1. Clinical Insights, Risk Stratification, and Enhancing Outcomes

2. VBWG CRUSADE. www.crusadeqi.com Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines CRUSADE: National quality improvement initiative Academic collaboration among cardiology and emergency medicine initiated in 2001 Cross collaboration with ACC and AHA Multi-industry sponsor Goal: Improve adherence to ACC/AHA guidelines for managing patients with ACS

3. VBWG CRUSADE: In-hospital mortality by age and acute treatment Boden WE et al. Circulation. 2005;112:II-745. *Aspirin, β-blockers, UFH/LMWH, GP IIb/IIIa inhibitors, clopidogrel <24 hours, PCI <48 hours N = 105,619 registry patients 3.1 3.5 5.2 6.7 8.7 10.4 17.6 0.6 1 1.8 2.7 3.5 10.7 6.5 0 2 4 6 8 10 12 14 16 18 20 0123456 Number of recommended therapies Age >75 yrs Age <75 yrs %

4. VBWG CRUSADE: Post-admission MI vs use of recommended therapies Boden WE et al. Circulation. 2005;112:II-745. Number of recommended therapies % 2.2 2.5 2.6 2.9 3.4 4.2 6.7 1 2 3 4 5 6 0123456 7 Adjusted OR 0.91 (95% CI 0.88–0.95) *Aspirin, β-blockers, UFH/LMWH, GP IIb/IIIa inhibitors, clopidogrel <24 hours, PCI <48 hours N = 105,619 registry patients

5. VBWG CRUSADE: Impact of early aggressive management strategy on in-hospital mortality No early invasive care (n = 9889) Early invasive care (cardiac cath <48 h, n = 8037) Bhatt DL et al. JAMA. 2004;292:2096-104.Adjusted for clinical differences and propensity score 88 72 26 74 94 78 89 51 0 20 40 60 80 100 Aspirin  -Blocker ClopidogrelHeparinGP IIb/IIIa inhibitor 14 Acute medical therapy (<24 h) 3.7 2.5 0 2 4 6 8 In-hospital mortality  32% P < 0.001 % % N = 17,926 registry patients

6. VBWG CRUSADE: NSTE ACS dosing of antithrombotics—Study overview Objective: Investigate association between dosing UFH, LMWH, and GP IIb/IIIa inhibitors and major clinical outcomes Design: Prospective observational analysis Population: Registry patients with NSTE ACS receiving antithrombotic agents Primary outcome: Relation between excessive dosing of UFH, LMWH, and GP IIb/IIIa inhibitors and major bleeding, in-hospital mortality, and length of stay Alexander KP et al. JAMA. 2005;294:3108-16. NSTE ACS = non–ST-segment elevation acute coronary syndromes

7. VBWG Alexander KP et al. JAMA. 2005;294:3108-16. Major predictors of overdosing Patients vulnerable to overdosing Older age (≥65 years) Female Diabetes CHF Low body weight Renal insufficiency

8. VBWG P < 0.001 for all treatment groups Alexander KP et al. JAMA. 2005;294:3108-16. 60 50 40 30 20 10 0 UFHLMWHGP IIb/IIIa inhibitors <65≥75 Results: Excess dosing by age 70 Patient age (years) Excess dose (%) 65–74

9. VBWG Results: Antithrombotic therapy dose and major bleeding Alexander KP et al. JAMA. 2005;294:3108-16. Data are for noncoronary bypass grafting and nontransfer population 35 30 25 20 15 10 5 0 Major bleeding (%) 207420632073714 UFH 23273998922237 LMWH 58791955178 GP IIb/IIIa inhibitors UnderdosedRecommendedMild excessMajor excess P < 0.001P = 0.25P < 0.001 N =

10. VBWG Alexander KP et al. JAMA. 2005;294:3108-16. Recommended dosing of antithrombotic agents DrugRecommended doseDosing adjustments UFHBolus 60–70 U/kg and infusion 12–15 U/kg per hr Patients >60 yr may require lower doses LMWH: Enoxaparin 1 mg/kg SC every 12 hr  dose by 50% by increasing interval to every 24 h if CrCl <30 mL/min GP IIb/IIIa inhibitor: Eptifibatide Bolus 180 µg/kg and infusion 2 µg/kg per min  infusion by 50% to 1 µg/kg per min if CrCl ≤50 mL per min or serum creatinine = 2–4 mg/dL GP IIb/IIIa inhibitor: Tirofiban Bolus 0.4 µg/kg and infusion 0.1 µg/kg per min  bolus and infusion by 50% to 0.05 µg/kg per min if CrCl ≤30 mL/min

