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: ffesmire@comcast.net

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?