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IIB IIIA Inhibitors in the Management of High Risk Non-ST
Elevation ACSFrancis M. Fesmire, MD, FACEP
Associate ProfessorUniversity of Tennessee College of Medicine
Director, Heart & Stroke CenterErlanger Medical Center, Chattanooga, TN
E-mail: [email protected]
Southern Belle City View
Center of Known Universe
City View from Lookout Point
Chattanooga Choo Choo
WHO – 2000, NCHS 2000AHA - 2000 Heart and Stroke Statistical Update
Ischemic Heart DiseaseIschemic Heart DiseaseUnstable Angina and Acute MIUnstable Angina and Acute MI
12,200,000 people in the US have had an MI, angina pectoris, or both
5,315,000 Americans visited Emergency Departments for chest pain in 1997
1,433,000 Americans hospitalized for IHD in 1996– 225,000 died before hospital
1,100,000 Americans will have a new or repeat IHD event this year
++++
Ischemic Discomfort Ischemic Discomfort at Restat Rest
No ST-Segment No ST-Segment ElevationElevation
Non-Q-wave MIUnstable Angina
Q-wave MI
ST-Segment Elevation
++ ++
( : positive cardiac biomarker)
EmergencyEmergencyDepartmentDepartment
In-Hospital -In-Hospital - 6-24hrs6-24hrs
PresentationPresentation
Spectrum of Acute Coronary SyndromesSpectrum of Acute Coronary Syndromes
NSTE ACS Pathophysiology:NSTE ACS Pathophysiology:
Thrombus
MicrovascularObstructionMicrovascularObstruction
Platelet-thrombin micro-emboliPlaque rupture
1st1st 2nd2nd 3rd3rd
CK-MBCK-MB
CK-MBCK-MBCK-MBCK-MB
CutoffCutoff TnT CurveTnT Curve
embolusembolus embolusembolus embolusembolus
Inflammation, spasm endothelial dysfunction
Evidence-Based Medicine:Evidence-Based Medicine:What’s the Problem?What’s the Problem?
““There is an unsettling truth about the practice of medicine. …There is an unsettling truth about the practice of medicine. …
study after study shows that few physicians systematically study after study shows that few physicians systematically
apply to everyday treatment the scientific evidence about apply to everyday treatment the scientific evidence about
what works best.”what works best.”
Millenson, ML. Demanding Medical Excellence: Doctors Millenson, ML. Demanding Medical Excellence: Doctors and Accountability in the Information Age. 1997and Accountability in the Information Age. 1997Millenson, ML. Demanding Medical Excellence: Doctors Millenson, ML. Demanding Medical Excellence: Doctors and Accountability in the Information Age. 1997and Accountability in the Information Age. 1997
Updated GuidelinesUpdated GuidelinesWeighing the EvidenceWeighing the Evidence
1994 version was starting point; literature searches added
more current reports
Weight of evidence grades:
= Data from many large, randomized trials
= Data from fewer, smaller randomized trials, careful analyses
of nonrandomized studies, observational registries
= Expert consensus
II IIaIIa IIbIIb IIIIII
Updated GuidelinesUpdated GuidelinesClasses of RecommendationsClasses of Recommendations
Intervention is useful and effective
Evidence conflicts/opinions differ but leans towards efficacy
Evidence conflicts/opinions differ but leans against efficacy
Intervention is not useful/effective and may be harmful
Intervention is useful and effective
Evidence conflicts/opinions differ but leans towards efficacy
Evidence conflicts/opinions differ but leans against efficacy
Intervention is not useful/effective and may be harmful
Non-STE Acute Coronary Non-STE Acute Coronary SyndromesSyndromes
