) 26
deaths with event
4.66 2.84, 7.63
20.4 16.8, 22.6
lt0.001
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
41
Time-updated covariate adjusted Cox model
relating 30-day events to 30-day mortality-
Complete model in 3,124 pts with successfully
implanted stents -
Attributable Deaths
HR 95 CI
P-value
Risk Factor
Stent thrombosis (definite) Incidence 57 (1.8) 5
deaths with event
10.62 3.96, 28.48
4.5 3.7, 4.8
lt0.001
Major bleeding (non CABG) Incidence 195 (6.2) 18
deaths with event
6.22 3.33, 11.60
15.1 12.6, 16.4
lt0.001
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
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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.
Conclusions
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.
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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
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Potential conflicts of interest

• Speakers 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

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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 CRUSADE( 1Q-2006 results) 2 Synergy results
JAMA 2004 3 OASIS -5 Yusuf et al, NEJM 2006 4
Cohen et al, JACC 2006
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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

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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 2007281598-60
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SWITCH
Definitions

• Switch Protocol mandated change in
  antithrombotic therapy at randomization
• Crossover Post randomization change in
  antithrombotic therapy due to physician choice

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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?

White HD. In Press JACC
50
ACUITY Primary Results
UFH/Enoxaparin GPI vs. Bivalirudin Alone
UFH/EnoxaparinGPI (N4603)
Bivalirudin alone (N4612)
PNI lt0.0001 PSup 0.015
PNI 0.011 PSup 0.32
PNI lt0.0001 PSup lt0.0001
11.7
30 day events ()
10.1
7.8
7.3
5.7
3.0
Net clinical outcome
Ischemic composite
Major bleeding
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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 200851173441
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ACUITY Switch Consort
excludes Arm B and pts. with multiple
crossovers, missing data
53
Consistent vs. Switch
Comparing Consistent therapy on Enox
GPIIb/IIIa Inhibition vs. Switch to Bivalirudin
Alone
Consistent Enox GPIIb/IIIa Inhibition (N 843)
Switch to Bivalirudin alone (N 765)
20
15
30 day events ()
10
5
0
Net clinical outcome
Ischemic composite
Major bleeding
White HD, et al. J Am Coll Cardiol 200851173441
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ACUITY Switch Consistent vs. Switch High
Risk
High Risk Patients
Comparing Consistent UFH/Enox vs Switch
Bivalirudin
Consistent UFH/Enox N 1581 Switch Bivalirudin N 1496 RR
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
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ACUITY SWITCH Consistent vs. Switch Patients
Undergoing PCI
PCI Patients
Comparing Consistent UFH/Enox vs Switch
Bivalirudin
Consistent UFH/Enox N 1236 Switch Bivalirudin N 1292 RR
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
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ACUITY Switch
30 Days
Prior Antithrombin Therapy
RR (95 CI)
Relative Risk 95 CI
0.93 (0.75-1.16)
Composite Ischemia
0.49 (0.36-0.66)
Major Bleeding
0.77 (0.65-0.92)
Net Clinical Outcome
0
1
2
Switch to Bivalirudin Better
Consistent UFH/Enox IIb/IIIa Better
White HD, et al. J Am Coll Cardiol 200851173441
57
ACUITY Switch
30 Days
Naïve to Antithrombin Therapy
RR (95 CI)
Relative Risk 95 CI
1.11 (0.83-1.49)
Composite Ischemia
0.52 (0.35-0.77)
Major Bleeding
0.85 (0.67-1.07)
Net Clinical Outcome
0
1
2
Randomization to Bivalirudin Better
Randomization toUFH/Enox IIb/IIIa Better
Green Lane Cardiovascular Service, Auckland City
Hospital, Auckland, NZ
White HD, et al. J Am Coll Cardiol 200851173441
58
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)
HR (95 CI)
PCI (n2528)
PCI (n2528)
Composite ischemia
1.10 (0.85-1.42)
Mortality
0.93 (0.58-1.48)
Major bleeding
0.52 (0.36-0.74)
PCI HIGH RISK(n1988)
PCI HIGH RISK(n1988)
Composite ischemia
1.14 (0.86-1.52)
Mortality
0.99 (0.60-1.63)
Major bleeding
0.56 (0.38-0.81)
0.1
1
10
0.1
1
10
White HD. In Press JACC
59
Naïve to Antithrombin Therapy
Randomized to Enox GPIIb/IIIa Inhibition (N
842)
Randomized to Bivalirudin (N 1427)
20
15
10
30 day events ()
5
0
Net clinical
Ischemic
Major
outcome
composite
bleeding
60
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