11. VBWG Peterson ED et al. ACC. March 2005; Orlando, Fla. Data on file at: Duke Clinical Research Institute. Jan 2001–Dec 2004. Median creatinine clearance (cc/min) Age (years) 0 65–7475–84>84 20 40 60 80 <65 10 30 50 70 Creatinine clearance vs age

12. VBWG Proper dosing of antithrombotic therapies is necessary to prevent bleeding complications in vulnerable patients Alexander KP et al. JAMA. 2005:294:3108-16. Clinical implications Early use of antithrombotic agents plays a key role in management of NSTE ACS, but dosing errors are common Altering dosing based on weight and renal function minimizes bleeding while preserving therapeutic benefit Dosing errors occur more often in elderly and others already vulnerable to bleeding Dosing errors predict an increased risk of major bleeding Patients receiving recommended doses of heparin and GP IIb/IIIa inhibitors alone or in combination have the lowest rates of bleeding

13. Clinical Insights, Risk Stratification, and Enhancing Outcomes Combination Therapy

14. VBWG INTERACT: Study design Enoxaparin 1 mg/kg per 12 h for 48 h UFH 70 U/kg IV bolus, then 15 U/kg per h for 48 h Evaluate safety and efficacy of GP IIb/IIIa inhibitors + enoxaparin vs UFH N = 746 with ischemic chest symptoms and ECG or CK-MB evidence of ACS Prospective, randomized multicenter study Primary safety outcome: 96 h non–CABG-related major hemorrhage Primary efficacy outcome: Recurrent ischemia detected by continuous ECG evaluation within 96 h Eptifibatide 180 µg/kg bolus, then 2.0 µg/kg per min for 48 h Goodman SG et al. Circulation. 2003;107:238-44.UFH = unfractionated heparin INTegrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment

15. VBWG Goodman SG et al. Circulation. 2003;107:238-44. Heparin † Enoxaparin* Patients (%) IschemiaBleeding (96 h) P = 0.0002 P < 0.0001 P = 0.03 P = 0.003 Major ‡ 380366 Minor ‡ n = 380366 48–96 hInitial 48 h 322302n = 357357 0 1 2 3 4 5 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 *Enoxaparin 1 mg/kg SC q 12 h for 48 h † UFH 70-U/kg bolus + 15-U/kg per h infusion for 48 h All patients: Eptifibatide 180-  g/kg bolus + 2-  g/kg per min infusion ‡ Non–CABG-related INTERACT: LMWH/UFH plus GP IIb/IIIa inhibitor in UA/NSTEMI—Primary outcomes

16. VBWG Effect on 30-day death/MI Goodman SG et al. Circulation. 2003;107:238-44. Proportion of patients Days since randomization Enoxaparin* + GP IIb/IIIa inhibitor UFH † + GP IIb/IIIa inhibitor P = 0.031 0 5 10 15202530 0 0.02 0.04 0.06 0.08 0.10 *Enoxaparin 1 mg/kg SC q 12 h for 48 h † UFH 70-U/kg bolus + 15-U/kg per h infusion for 48 h All patients: Eptifibatide 180-  g/kg bolus + 2-  g/kg per min infusion INTERACT: LMWH/UFH plus GP IIb/IIIa inhibition in UA/NSTEMI

17. VBWG SYNERGY: Study design EnoxaparinUFH Compare enoxaparin vs UFH and define role of enoxaparin N = 10,027 high-risk NSTEMI patients managed with early PCI Prospective, randomized, open-label, multicenter study Primary outcome: Death or MI ≤30 days Primary safety outcome: Major bleeding or stroke GP IIb/IIIa inhibitor, aspirin, and clopidogrel SYNERGY Trial Investigators. JAMA. 2004;292:45-54. Superior Yield of the New Strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa Inhibitors

18. VBWG Concomitant medications (%) Aspirin 95.2 94.7 Clopidogrel 62.563.3 GP IIb/IIIa inhibitor 56.558.2  -Blocker86.485.9 ACE inhibitor63.862.2 Statin69.270.0 SYNERGY Trial Investigators. JAMA. 2004;292:45-54. 14.0% Primary outcome (death or MI) UFH Enoxaparin 14.5% Proportion of patients HR 0.96 (95% Cl 0.86–1.06) 0.1 0.2 102030 Days from randomization No. at Risk UFH Enoxaparin 4920 4936 4458 4508 4343 4375 4301 4338 4279 4313 4261 4300 3509 3550 0 Enox n = 4993 UFH n = 4985 SYNERGY: Enoxaparin vs UFH with GP IIb/IIIa inhibition in ACS with early PCI 0

