Translating Advances in NSTEMI and STEMI into Real World Institutional Practice

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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

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University of Vermont Post-PCI Bleeding and
Vascular Complication Rates
NNE Rate 2.0 in 2006
Any Transfusion, RPH or Repair Bleeding
Complication
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Incorporation of Bivalirudin in Cath Lab for
NSTEMI in 2003A Cautious Beginning
Bivalirudin GP IIb/IIIa Inhibitor UFH alone
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Signs of Hope Since 2004
P lt 0.001 for temporal trend

• Arterial injury and/or arterial injury related
  bleeding
• N 36,631 Patients Undergoing PCI, NNE Registry

Dauerman, Applegate and Cohen, JACC 2007
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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)

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NSTEMI Transfers, Upstream Strategies,
andResults of Clinical Trials
Non ST-Elevation Myocardial Infarction
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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
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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.
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REPLACE-2 One-Year Cumulative Mortality in
Prespecified High-Risk Subgroups
Cumulative mortality at 1 year
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Bivalirudin with provisional GP IIb/IIIa
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Heparin GP IIb/IIIa
4
Percentage ()
2
0
UA or ACS
D
i
a
b
e
t
e
s
U
A

ACS
CrCl 60
Age gt75
Age gt65
(n1,330)
(n2,046)
(n1,606)
(n2,489)
(n795)
(n1,010)
(n2,553)
UA at any time, within preceding 48 hours or
before. ACS defined as UA within preceding 48
hours or MI within prior 7 days. CrCl creatinine
clearance.
Lincoff AM et al. JAMA. 2004292696-703. Stone
GW. J Invasive Cardiol. 200416(suppl G)12-17.
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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.

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The University of Vermont ExperienceGPI Trigger
Strategy Impact of REPLACE 2 and ACUITY Trials
91 Bivalirudin Use
REPLACE 2 ACUITY

• Elective PCI24
• Urgent PCI30
• Emergent PCI30
• Pre-Load Clopidgrel in 60 and Switching in 45
  of Patients
• Note Increasing utilization of bivalirudin but
  with maintained trigger-induced adjunctive use of
  GP IIb/IIIa antagonist

Ahmed B and Dauerman HL, Submitted ESC 2008
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If Patient is not Clopidogrel Exposed, Do We
Use Bivalirudin? Definitions?
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)
Not Thienopyridine Exposed
Thienopyridine Exposed
Stone GW, McLaurin BT. NEJM. 2006 Nov
23355(21)2203-16
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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
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ACUITY PCI Impact of Clopidogrel
PCI troponin patients 1-year Mortality Hazard Ratio 95 CI HR (95 CI)
Clopidogrel at any time prior to hospitalization,
randomization or end of angiography (n1,891)
1.07 (0.66-1.73)
1.09 (0.46-2.58)
0.56 (0.17-1.93)
3.07 (0.32-29.49)
Clopidogrel after end of angio-graphy to 30 post
PCI (n649)
Clopidogrel after 30 post PCI (n307)
No clopidogrel (n51)
0.1
1
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Bivalirudin Alone Better
UFH/Enox IIb/IIIa Better
H.White ESC 2007
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Does Periprocedural Infarct Increase With
Upstream and Downstream Bivalirudin? No!
Outcome 2005 1st 6 months N373 2007 1st 6 Months 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
Clopidogrel preload in approx 60 of PCI
patients CK-MB on all patients the day after PCI
(University of Vermont data)
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STEMI Switching, Clopidogrel and Stent Thrombosis
ST-Elevation Myocardial Infarction
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The Standard of Care for STEMI PCI in
2005 National Registry of Myocardial Infarction-5
Dauerman and French, Coronary Artery Disease, 2006
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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
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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
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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
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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
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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
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The Bivalirudin Strategy for STEMI PCI
ASA, clopidogrel 600 po x 1, bivalirudin and stent
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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
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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
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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
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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
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The Data on GPI and Bivalirudin for Large
Thrombus Patients is Favorable (ACUITY)
p0.37
p0.58
p0.22
p0.61
p0.67
p0.03
G. Stone et al. Lancet 2007 369 90719
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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
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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

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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
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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!