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Clinical Trials of GP IIb/IIIa Inhibition

Clinical Trials of GP IIb/IIIa Inhibition. Major Trials of GP IIb/IIIa Inhibitors in ACS GP IIb/IIIa Inhibitors in PCI GP IIb/IIIa Inhibition in Patients With Diabetes. Clinical Trials of GP IIb/IIIa Inhibition. Major Trials of GP IIb/IIIa Inhibitors in ACS.

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Clinical Trials of GP IIb/IIIa Inhibition

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  1. Clinical Trials of GP IIb/IIIa Inhibition Major Trials of GP IIb/IIIa Inhibitors in ACS GP IIb/IIIa Inhibitors in PCI GP IIb/IIIa Inhibition in Patients With Diabetes

  2. Clinical Trials of GP IIb/IIIa Inhibition Major Trials of GP IIb/IIIa Inhibitors in ACS

  3. Efficacy of GP IIb/IIIa inhibition on death or MI in PCI or ACS Death or MI at 30 days FavorsGP IIb/IIIa Favorsplacebo Trial N Elective PCI EPIC 2099 IMPACT II 4010 EPILOG 2792 CAPTURE 1265 RESTORE 2139 EPISTENT 2399 PRISM 3231 PRISM-PLUS 1570* PARAGON 2282 PURSUIT 10,948 Overall 30,366 ACS 0.79 (0.73–0.85)P < 10–9 0 1 2 Odds ratio (95% CI) *Does not include 345 patients In the tirofiban only group, which was stopped prematurely Antman EM et al. Am Heart J. 2003;146:S18-S22.

  4. PRISM-PLUS: Study design Platelet-Receptor Inhibition for ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS) N = 1915 with unstable angina or non–Q-wave MIRandomized, double-blind study Tirofiban*n = 345 Heparinn = 797 Tirofiban + heparinn = 773 Infusion for 71.3 ± 20 hoursAngiography + angioplasty during Tx after 48 hours (prn) Primary outcome:Death, MI, refractory ischemia ≤7 days PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-97. *Stopped prematurely due to high mortality at 7 days

  5. PRISM-PLUS: Benefits at 30 days similar with/without PCI Death or MI Death/MI/RI 30 30 24.7 25 25 21.3 18.7 20 20 18.1 15 15 Outcomesat 30 days 13.0 11.5 8.9 8.3 10 10 5 5 0 0 No PCI n = 1069 PCI n = 501 No PCI n = 1069 PCI n = 501 RRR (95% CI) 23%↓ 0.50–1.12 36%↓ 0.34–1.08 12%↓ 0.63–1.15 27%↓ 0.44–1.04 Heparin Tirofiban + heparin RI = recurrent ischemia Morrow DA et al. Am J Cardiol. 2004;94:774-6.

  6. PRISM-PLUS: Benefit of GP IIb/IIIa inhibition by risk profile 28.2 21.9 0.69 0.04 8.7 13.6 1.6 0.1 32.4 22.2 0.60 0.06 13.7 13.4 0.98 0.9 Death/MI/RI Favorstirofiban/heparin Favorsheparin H T+H OR P No PCI High risk (n = 664) Low risk (n = 405) PCI High risk (n = 280) Low risk (n = 221) 0.1 1 10 Odds ratio (95% CI) H = heparin; T = tirofiban High risk = TIMI risk score ≥4RI = refractory ischemia Morrow DA et al. Am J Cardiol. 2004;94:774-6.

  7. PURSUIT: Study design Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy N = 10,948 Chest pain <24 hours + ECG changes of ischemia orElevated CK-MB >ULN for hospital Randomized, double-blind study Placebon = 4739 High-dose eptifibatide* 180-µg/kg bolus, then 2.0 µg/kg per min for 72 h (96 h with coronary intervention)n = 4722 Primary outcome:Composite death/nonfatal MI ≤30 days *Lower-dose eptifibatide (n = 1487) stopped after safety of high-dose was shown PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-43.