19. VBWG PCI-CURE: Substudy design Clopidogrel 300 mg pre-PCI, Open-label thienopyridine 2–4 wk, Clopidogrel 3–12 mo Placebo pre-PCI, Open-label thienopyridine 2–4 wk, Placebo 3–12 mo Evaluate pre/post-PCI benefit of clopidogrel N = 2658 with NSTEMI Double-blind, placebo-controlled, multicenter prespecified post-randomization analysis Aspirin 75–325 mg (all patients) Primary outcome: CV death, MI, revascularization at 30 days Follow-up: 1 month Mehta SR et al. Lancet. 2001;358:527-33. Percutaneous Coronary Intervention substudy of Clopidogrel in Unstable angina to prevent Recurrent ischemic Events

20. VBWG Mehta SR et al. Lancet. 2001;358:527-33. CV death, MI, or urgent target vessel revascularization *Unadjusted 30% RRR* P = 0.03 0.08 0.06 0.04 0.02 0 051015202530 Days of follow-up Cumulative hazard rates P = 0.03 Clopidogrel Placebo PCI-CURE: Reduction in primary outcome at 30 days

21. VBWG ISAR-REACT: Study design Clopidogrel 600 mg ≥2 h prior to PCI Aspirin 325–500 mg Evaluate abciximab + clopidogrel loading dose in PCI N = 2159 undergoing elective PCI Double-blind, randomized, placebo-controlled multicenter study Primary outcome: All-cause death, MI, urgent revascularization Abciximab 0.25 mg/kg bolus, then 0.125 µg/kg per min for 12 h + UFH 70 U/kg Placebo + UFH 140 U/kg Follow-up: 1 month Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment Kandzari DE et al. J Am Coll Cardiol. 2004;44:2133-6.

22. VBWG Kandzari DE et al. J Am Coll Cardiol. 2004;44:2133-6. All-cause death, MI, urgent revascularization Death, MI, urgent revascularization (%) Time from randomization (days) 051015202530 P = 0.79 0 2 4 6 8 10 <3 h 3–6 h 6–12 h >12 h Major bleeding (%) 1.6 0.5 0.4 1.1 ISAR-REACT: Timing of loading dose and primary outcome

23. VBWG Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect von Beckerath N et al. Circulation. 2005;112:2946-50. 120 ADP (5 µmol/L)-induced aggregation (%) 80 100 60 40 20 0 300 mg600 mg900 mg P = 0.01P = 0.59 P = 0.001 Maximal ADP-induced platelet aggregation after 4 hours Clopidogrel (loading dose) ISAR-CHOICE: No additional platelet effect with doses >600 mg

24. VBWG ISAR-SWEET: Study design Aspirin 500 mg and heparin Evaluate abciximab + clopidogrel loading dose in PCI N = 701 with diabetes, undergoing elective PCI Double-blind, randomized, placebo-controlled multicenter study Primary outcome: All-cause death and MI at 1 year Clopidogrel 600 mg ≥2 h prior to PCI Abciximab 0.25 mg/kg bolus, then 0.125 µg/kg per min for 12 h n = 351 Clopidogrel 600 mg ≥2 h prior to PCI Placebo n = 350 Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics Mehilli J et al. Circulation. 2004;110:3627-35.TVR = target vessel revascularization

25. VBWG Mehilli J et al. Circulation. 2004;110:3627-35. All-cause death, MI (%) 10 8 6 4 2 0 Time from randomization (months) 0123456789101112 Abciximab Placebo RR 0.97 (0.58–1.62) P = 0.91 ISAR-SWEET: Neutral effect on primary outcome in diabetes

26. VBWG Mehilli J et al. Circulation. 2004;110:3627-35. Incidence (%) Angiographic restenosis Target lesion revascularization AbciximabPlacebo 40 30 20 10 0 P = 0.01 P = 0.03 ISAR-SWEET: Reduction in restenosis and target vessel revascularization in diabetes 28.9 37.8 23.2 30.4 RRR = 24% RRR = 22%