61
REPLACE-2 SWITCH Analysis
Overall population Urgent or elective PCI
patients (N6,002)1
Randomize
Bivalirudin 0.75 mg/kg bolus/1.75 mg/kg/h
infusion with provisional GP IIb/IIIa (n2,994)1
UFH 65 U/kg with planned GP IIb/IIIa (n3,008)1
Prior UFH (n287)2
Naïve no prior AT (n2,345)2
Prior LMWH (n258)2
Naïve no prior AT (n2,325)2
Prior UFH (n349)2
Prior LMWH (n313)2
Protocol major/minor bleeding, TIMI bleeding,
transfusion, mortality
ATantithrombin.
1. Lincoff ML et al. JAMA. 2004292696-703. 2.
Gibson CM et al. Am J Cardiol. 2007991687-1690.
62
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

34.8
33.8
35

28.6
30
25

Protocol major/minor bleed
20
16.7
15.6
15.3
15
10
5
0
PNS for all 3-way comparisons versus
bivalirudin alone Plt.05 vs prior treatment with
UFH or enoxaparin naïveno prior AT therapy in
preceding 48 hours.
Gibson CM et al. Am J Cardiol. 2007991687-1690.
63
TIMI Major/Minor Bleeding bySWITCH and
Randomized Therapy

• 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
TIMI major/minor bleed
3

1.9
1.9
2
1.4
1
0
PNS for all 3-way comparisons versus
bivalirudin alone naïveno prior AT therapy in
preceding 48 hours.
Gibson CM et al. Am J Cardiol. 2007991687-1690.
64
SWITCH
15
p 0.39
13
10
7
Major Bleeding
5
3
n 30
n 31
n 30
0
GPI (0 - 4 hr)
GPII (4 - 8 hr)
GPIII (8 - 12 hr)
Time from last enoxaparin dose
Waksman et al. J Invasive Cardiol 200618370
65
HORIZONS AMI Switching Data
UFH pre-procedure was administered to 65.8 of
bivalirudin pts and 76.3 of heparin
GPIIb/IIIa pts
Bivalirudin with "provisional" GP IIb/IIIa
Heparin GP IIb/IIIa
Pint0.47
10
10
Pint0.08
8.5
7.5
8
7.2
8
5.6
5.2
5.2
6
6
4.8
4.6
30-Day Major Bleeding
30-Day MACE
4
4
2
2
RR 95CI 0.81 0.58,1.14
RR 95CI 1.39 0.85,2.28
RR 95CI 0.57 0.42,0.77
RR 95CI 0.69 0.43,1.12
0
0
UFH pretreatment
No UFH
UFH pretreatment
No UFH
(n2,553)
pretreatment
(n2,553)
pretreatment
(n1,042)
(n1,042)
66
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
67
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

68
(No Transcript)
69
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
70
Potential conflicts of interest

• Speakers name Keith A A Fox
• ? I have the following potential conflicts of
  interest to report
• ? Consulting
• ? Research grants/speaker honoraria
  sanofi-aventis, Bristol-Myers Squibb, and
  GlaxoSmithKline
• ? Stockholder of a healthcare company
• ? Owner of a healthcare company
• ? Other(s)
• ? I do not have any potential conflict of interest

.
71
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

72
Factors Contributing to the Balance of Risks
Reduced Thrombotic and Embolic Events
Cerebral and Systemic Bleeding Events
73
Hierarchy of Bleeding Risk
A consistent definition of bleeding is required
74
Major Bleeding in ACS GRACE Registry
6
5
4
Overall ACS
Unstable angina
Patients
3
Non-ST MI
2
ST-MI
1
Major 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

