1. AHA 2011 Late Breaking Trials Synthesis and Critical Review

2. AHA 2011 Late Breaking RCTs ISAR-REACT-4: UFH + abciximab vs. bivalirudin monotherapy in pts with NSTEMI Undergoing PCI ATLAS ACS 2 TIMI 51: Two doses of rivaroxaban vs. placebo in pts with ACS treated with aspirin and clopidogrel AIDA STEMI: IC vs IV abciximab in pts with STEMI undergoing primary PCI

3. ACUITY Design – First Randomization *Stratified by pre-angiography thienopyridine use or administration Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Moderate and high risk ACS (n=13,819) Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice Aspirin in all Clopidogrel dosing and timing per local practice UFH/Enox + GP IIb/IIIa (n=4,603) Bivalirudin + GP IIb/IIIa (n=4,604) Bivalirudin Alone (n=4,612) R* Medical management PCI CABG Stone GW et al. N Engl J Med 2006;335:2203–16

4. Management Strategy (N=13,819) 56.4% 11.4% 32.2% CABG (n=1,539) Medical Rx (n=4,491) PCI (n=7,789) Heparin + IIb/IIIa N = 2,561 Bivalirudin + IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619 Stone GW et al. N Engl J Med 2006;335:2203–16 77% CK-MB or troponin + 68% preloaded with clopidogrel

5. 0 5 10 15 05101520253035 Event Rate (%) Days from Randomization *Heparin=unfractionated or enoxaparin Estimate P (log rank) 8.4% Heparin* + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) 0.15 9.4% Bivalirudin alone (N=2619) 0.45 8.9% Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone P=0.36 ACUITY PCI Composite Ischemia (N=7,789) Stone GW et al. Lancet 2007;369:907-19

6. ACUITY PCI Ischemia Endpoints (N=7,789) Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone *Heparin=unfractionated or enoxaparin p=0.16p=0.45 p=0.37p=0.53 p=0.16p=0.19 p=0.31P=0.87 Stone GW et al. Lancet 2007;369:907-19

7. ACUITY Adjudicated Stent Thrombosis PCI Patients With ≥1 Stent Implanted (N=7,211) RR 1.00 [0.61-1.64] p=0.99 RR 1.23 [0.77-1.96] p=0.39 RR 0.82 [0.51-1.30] p=0.39 Stone GW et al. Lancet 2007;369:907-19

8. ACUITY PCI Bleeding Endpoints (N=7,789) Heparin + IIb/IIIa (N=2561) Bivalirudin + IIb/IIIa (N=2609) Bivalirudin alone (N=2619) P Value ACUITY Scale - Major Bleed, all7.3%8.0%4.2% <0.001 - Major, non-CABG6.8%7.5%3.5% <0.001 - Minor, non-CABG26.0%28.4%14.9% <0.001 TIMI Scale - Any7.8%8.5%4.5% <0.001 - Major2.3%2.4%0.8% <0.001 - Minor7.5%8.2%4.2% <0.001 Transfusions, non-CABG 3.0%3.9%1.7% 0.002 *P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor Stone GW et al. Lancet 2007;369:907-19

9. ISAR-REACT-4 1,721 Pts with NSTEMI (CK-MB or troponin+) undergoing PCI Pre-treated with aspirin and 600 mg of clopidogrel Double-blind (double-dummy drug) UFH + Abciximab Bolus UFH 70 U/kg Bolus Abcx 0.25 mg/kg + infusion 0.125 μg/kg/min x12h N=861 Bivalirudin Bolus 0.75 mg/kg + infusion 1.75 mg/kg/hr for duration of PCI N=860 Primary endpoint = death, large MI, urgent TVR, or major bleeding at 30d Powered for superiority of UFH/Abcx over bivalirudin Kastrati A et al. N Engl J Med 2011: on-line R

10. ISAR-REACT-4: Primary endpoint Kastrati A et al. N Engl J Med 2011: on-line Days 0 5 10 15 20 051015202530 Death, large MI, urgent TVR, or major bleeding (%) RR (95%CI) = 0.99 (0.74–1.32) P=0.94 Bivalirudin (n=860) UFH + Abciximab (n=861) 10.9% 11.0%