Standard therapy:– Oxygen– ASA– Nitrates– Beta-blockers– Low Molecular Weight or Unfractionated
Heparin
Parenteral inhibitors of GP IIb-IIIa
Antibody• abciximab (ReoPro, Centocor/Lilly)
Cyclic peptide• eptifibatide (INTEGRILIN®, COR/Key)
Nonpeptide• tirofiban HCI (Aggrastat, Merck)
ACS GP IIb\IIIa Inhibitor Trials*ACS GP IIb\IIIa Inhibitor Trials*
PRISM-PLUS (1998) - TirofibanPRISM (1998) - TirofibanPURSUIT (1998) - EptifibatidePARAGON A (1998) - LamifibanGUSTO IV ACS (2001) - Abciximab
*>1000 Patients UA/NSTEMI
ACS GP IIb\IIIa Trials*ACS GP IIb\IIIa Trials*Trial PLACEBO GP IIb/IIIa Risk Ratio
PRISM-PLUS 11.9 8.7 0.7 (0.51-0.96)
PRISM 7.1 5.8 0.8 (0.61-1.05)
PURSUIT 15.7 14.2 0.91(0.82-1.0)
PARAGON 11.7 10.6 0.9 (0.82-1.00)
GUSTO IV 8 8.7 1.1 (068-1.2)
ALL 11.9 10.5 0.88 (0.82-0.94)
*Death or MI
19.6
13
19
5.84.3
11
0
10
20
CAPTURE PRISM PARAGON-B
30-D
ay D
eath
or
MI
(%) Placebo
GP IIb/IIIa
GP IIb/IIIa Inhibition for Non ST GP IIb/IIIa Inhibition for Non ST ACS: ACS:Enhanced Benefit in Patients with +TroponinEnhanced Benefit in Patients with +Troponin
GP IIb/IIIa Inhibition for Non ST GP IIb/IIIa Inhibition for Non ST ACS: ACS:Enhanced Benefit in Patients with +TroponinEnhanced Benefit in Patients with +Troponin
Reduction in Death/MI with GP IIb-IIIa Inhibitors Reduction in Death/MI with GP IIb-IIIa Inhibitors by Troponin Levels in RCTsby Troponin Levels in RCTs
Reduction in Death/MI with GP IIb-IIIa Inhibitors Reduction in Death/MI with GP IIb-IIIa Inhibitors by Troponin Levels in RCTsby Troponin Levels in RCTs
Troponin-NegativeTroponin-NegativeTroponin-PositiveTroponin-Positive
PARAGONPARAGON BB
PRISMPRISM
CAPTURECAPTURE
COMBINEDCOMBINED
0.1250.125 1111 22 22
Newby, Circulation 2001Newby, Circulation 2001Newby, Circulation 2001Newby, Circulation 2001
0.1250.1250.50.50.50.5
Boersma Meta-Analysis of GP IIb\IIIa TrialsBoersma Meta-Analysis of GP IIb\IIIa Trials
31,402 Patients from Six Major Trials (including GUSTO-IV ACS) not scheduled for early coronary revascularization
11,965 of patients underwent PCI/CABG within 30 days
3530 (11.2%) patients with 30-day death or MI
Boersma et al: Lancet 2002;359:189-198
Boersma Meta-Analysis of GP IIb\IIIa TrialsBoersma Meta-Analysis of GP IIb\IIIa Trials
9 percent reduction in odds of death or MI at 30 days
Absolute benefit largest in high risk patientsNo treatment benefit in woman unless
troponin positiveMajor bleeding complications increased by
1.45 (no increase in intracranial bleeding)
Boersma Meta-Analysis of GP IIb\IIIa TrialsBoersma Meta-Analysis of GP IIb\IIIa Trials
Odds ratio for death or MI in Treatment group as compared to placebo:– 0.89 (0.80-0.98) in patients undergoing
PCI/CABG– 0.95 (0.86-1.05) in patients not undergoing
PCI/CABGConclude that GP IIb/IIIa inhibitor
treatment of substantial benefit in patients undergoing coronary revascularization
What is the Evidence for Early What is the Evidence for Early “Upstream” Utilization of GP “Upstream” Utilization of GP
IIb/IIIa InhibitorsIIb/IIIa Inhibitors
0%0%
10%10%
20%20%
30%30%
40%40%
50%50%
0-2 X ULN0-2 X ULN >2-5 X ULN >2-5 X ULN > 5 X ULN> 5 X ULN
EptifibatideEptifibatide PlaceboPlacebo
Attenuation of Myocardial Necrosis Attenuation of Myocardial Necrosis Upstream GP IIb/IIIa Blockade in PURSUITUpstream GP IIb/IIIa Blockade in PURSUIT
Attenuation of Myocardial Necrosis Attenuation of Myocardial Necrosis Upstream GP IIb/IIIa Blockade in PURSUITUpstream GP IIb/IIIa Blockade in PURSUIT
