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IIB IIIA Inhibitors in the Management of High Risk Non-ST Elevation ACS Francis M. Fesmire, MD, FACEP Associate Professor University of Tennessee College.

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Presentation on theme: "IIB IIIA Inhibitors in the Management of High Risk Non-ST Elevation ACS Francis M. Fesmire, MD, FACEP Associate Professor University of Tennessee College."— Presentation transcript:

1 IIB IIIA Inhibitors in the Management of High Risk Non-ST Elevation ACS Francis M. Fesmire, MD, FACEP Associate Professor University of Tennessee College of Medicine Director, Heart & Stroke Center Erlanger Medical Center, Chattanooga, TN E-mail: ffesmire@comcast.net

2 Southern BelleCity View Center of Known Universe

3 City View from Lookout Point

4 Chattanooga Choo Choo

5 WHO – 2000, NCHS 2000 AHA - 2000 Heart and Stroke Statistical Update Ischemic Heart Disease Unstable 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

6 + + Ischemic Discomfort at Rest No ST-Segment Elevation Non-Q-wave MIUnstable Angina Q-wave MI ST-Segment Elevation + + + + ( : positive cardiac biomarker) EmergencyDepartment In-Hospital - 6-24hrs 6-24hrs Presentation Spectrum of Acute Coronary Syndromes

7 NSTE ACS Pathophysiology: Thrombus Microvascular Obstruction Microvascular Obstruction Platelet-thrombin micro-emboliPlaque rupture 1st 2nd 3rd CK-MB Cutoff TnT Curve embolus Inflammation, spasm endothelial dysfunction

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10 Evidence-Based Medicine: Whats the Problem? There is an unsettling truth about the practice of medicine. …study after study shows that few physicians systematically apply to everyday treatment the scientific evidence about what works best. Millenson, ML. Demanding Medical Excellence: Doctors and Accountability in the Information Age. 1997 Millenson, ML. Demanding Medical Excellence: Doctors and Accountability in the Information Age. 1997

11 Updated Guidelines Weighing 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

12 I I IIa IIb III Updated Guidelines Classes 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

13 Non-STE Acute Coronary Syndromes Standard therapy: – Oxygen – ASA – Nitrates – Beta-blockers – Low Molecular Weight or Unfractionated Heparin

14 Parenteral inhibitors of GP IIb-IIIa Antibody abciximab (ReoPro, Centocor/Lilly) Cyclic peptide eptifibatide (INTEGRILIN ®, COR/Key) Nonpeptide tirofiban HCI (Aggrastat, Merck)

15 ACS GP IIb\IIIa Inhibitor Trials* PRISM-PLUS (1998) - Tirofiban PRISM (1998) - Tirofiban PURSUIT (1998) - Eptifibatide PARAGON A (1998) - Lamifiban GUSTO IV ACS (2001) - Abciximab *>1000 Patients UA/NSTEMI

16 ACS GP IIb\IIIa Trials* TrialPLACEBOGP IIb/IIIaRisk Ratio PRISM-PLUS11.98.70.7 (0.51-0.96) PRISM7.15.80.8 (0.61-1.05) PURSUIT15.714.20.91(0.82-1.0) PARAGON11.710.60.9 (0.82-1.00) GUSTO IV88.71.1 (068-1.2) ALL11.910.50.88 (0.82-0.94) *Death or MI

17 19.6 13 19 5.8 4.3 11 0 10 20 CAPTUREPRISMPARAGON-B 30-Day Death or MI (%) Placebo GP IIb/IIIa GP IIb/IIIa Inhibition for Non ST ACS: Enhanced Benefit in Patients with +Troponin

18 Reduction in Death/MI with GP IIb-IIIa Inhibitors by Troponin Levels in RCTs Troponin-NegativeTroponin-Positive PARAGON B PRISM CAPTURE COMBINED 0.125 1 1 22 Newby, Circulation 2001 0.125 0.50.5

19 Boersma 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

20 Boersma 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 patients No treatment benefit in woman unless troponin positive Major bleeding complications increased by 1.45 (no increase in intracranial bleeding)

21 Boersma 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/CABG Conclude that GP IIb/IIIa inhibitor treatment of substantial benefit in patients undergoing coronary revascularization

22 What is the Evidence for Early Upstream Utilization of GP IIb/IIIa Inhibitors

23 0% 10% 20% 30% 40% 50% 0-2 X ULN >2-5 X ULN > 5 X ULN EptifibatidePlacebo Attenuation of Myocardial Necrosis Upstream GP IIb/IIIa Blockade in PURSUIT - 6.37% + 6.96% - 0.60% p < 0.001 Alexander, ACC 1999 Peak CK-MB Levels

24 0 0 10 20 30 40 0 0 30 60 90 120 150 180 Death or MI (%) Days After Randomization Eptifibatide Placebo 27.6% 32.7% p = 0.02 Marso, Circulation 2000 Platelet GP IIb/IIIa Blockade for Non-ST ACS: Pre-Treatment Before CABG in PURSUIT

25 GP IIb/IIIa Inhibitor During Medical Rx and After PCI: CAPTURE, PURSUIT, PRISM-PLUS 0% 2% 4% 6% 8% 10% PCI N=2754 P=0.001 N=12,296 +24 h+48 h+72 h+24 h+48 h Boersma et al. Circulation. 1999;100:2045-2048. 4.3% 2.9% 8.0% 4.9% Death or MI Death or MI Medical Rx Post PCI Control GP IIb/IIIa inhibitor 0

26 NRMI 4 Incidence of In-hospital Events Reduced with Early GP IIb-IIIa Inhibition in the NSTEMI patient P < 0.0001 6.3% 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)

27 In-Hospital Mortality by Risk Score: Early GP IIb-IIIa Use versus Not in the NSTEMI patient 0 2 4 6 8 10 12 14 16 18 20 22 <=567891011>=12 % In-hosp Mortality GP IIb-IIIa <24 Hrs>24 Hrs or Not NRMI 4 (July 2000-April 2001)

28 Importance of Rapid Time to Treatment with Eptifibatide in Non-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% 12 hours Bhatt and Topol. JAMA. 2000;284:1549-58.

29 Hospital Care Anti-Thrombotic Therapy: Platelet GP IIb/IIIa Inhibitors -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 I I IIa IIb III *High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability (CHF, new MR, BP, HR); rest CP w/ ST ; VT; positive cardiac markers

30 Questions?


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