Definition of bleeding
European Heart Journal (2003) 24, 18151823
75
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
76
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
77
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 1997952508-2516 12
78
The Role and Implications of Bleeding in ACS
Bleeding and Outcome?
79
Bleeding and Outcomes in ACS
Kaplan Meier Curves for 30-Day Death, Stratified
by Bleed Severity N26,452 ACS patients from
GUSTO IIb, PARAGON A, PARAGON B, PURSUIT
1.00 0.95 0.90 0.85 0.80 0.75 0.70
None Mild Moderate Severe
0 5 10 15
20 25 30
log rank p-value for all four categories
lt0.0001 log-rank p-value for no bleeding vs. mild
bleeding 0.02 log-rank p-value for mild vs.
moderate bleeding lt0.0001 log-rank p-value for
moderate vs. severe lt0.001
Days to Death
Rao SV, et al. Am J Cardiol. 2005 Nov
196(9)1200-6.
80
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
81
30 Day Death According to BleedingOASIS
Registry, OASIS-2, CURE
14
12
10
Bleeding
8
Cumulative Events,
6
4

2
No Bleeding
0
0
5
10
15
20
25
30
Days
No. at Risk
No Bleeding
33676
33419
33157
32990
32879
32769
32710
Bleeding
470
459
440
430
420
410
408

J Eikelboom et al Circulation 2006
82
The Role and Implications of Bleeding in ACS
The impact of renal dysfunction
83
SYNERGY Clinical Outcomes and ProceduresCreatini
ne Clearance (CrCl)
CrCl lt 30 N156 CrCl 30-60 N2732 CrCl ? 60 N7011 p-value
30-Day Outcomes
Death/MI 24.4 17.3 12.7 lt0.0001
Death 15.4 5.7 1.8 lt0.0001
Cardiac Cath 80.1 88.8 93.7 lt0.0001
PCI 35.0 42.4 51.5 lt0.0001
CSBG 17.1 20.0 20.2 0.84
In-Hospital Bleeding
GUSTO Severe 7.7 3.7 1.8 lt0.0001
P-value from logistic regression with CrCl as
continuous variable in-hospital
84
Increased Risks Associated with Transfusion
The Role and Implications of Bleeding in ACS
85
CRUSADE Bleeding Risks Transfusion by Age
14.9 overall 10.3 non-CABG
20
18.5
17.9
14.1
15
10.3
9.7
RBC Transfusion
10
4.5
5
0
lt65 yrs
65-75 yrs
gt 75 yrs
Non-CABG
Overall
Through Q2 2004 (n74,271)
-- Yang, J Am Coll Cardiol 2005461490-5
86
Transfusion and 30-day Mortality
3.8
Adjusted for transfusion propensity
3.5
Adjusted for baseline characteristics
Adjusted for baseline characteristics,
bleeding propensity, transfusion propensity,
nadir HCT
3.9
1.0
10
0.1
Odds Ratio
Cox model, transfusion time-dependent covariate
-- Rao SV, et. al., JAMA 2004
87
Does Prevention of Bleeding Improve Long-term
Outcome?
The Role and Implications of Bleeding in ACS
88
1-Year Mortality
Multivariate Logistic Model
Predictor Odds Ratio 95Confidence Interval p-value
CrCl lt30 ml/min 7.9 2.7-22.4 lt0.001
CrCl 30-60 ml/min 3.8 2.2-6.6 lt0.001
CrCl 60-90 ml/min 1.7 1.0-2.7 lt0.001
Major Bleed 3.67 2.1-6.5 lt0.001
Non-Q MI 2.58 1.5-4.4 0.004
Diabetes 1.74 1.3-2.6 0.005
89
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
Attributable deaths
HR 95 CI
P-value
HR (95 CI)
Myocardial infarction 2.51 (1.95-3.25) lt0.0001
Major bleeding without or before transfusion 2.00 (1.30-3.06) lt0.0001
Major bleeding after transfusion 3.93 (2.95-5.24) lt0.0001
51.5
66.5
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
90
Predictors of Major Bleeding
Results The ACUITY Trial PCI Population
P-value
RR (95 CI)
Risk ratio 95 CI
Age gt75 (vs. 55-75)
Anemia
CrCl lt60mL/min
Diabetes
Female gender
High-risk (ST / biomarkers)
Hypertension
No prior PCI
Prior antithrombotic therapy
Heparin(s) GPI (vs. Bivalirudin)
1.56 (1.19-2.04) 0.0009
1.89 (1.48-2.41) lt0.0001
1.68 (1.29-2.18) lt0.0001
1.30 (1.03-1.63) 0.0248
2.08 (1.68-2.57) lt0.0001
1.42 (1.06-1.90) 0.0178
1.33 (1.03-1.70) 0.0287
1.47 (1.15-1.88) 0.0019
1.23 (0.98-1.55) 0.0768
2.08 (1.56-2.76) lt0.0001
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
91
Major Bleeding at 30 Days UFH/Enox versus
Fondaparinux
OASIS 5 6
UFH/Enoxaparin
0.04
0.03
Fondaparinux
Cumulative Hazard
0.02
HR 0.67 95 CI 0.59-0.76 Plt0.00001
0.01
0.0
0
5
10
15
20
25
30
Days
92
Mortality Day 30
OASIS 5
Enoxaparin
0.03
Fondaparinux
0.02
Cumulative Hazard
HR 0.83 95 CI 0.71-0.97 P0.022
0.01
0.0
0
3
6
9
12
15
18
21
24
27
30
Days
Yusuf et al NEJM 2006
93
Relative Impact of MI, Refractory Ischemia or
Bleeding on Mortality
OASIS 5
Crude Odds Ratio for Death (95 CI) Crude Odds Ratio for Death (95 CI) 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)
94
Minimizing the Risks of Bleeding?
The Role and Implications of Bleeding in ACS
95
Excessive Dosing of Anticoagulants by Age
70
64.5
60
50
38.5
37
40
33.1
Excessive Dose
28.7
30
16.5
20
12.5
12.5
8.5
10
0
LMW Heparin
UF Heparin
GP IIb/IIIa
lt 65 yrs
65-75 yrs
gt75 yrs
96
Dosing Combinations and Transfusions Heparin
GP IIb-IIIa Inhibitors
20
18.5
18
16
14
12
9
10
RBC Transfusions
8
6
4.1
4
2
0
Both Right
1 Excessive
Both Excessive
Among patients receiving both Heparin (UFH or
LMWH) and GP IIb-IIIa Inhibitors
97
Bleeding and Resource Use Predictors of Total
Costs
14,000
12,409
12,000
10,000
8,000
7,188