27. VBWG CLEAR PLATELETS: Study design Clopidogrel 300 mg* Compare effects of antiplatelet regimens on platelet reactivity and occurrence of myocardial necrosis N = 120 undergoing elective stenting 2 x 2 factorial study Primary aim: Compare effects of four regimens Clopidogrel 300 mg* + eptifibatide † Clopidogrel 600 mg* + eptifibatide † Secondary aim: Effect of treatment on platelet reactivity and postprocedural myocardial necrosis Clopidogrel 600 mg* Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of PLATELETS Gurbel PA et al. Circulation. 2005;111:1153-9. *Loading dose immediately after stenting, then 75 mg/d † Double bolus (180  g/kg) followed by infusion (2  g/kg per min) for 18–24 hours postprocedure

28. VBWG § Gurbel PA et al. Circulation. 2005;111:1153-9. * Response to adenosine diphosphate 5  mol/L Platelet reactivity * Platelet inhibition * † P ≤ 0.001 C or D vs A or B ‡ P = 0.001 A vs B § P = 0.002 A vs B  P < 0.001 C or D vs A or B ABCD Aggregation (%) 0 10 20 30 40 50 60 70 18–24 h3 h8 h Time (post-stenting) Relative inhibition (%) A B C D 0 20 40 60 80 100 120 ‡ † † † ‡ ‡ Group CLEAR PLATELETS: Platelet effects vs clopidogrel dose and GP IIb/IIIa inhibition A: Clopidogrel 300 mg B: Clopidogrel 600 mg C: Clopidogrel 300 mg + eptifibatide D: Clopidogrel 600 mg + eptifibatide 

29. VBWG Gurbel PA et al. Circulation. 2005;111:1153-9. CK-MB releaseTroponin release Clopidogrel 300 mg Clopidogrel 600 mg Clopidogrel 300 mg + eptifibatide Clopidogrel 600 mg + eptifibatide 0 CK-MB (>3x ULN) 10 20 Patients (%) 0 10 20 30 Troponin-I (> ULN) *P < 0.05 vs clopidogrel 300 or 600 mg † P = 0.04 vs clopidogrel 300 mg ‡ P = 0.08 vs clopidogrel 600 mg ULN = upper limit of normal † ‡ * CLEAR PLATELETS: Effect of clopidogrel dose and GP IIb/IIIa inhibition on cardiac biomarkers *

30. VBWG Clopidogrel response variability: 300 mg vs 600 mg Gurbel PA. J Am Coll Cardiol. 2005;45:1392-96. N = 190 0 3 6 9 12 15 18 21 24 27 30 33 ≤-30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] (60,70] > 70 300 mg clopidogrel  Platelet aggregation (5 µM ADP-induced) at 24 hours Patients (%) Resistance 300 mg = 28% 600 mg clopidogrel Nonresponsiveness Resistance 600 mg = 8%

31. VBWG Matetzky S et al. Circulation. 2004;109:3171-5. 120 100 80 60 40 20 0 ADP-induced platelet aggregation Clopidogrel resistance 123456 Days 4th Q 3rd Q 2nd Q % 1st Q 40 35 25 15 10 0 1st n = 15 Recurrent CV events at 6 months 30 20 5 % 2nd n = 15 3rd n = 15 4th n = 15 Quartiles 40 6.7 0 0 P = 0.007 Clopidogrel resistance associated with increased CV risk

32. VBWG REPLACE-2: Study design Bivalirudin 0.75 mg/kg bolus, 1.75 mg/kg per h during PCI Provisional GP IIb/IIIa inhibitor Evaluate bivalirudin vs heparin + GP IIb/IIIa blockade post-PCI N = 6010 undergoing PCI Randomized, double-blind multicenter study Primary outcome: Death, MI, repeat revascularization, or in-hospital major bleeding in ≤30 days Secondary outcome: Death, MI, repeat revascularization ≤30 days Lincoff AM et al. JAMA. 2003;289:853-63. Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events Heparin 65 U/kg bolus Planned GP IIb/IIIa inhibitor

33. VBWG 0.2 DeathMIUrgent revascMajor bleedComposite 2.4 1.2 1.4 7.0 6.2 0.4 9.2 10.0 10 8 6 4 2 0 Heparin + GP IIb/IIIa inhibitor (n = 3008) Bivalirudin (n = 2994) P = 0.32P = 0.26P = 0.23P = 0.44P < 0.001 Lincoff AM et al. JAMA. 2003;289:853-63. 4.1 % REPLACE-2: Death, MI, urgent revascularization, major bleeding