  8. PURSUIT: Pre-PCI GP IIb/IIIa inhibition prevents early MI 10 HR = 0.29 P < 0.001 Placebo 5.5% Pre-PCI MI (%) 5 Eptifibatide 1.7% 0 3 1 0 2 Days from enrollment Kleiman NS et al. Circulation. 2000;101:751-7.

  9. PURSUIT: GP IIb/IIIa inhibition prevents death with/without early PCI Death or myocardial reinfarction % Placebo Eptifibatide Favors eptifibatide Favors placebo 96 Hours Early PCI 15.3 9.2 No early PCI 7.7 5.5 7 Days Early PCI 16.0 9.9 No early PCI 10.8 8.8 30 Days Early PCI 16.7 11.2 No early PCI 15.0 12.2 6 Months Early PCI 19.8 15.1 No early PCI 18.6 15.3 0.5 1 2 OR (95% CI) Early PCI: n = 450No early PCI: n = 1316 Lincoff AM et al. Circulation 2000;102:1093-100.

  10. PURSUIT: Importance of timing GP IIb/IIIa inhibition on outcomes 3.0 2.8 2.3 2.5 Difference in rate of death or MI, eptifibatide vs placebo(%) 2.0 1.7 1.5 1.0 0.5 0 0.0 <6 6–12 12–24 >24 Time to treatment (hours) N = 9471 Bhatt DL et al. JAMA. 2000;284:1549-58. .

  11. TACTICS-TIMI 18: Study design Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction N = 2220 with unstable angina/NSTEMI ASAUnfractionated heparinTirofiban 0.4 µg/kg per min over 30 min, then 0.1 µg/kg per min for 48 h, including 12 h post-PCI Conservative approach ETT/cath/PCI for recurrent or demonstrated ischemia Invasive approach Cath within 4–48 hours with revascularization if anatomy suitable Primary outcome:Death, MI, rehospitalization for ACS ETT = exercise tolerance test Cannon CP et al. N Engl J Med. 2001;344:1879-87.

  12. TACTICS-TIMI 18 vs TIMI IIIB: Effects of early PCI GP IIb/IIIa inhibition P = 0.003 Deaths/MI/ACS at 6 months 39 40 P = 0.005 38%  in death/MI/ACS in TACTICS-TIMI 18 vs TIMI IIIB (P < 0.0001) P < 0.0001 30 24 23 22 Events* (%) 18 20 12 10 0 Low (0–2) Intermediate (3–4) High (5–7) TIMI risk score category TIMI IIIB TACTICS-TIMI 18 *Adjusted for baseline differences Sabatine MS et al. Circulation. 2004;109:874-80.

  13. Longer infusion* TIMI myocardial perfusion grade 3: OR 0.52 (P = 0.012) TIMI flow grade 3: OR 0.61 (P = 0.054) Minimum diameter (P = 0.032) TACTICS-TIMI 18: Duration of GP IIb/IIIa inhibitor pre-PCI influences TIMI flow P = 0.013 50 43.4 40 TIMI myocardial perfusion grade 3 (%) 29.9 30 20 10 0 <21 >21 Treatment duration (hours) *Controlled for baseline troponin T Gibson CM et al. Am J Cardiol. 2004;94:492-4.

  14. Clinical Trials of GP IIb/IIIa Inhibition GP IIb/IIIa Inhibitors in Planned PCI

  15. ESPRIT: Study design Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy Assess effect of novel, double-bolus dose eptifibatide in coronary stenting N = 2064 undergoing stent implantation Randomized, controlled study Eptifibatide 180-µg/kg double-bolus 10 min apart+ continuous infusion 2.0 µg/kg per min for 18–24 h Placebo Aspirin + heparin + thienopyridine Primary outcome:Death, MI, urgent revascularization and thrombotic bailout after GP IIb/IIIa inhibitor ≤48 h Secondary outcome:Death/MI/urgent revascularization at 30 days ESPRIT Investigators. Lancet. 2000;356:2037-44.