6,000
5,255
3,370
4,000
2,488
2,436
2,164
1,336
2,000
1,158
0
Mod/Sev
UA
Cath
PCI
CABG
Pacemaker
IABP
ICU day
Non-ICU
Bld
day
N1235 pts from GUSTO IIb
Model C-index0.87 Adjusted for patient
characteristics
Rao SV, et. al. AHJ 2008.
98
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

99
Translating Advances in NSTEMI and STEMI into
Real World Institutional Practice
The Science and Medicine of ACS

• Harold L. Dauerman, MD
• Director, Cardiovascular Catheterization
  Laboratories
• Professor of Medicine
• University of Vermont
• Fletcher Allen Health Care

100
Potential conflicts of interest

• Speakers 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

101
University of Vermont Post-PCI Bleeding and
Vascular Complication Rates
4
3.5
3
NNE Rate 2.0 in 2006
2.5
Bleeding Complication,
2
1.5
1
0.5
0
2001
2002
2003
2004
2005
2006
2007
Any Transfusion, RPH or Repair Bleeding
Complication
102
Incorporation of Bivalirudin in Cath Lab for
NSTEMI in 2003A Cautious Beginning
Bivalirudin GP IIb/IIIa Inhibitor UFH alone
103
Signs of Hope Since 2004
4
P lt 0.001 for temporal trend
3.37
3.5
3.2
3
2.51
2.5
2.11
1.96
Major Vascular Complications,
2
1.5
1
0.5
0
2002
2003
2004
2005
2006
Arterial injury and/or arterial injury related
bleeding N 36,631 Patients Undergoing PCI, NNE
Registry
Dauerman, Applegate and Cohen, JACC 2007
104
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 dont overdose patients.
• 2008 A standardized STEMI bivalirudin approach
• For upstream AMI utilization, bivalirudin ordered
  from pharmacy
• In collaboration with ED (EDICT for ACS Strategy)