- 6.37%- 6.37%
+ 6.96% + 6.96%
- 0.60%- 0.60%
p < 0.001
Alexander, ACC 1999Alexander, ACC 1999Alexander, ACC 1999Alexander, ACC 1999 Peak CK-MB LevelsPeak CK-MB LevelsPeak CK-MB LevelsPeak CK-MB Levels
00
1010
2020
3030
4040
00 3030 6060 9090 120120 150150 180180
Dea
th o
r M
I (%
)D
eath
or
MI
(%)
Days After RandomizationDays After Randomization
EptifibatideEptifibatide
PlaceboPlacebo
27.6%27.6%
32.7%32.7%
p = 0.02p = 0.02
Marso, Circulation 2000Marso, Circulation 2000Marso, Circulation 2000Marso, Circulation 2000
Platelet GP IIb/IIIa Blockade for Non-ST Platelet GP IIb/IIIa Blockade for Non-ST ACS: ACS: Pre-Treatment Before CABG in PURSUITPre-Treatment Before CABG in PURSUIT
Platelet GP IIb/IIIa Blockade for Non-ST Platelet GP IIb/IIIa Blockade for Non-ST ACS: ACS: Pre-Treatment Before CABG in PURSUITPre-Treatment Before CABG in PURSUIT
GP IIb/IIIa Inhibitor During Medical Rx and After PCI: CAPTURE, PURSUIT, PRISM-PLUS
GP IIb/IIIa Inhibitor During Medical Rx and After PCI: CAPTURE, PURSUIT, PRISM-PLUS
0%
2%
4%
6%
8%
10%
PCIPCI
N=2754N=2754PP=0.001=0.001
N=12,296N=12,296PP=0.001=0.001
+24 h +48 h +72 h +24 h +48 h
Boersma et al. Boersma et al. CirculationCirculation. 1999;100:2045-2048.. 1999;100:2045-2048.
4.3%4.3%
2.9%2.9%
8.0%8.0%
4.9%4.9%
Dea
th o
r M
ID
eath
or
MI
Medical RxMedical Rx Post PCIPost PCI
Control
GP IIb/IIIa inhibitor
0
NRMI 4
0
2
4
6
8
10
<24hrs Early Use
>24hrs No Early Use
Incidence of In-hospital Events Reduced with Early GP IIb-IIIa Inhibition in the
NSTEMI patient
Incidence of In-hospital Events Reduced with Early GP IIb-IIIa Inhibition in the
NSTEMI patient
P < 0.00016.3%
9.6%
3.3%
Death
P < 0.0001.5% (~50%)
1.2%0.7%
Stroke
(n=15,379) (n=45,391) (n=15,379) (n=45,391)
NRMI 4 (July 2000-July 2001)
In-Hospital Mortality by Risk Score:In-Hospital Mortality by Risk Score: Early GP IIb-IIIa Use versus Not in the NSTEMI patientEarly GP IIb-IIIa Use versus Not in the NSTEMI patient
0
2
4
6
8
10
12
14
16
18
20
22
<=5 6 7 8 9 10 11 >=12
% I
n-h
osp
Mo
rtal
ity
GP IIb-IIIa <24 Hrs >24 Hrs or Not
NRMI 4 (July 2000-April 2001)
Importance of Rapid Time to Importance of Rapid Time to Treatment with Eptifibatide in Treatment with Eptifibatide in
Non-ST Elevation ACSNon-ST Elevation ACS
Importance of Rapid Time to Importance of Rapid Time to Treatment with Eptifibatide in Treatment with Eptifibatide in
Non-ST Elevation ACSNon-ST Elevation ACS
% absolute reduction in death or
MI combined at 30 days
(n=2,522) (n=2,041) (n=4,908)
1.4%
2.3%
2.8%
< 6 hours 6-12 hours > 12 hours
Bhatt and Topol. Bhatt and Topol. JAMAJAMA. 2000;284:1549-58.. 2000;284:1549-58.
Hospital CareHospital CareAnti-Thrombotic Therapy: Platelet GP IIb/IIIa Anti-Thrombotic Therapy: Platelet GP IIb/IIIa
InhibitorsInhibitors
-GP IIb/IIIa Inhibitor in addition to ASA and Heparin for patients in whom PCI is planned
-Eptifibatide or Tirofiban for high risk* patients if medically managed
-GP IIb/IIIa Inhibitor in addition to ASA and Heparin for patients in whom PCI is planned
-Eptifibatide or Tirofiban for high risk* patients if medically managed
II IIaIIa IIbIIb IIIIII
*High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability (CHF, new MR, BP, HR); rest CP w/ ST ; VT; positive cardiac markers
*High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability (CHF, new MR, BP, HR); rest CP w/ ST ; VT; positive cardiac markers
Questions?Questions?