  16. ESPRIT: Outcomes at 48 hours Eptifibatidebetter Placebo better Eptifibatide Placebo RR P 6.6 10.5 0.63 0.0015 Primary endpoint 6.0 9.3 0.65 0.0045 Death/MI/UTVR 5.5 9.2 0.60 0.0013 Death/MI 3.4 5.1 0.67 0.053 Death/Large MI 3.3 4.9 0.67 0.064 Large MI 5.4 9.0 0.60 0.0015 All MI 0.6 1.0 0.60 0.30 UTVR 1.0 2.1 0.48 0.029 Thrombotic bailout 5.4 0.1 0.2 0.50 0.55 Death 0 0.5 1 1.5 2 Relative Risk N = 2064 UTVR = urgent target vessel revascularization ESPRIT Investigators. Lancet. 2000;365:2037-44.

  17. ESPRIT: Primary outcome over time Death/MI/TVR/thrombotic bailout within 48 hours RR = 0.76 (95% Cl 0.63–0.93) P = 0.0068 25 20 RR = 0.65 (95% Cl 0.49–0.87) P = 0.0034 RR = 0.65 (95% Cl 0.47–0.87) P = 0.0045 Primary endpoint (%) 15 10 5 0 30 days 12 months 48 hours Placebo Eptifibatide Granada JF, Kleiman NS. Am J Cardiovasc Drugs. 2004:4:31-41. TVR = target vessel revascularization

  18. GP IIb/IIIa inhibition in planned PCI Death, MI, or urgent revasc at 30 days P GP IIb/IIIa (%) Placebo (%) Favors GP IIb/IIIa Favors placebo EPIC 11.4 12.8 Abciximab B 0.430 8.3 12.8 Abciximab B+I 0.008 EPILOG 5.2 11.7 Abciximab LDH <0.001 5.4 11.7 Abciximab SDH <0.001 EPISTENT 5.3 10.8 Abciximab + stent <0.001 6.9 10.8 Abciximab + PCI 0.007 IMPACT II 9.2 11.4 Eptifibatide 135/.5 0.063 9.9 11.4 Eptifibatide 135/.75 0.220 RESTORE 8.0 10.5 Tirofiban 0.052 CAPTURE 11.3 15.9 Abciximab 0.012 RAPPORT 5.8 11.2 0.030 Abciximab 0.25 1.0 4.0 Odds ratio (95% CI) B = bolus; B+I = bolus + infusion; LDH = low-dose heparin; SDH = standard-dose heparin Lincoff AM et al. J Am Coll Cardiol. 2000;35:1103-15.

  19. Timing of catheterization: Weekday vs weekend hospital admission N = 56,352 with UA/NSTEMI (CRUSADE) 60 Weekday 50 40 Proportion undergoing cardiac catheterization (%) Weekend 30 20 P < 0.001 by log-rank statistic 10 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time from admission (hours) Ryan JW et al. Circulation. 2005;112:3049-57.

  20. Weekend delay in catheterization does not increase adverse events N = 56,352 with UA/NSTEMI (CRUSADE) Weekday patients (n = 45 548) Weekend patients (n = 10 804) Adjusted OR (95% CI) In-Hospital Outcomes Death 4.1 4.4 1.02 (0.92–1.13) Reinfarction 3.0 2.9 0.96 (0.86–1.07) Death or MI 6.6 6.6 0.98 (0.91–1.07) Cardiogenic shock 2.6 2.8 1.05 (0.92–1.21) Stroke 0.8 0.8 0.96 (0.86–1.07) CHF 8.6 9.2 1.00 (0.93–1.08) Any adverse event 14.5 15.1 1.00 (0.94–1.06) Ryan JW et al. Circulation. 2005;112:3049-57.