105
NSTEMI Transfers, Upstream Strategies,
andResults of Clinical Trials
Non ST-Elevation Myocardial Infarction
106
What We Really Do With Transfers? September 24,
2007 email from me
To Sullivan, Claudia A. Cc Ades, Philip
A. Subject 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. DNRreverse POLST (wants a cath, but
no CABG). Echo today, cath tomorrow (or today if
unstable). Thanks, Harry
107
Protocol Major/Minor Bleed by SWITCH and
Randomized Therapy

Protocol major/minor bleed

Naïve? UFH GP IIb/IIIa (n2,325)
LMWH?Bivalirudin (n258)
UFH?Bivalirudin (n287)
LMWH?UFH GP IIb/IIIa (n313)
UFH?UFH GP IIb/IIIa (n349)
Naïve?Bivalirudin (n2,345)
PNS for all 3-way comparisons versus
bivalirudin alone Plt.05 vs prior treatment with
UFH or enoxaparin naïveno prior AT therapy in
preceding 48 hours.
Gibson CM et al. Am J Cardiol. 2007991687-1690.
108
Transfer to Cardiology Floor

• Enoxaparin heldwait 8 hours from community
  hospital last dose.
• Then, start upstream bivalirudin
• Patient pain free1st case next A.M
• DES, no eptifibatide, closure device, 150 mg
  clopidogrel
• Ambulate at 6 hours
• D/C following 0900 A.M.

109
If Patient is not Clopidogrel Exposed, Do We Use
Bivalirudin? Definitions?
UFH/Enoxaparin IIb/IIIa (N811)
UFH/Enoxaparin IIb/IIIa (N1722)
Bivalirudin Alone (N804)
Bivalirudin Alone (N1789)
RR 95CI 0.81 (0.68-0.96)
RR 95CI 0.96 (0.77-1.20)
RR 95CI 0.50 (0.37-0.67)
RR 95CI 1.07 (0.83-1.39)
RR 95CI 1.37 (1.00-1.88)
RR 95CI 0.61 (0.39-0.97)
13.8
11.1
8.4
8.1
7.2
3.6
Net clinical
Ischemic
Major bleeding
outcomes
composite
Not Thienopyridine Exposed
Thienopyridine Exposed
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16
110
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 N3429, RR 0.92 95 CI
0.74,1.15
Peri-PCI Clopidogrel N1044, RR 1.26 95 CI
0.82,1.92
pinteraction 0.35
Post-PCI Clopidgrel (gt 30 minutes After
PCI) N519 RR 1.48 95 CI 0.89, 2.47
No Clopidogrel N88 RR 2.62 95 CI 0.89, 7.72
0
1
2
3
4
5
6
7
8
Bivalirudin alone better
Heparin GPIIb/IIIa better
S. Steinhubl TCT 2007
111
Does Periprocedural Infarct Increase With
Upstream and Downstream Bivalirudin? No!
ACS PCI Outcomes 2005 Bival 61 N373 2007 Bival 91 N361 P value
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