11. ISAR-REACT-4: Composite ischemia Kastrati A et al. N Engl J Med 2011: on-line Days 0 5 10 15 20 051015202530 Death, MI, or urgent TVR (%) RR (95%CI) = 0.96 (0.74–1.25) P=0.76 Bivalirudin (n=860) UFH + Abciximab (n=861) 12.8% 13.4%

12. UFH + Abcx (n=861) Bivalirudin (n=860) RR (95%CI) Death, MI, or urgent TVR12.8%13.4%0.96 (0.74–1.25) - Death 1.4% 1.6%0.86 (0.40–1.85) - Q-wave MI1.3%0.9%1.37 (0.56–3.40) - Large MI6.6%7.0%0.94 (0.66–1.36) - Any MI12.0%11.4%1.06 (0.80–1.39) - Urgent TVR0.8%1.3%0.63 (0.25–1.62) Stroke0.5%0.7%0.67 (0.20–2.34) Definite stent thrombosis0.6%0.7%0.83 (0.25–2.72) ISAR-REACT-4: 30-day efficacy endpoints Kastrati A et al. N Engl J Med 2011: on-line

13. ISAR-REACT-4: Major bleeding Kastrati A et al. N Engl J Med 2011: on-line Days 0 5 10 15 20 051015202530 Major bleeding* (%) RR (95%CI) = 1.84 (1.10–3.07) P=0.02 Bivalirudin (n=860) UFH + Abciximab (n=861) 2.6% 4.6% *Intracranial, intraocular, or RP hemorrhage;  hgb >4 g/dL with overt bleeding or ≥2U RBC Rx

14. UFH + Abcx (n=861) Bivalirudin (n=860) RR (95%CI) Major bleeding (protocol)*4.6%2.6%1.84 (1.10–3.07) - Intracranial 0.1% - Retroperitoneal0.5%0.1% -  Hgb >4g/dL w/source - Pericardial0.5%0.1% - GI1.0%0.7% - GU0.3%0.1% - Access site1.8%0.8% - Other0.2% - ≥2U Rx w/o source0.2%0.3% TIMI major bleeding2.2%1.9%1.19 (0.61–2.31) TIMI minor bleeding7.7%4.3%1.82 (1.22–2.70) ISAR-REACT-4: 30-day safety endpoints Kastrati A et al. N Engl J Med 2011: on-line *Intracranial, intraocular, or RP hemorrhage;  hgb >4 g/dL with overt bleeding or ≥2U RBC Rx

15. Questions after ACUITY PCI and ISAR-REACT-4 Should the standard of care in all patients with NSTEACS undergoing an invasive management strategy be: - Aspirin - Aspirin - Pre-loading with an ADP antagonist - Pre-loading with an ADP antagonist - Procedural anticoagulation with bivalirudin (withholding GPIIb/IIIa inhibitor use for refractory procedural thrombotic complications) rather than heparin plus the routine use of a GPIIb/IIIa inhibitor? - Procedural anticoagulation with bivalirudin (withholding GPIIb/IIIa inhibitor use for refractory procedural thrombotic complications) rather than heparin plus the routine use of a GPIIb/IIIa inhibitor?

16. Recent ACS: STEMI, NSTEMI, UA - No increased bleeding risk, no warfarin, no ICH, no prior stroke if on ASA + thienopyridine - Stabilized 1-7 days post-index event (median 4.7 days) PRIMARY ENDPOINTS: EFFICACY: CV Death, MI, or Stroke* SAFETY: TIMI major bleeding not associated with CABG Event driven trial of 1,002 events in 15,342 patients** RIVAROXABAN 5.0 mg BID N=5,176 ASA + Thieno, n=4,827 ASA, n=349 Stratified by thienopyridine use (93%) ASA 75 to 100 mg/day Placebo N=5,176 ASA + Thieno, n=4,821 ASA, n=355 RIVAROXABAN 2.5 mg BID n=5,174 ASA + Thieno, n=4,825 ASA, n=349 * Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke ** 184 subjects were excluded from the efficacy analyses prior to unblinding Mega JL et al. NEJM 2011: On-line 60% underwent PCI STEMI 50.3% NSTEMI 25.6% UA 24.0%