  21. Clinical Trials of GP IIb/IIIa Inhibition GP IIb/IIIa Inhibition in Patients With Diabetes

  22. Accelerated CAD progression in diabetes Inflammation hsCRP, IL-6. VCAM-1, ICAM-1, P-selectin, sCD40L, TNF-, TSP-1 Prothrombotic state GP IIb/IIIa receptors Platelet factor 4 Fibrinogen, TF, vWf PAI-1 Protein C Endothelial dysfunction Hyperglycemia Free fatty acids Insulin resistance RAGE/AGE Dyslipidemia CAD progression and/orworse outcomes post-PCI Restenosis Hyperinsulinemia RAGE/AGE PPAR- modulation TSP-1 Associated conditions Renal dysfunction LV dysfunction Peripheral vascular disease Atherosclerotic burden Diffuse disease Multivessel disease Negative remodeling RAGE = receptor for advanced glycation end-products (AGE)TSP-1 = thrombospondin-1 Roffi M, Topol EJ.Eur Heart J. 2004;25:190-8.

  23.  Membrane fluidity Altered Ca+2 and Mg+2 homeostasis  Arachidonic acid metabolism  Thromboxane A2 synthesis  Prostacyclin production  NO production  Antioxidants  Activation-dependent adhesion molecules (eg, GP IIb/IIIa, P-selectin) Altered platelet functions in diabetes These changes contribute to increased platelet aggregability and adhesiveness in diabetes Colwell JA, Nesto RW. Diabetes Care. 2003;26:2181-8.

  24. PURSUIT: Outcomes in diabetic vs nondiabetic US patients 30-day death or MI Eptifibatide better Placebo better Diabetes No diabetes 0.33 1.0 3.0 Odds ratio (95% CI) Lincoff AM et al. Circulation. 2000;102:1093-100.

  25. PRISM-PLUS: Outcomes in diabetic NSTEMI patients by treatment strategy Tirofiban + heparin(%) Heparin(%) 30-day outcomes Composite All diabetic patients undergoing 21.2 PCI 25.4 25.6 44.9 CABG 22.5 Medical management 17.7 MI/Death All diabetic patients undergoing 1.9 PCI 12.7 CABG 2.6 26.5 Medical management 7.6 11.2 0.1 0.5 1 5 10 Risk ratio (95% CI) Théroux P et al. Circulation. 2000;102:2466-72.

  26. TACTICS-TIMI 18: Death/MI/ACS in ACS patients with/without diabetes 30 Invasive 27.7 27% Conservative 25 13% 20.1 20 Event rate* at 6 months (%) 16.4 14.2 15 10 5 0 Diabetes No diabetes *Death, MI, rehospitalization for ACSPatients treated with aspirin, clopidogrel, and tirofiban Roffi M et al. Eur Heart J. 2004;25:190-8.

  27. EPISTENT, ESPRIT: Effect on 1-year mortality in planned PCI by diabetes status Evaluation of Platelet Inhibition in STENTing Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy 5 EPISTENT(Abciximab) ESPRIT(Eptifibatide) 4.1 4 3.5 1-year mortality (%) 3 1.9 2 1.5 1.4 1.3 1.2 1.0 1 0 Diabetes No diabetes Diabetes No diabetes GP IIb/IIIa inhibitor Placebo Lincoff AM. Circulation. 2003;107:1556-9.

  28. PCI in patients with ACS and diabetes • Patients with ACS plus diabetes are at higher risk for recurrent events but derive greater benefit from aggressive therapy • Mainstays of acute-phase therapy in diabetic ACS: • Triple antiplatelet therapy: Aspirin, clopidogrel, GP IIb/IIIa inhibition • Heparin or LMWH • Early invasive assessment and, if appropriate, stent-based PCI • Despite sharp declines in restenosis rates with drug-eluting stents, patients with ACS plus diabetes remain at high risk for repeat revascularization Roffi M, Topol EJ. Eur Heart J. 2004;25:190-8.

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