• Submitted, TCT 2008

Clopidogrel preload in approx 60 of PCI
patients CK-MB on all patients the day after PCI
(University of Vermont data)
112
STEMI Switching, Clopidogrel and Stent Thrombosis
ST-Elevation Myocardial Infarction
113
The Standard of Care for STEMI PCI in
2005 National Registry of Myocardial Infarction-5
Dauerman and French, Coronary Artery Disease, 2006
114
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
115
Primary PCI for STEMI Community Hospital
Algorithm ASA, Clopidogrel and UFH and then
Switch to Bivalirudin at UVM
Time from ED Presentation at NWMC to Open Artery
at FAHC 88 Minutes
116
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 (N1802) Bivalirudin (N1800)
UFH pre randomization 65.6 65.6
Antithrombin in CCL
UFH 98.9 4.1
Bivalirudin 0.4 96.9
Peak ACT 264 228, 320 357 300, 402
GP IIb/IIIa in CCL 94.5 7.2
Bail-out per protocol - 4.4
Abciximab 49.9 4.0
Eptifibatide 44.4 3.1
Tirofiban 0.2 0.1
97.7 and 7.5 during PCI. For giant thrombus
or refractory no reflow after PCI. CCL cardiac
catheterization laboratory
G Stone TCT 2007
117
Bivalirudin Improves Mortality in STEMI
3.1
Death ()
2.1
HR 95CI 0.66 0.44, 1.00 P0.048
Time in Days
G Stone TCT 2007
118
The UVM STEMI Order SheetOne 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, LFTs, 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 gt90. 14. Lopressor 5 mg
IVP x 1 if HR gt 80 and SBP gt 140
119
The Bivalirudin Strategy for STEMI PCI
ASA, clopidogrel 600 po x 1, bivalirudin and stent
120
What About The Stent Thrombosis Risk?
UFH GP IIb/IIIa (N1553) Bivalirudin (N1571) P Value
ARC definite or probable 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 (gt24 hrs 30d) 1.7 1.2 0.30
G Stone TCT 2007
Protocol definition of stent thrombosis, CEC
adjudicated
121
Risk Stratification For STEMI Stent
Thrombosis The Importance of Thrombus Burden
Sianos, G. et al. J Am Coll Cardiol
200750573-583
Large thrombus burden (LTB), defined as thrombus
burden gt  2 vessel diameters Approx 25 of STEMI
122
Drug Eluting Stent Thrombosis and Large Thrombus
Burden Modifying Strategy In Highest Risk
Patients
15 12 9 6 3 0

• Large Thrombus
• Burdengt 5 fold
• Increased Risk of 30 Day Stent Thrombosis

LTB vs. STB, plt0.001
8.2
LTB
Cumulative IRA-ST Rate ()
5.8
3.2
Total Population
2.7
2.1
3.2
Thrombectomy Prolonged Bivalirudin GPI
STB
1.4
1.1
1.3
0.7
0.5
0.7
0 1 3 6 9 12 15
18 21 24
Months of follow-up
Sianos, G. et al. J Am Coll Cardiol
200750573-583
123
ACUITY and Large Thrombus DataThe Rationale for
Selective Adjunctive GPI

ACUITY Heparin IIb/IIIa (N222) Bivalirudin IIb/IIIa (N241) Bivalirudin alone (N249) 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
124
Projecting What Happens if You Use GPI in 25 of
Your Bivalirudin STEMI Patients
P lt 0.001
Still P lt 0.001
UVM Implemented HORIZONS25
HORIZONS 7
Assumes Bival GPI bleeding rate of 6.8
125
Incorporation of HORIZONS AMI and Large Thrombus
DataSTEMI Algorithm

• ED STEMI25 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

126
STEMI Within 24 Hours CP
PCI Capability or lt 60 minute Transfer Time
No PCI Capability and gt 60 minute Transfer Time
ASA 325 po
UFH or Bivalirudin GPI Optional Avoid if High
Bleed Risk B Blockers ONLY if HTN
UFH (60 U/Kg) Beta Blockers only if HTN
Clopidogrel 300 po
Clopidogrel 600 po
90 minutes To Open Artery
Lytic Contraindicated
Emergent Transfer
Primary PCI with Stenting GPI/Thrombectomy if
Large Thrombus or as Bailout Otherwise,
Bivalirudin Alone
Rescue PCI Class I Indication
Continue bivalirudin for 2 hours after PCI
If Reperfusion Fails, Emergent PCI with stent
TNK and UFH
ASA/Clopidogrel Statin Groin Closure Cardiac
Rehab Lopressor 12.5 bid
Transfer
Transfer from Community ER To PCI Site
If no CP and less than 50 ST Elevations, PCI at
12-24 Hours with Stent
The NSTEMI Paradigm of 4-48 Hours
127
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 choicethen 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.

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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
  doesnt 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? Well answer your questions!