17. Primary Efficacy Endpoint: CV Death, MI or Stroke HR and 95% CI estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; ARR=Absolute Relative Reduction; NNT=Number needed to treat; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID. Months Rivaroxaban (both doses) HR 0.84 (0.74-0.96) ARR 1.7% NNT = 59 mITT p = 0.008 ITT p = 0.002 10.7% 8.9% CV death, MI or stroke (%) Placebo Mega JL et al. NEJM 2011: On-line Mean duration of study drug 13.1 months

18. Efficacy Endpoints Mega JL et al. NEJM 2011: On-line CV death, MI or stroke 12 Days 10 8 6 4 2 0 0 90 180 270 360 450 540 630 720 Rivaroxaban Placebo CV death Days 5 4 3 2 1 0 0 90 180 270 360 450 540 630 720 Rivaroxaban Placebo 5 mg bid 4.0% 4.1% P=0.02 CV death, MI or stroke HR (95%CI)= 0.84 (0.72-0.97) 12 Days 10 8 6 4 2 0 0 90 180 270 360 450 540 630 720 Rivaroxaban Placebo CV death Days 0 0 90 180 270 360 450 540 630 720 Rivaroxaban Placebo 5 4 3 2 1 2.5 mg bid 10.7% 2.7% 4.1% 9.1% 9.1% 8.8% 8.8% 10.7% HR (95%CI)= 0.85 (0.73-0.98) P=0.03 P=0.002 HR (95%CI)= 0.66 (0.51-0.86 HR (95%CI)= 0.94 (0.75-1.20) P=0.63

19. Efficacy Endpoints Mega JL et al. NEJM 2011: On-line Placebo (n=5,113) Rivaroxaban combined (n=10,229) Rivaroxaban 2.5 mg bid (n=5,114) Rivaroxaban 5 mg bid (n=5,115) CV death, MI or stroke (1  EP) 10.7%8.9%**9.1%*8.8%* - CV death 4.1%3.3%*2.7%**4.0% - MI 6.6%5.5%*6.1%4.9%** - Stroke, any 1.2%1.6%1.4%1.7% - Ischemic 1.0%0.9%1.0%0.9% All-cause death, MI or stroke (2  EP) 11.0%9.2%**9.3%**9.1%* - All-cause death 4.5%3.7%*2.9%**4.4% Stent thrombosis † 2.9%2.3%*2.2%*2.3%* *P<0.05 vs placebo; **P<0.01 vs placebo † ARC def/prob/poss

20. Primary Safety Endpoint TIMI Major Bleeding (non-CABG) Mega JL et al. NEJM 2011: On-line Days Rivaroxaban (both doses) HR 3.96 (2.46 - 6.38) P<0.001 0.6% 2.1% Non-CABG TIMI Major Bleeding (%) Placebo 5% 4% 3% 2% 1% 0% 0 90 180 270 360 450540630720

21. Rivaroxaban Placebo 5 mg bid P<0.001 HR (95%CI)= 3.46 (2.08-5.77) Rivaroxaban Placebo 2.5 mg bid 1.8% 0.6% 2.4% HR (95%CI)= 4.47 (2.71-7.36) P<0.001 Primary Safety Endpoint TIMI Major Bleeding (non-CABG) Mega JL et al. NEJM 2011: On-line Days 5% 4% 3% 2% 1% 0% 0 90 180 270 360 450540630720 Days 5% 4% 3% 2% 1% 0% 0 90 180 270 360 450540630720

22. Safety Endpoints Mega JL et al. NEJM 2011: On-line Placebo (n=5,113) Rivaroxaban combined (n=10,229) Rivaroxaban 2.5 mg bid (n=5,114) Rivaroxaban 5 mg bid (n=5,115) TIMI major bleeding (non-CABG) (1  EP) 0.6%2.1%***1.8%***2.4%*** TIMI minor bleeding 0.5%1.3%**0.9%1.6%*** TIMI any bleeding † 7.5%14.5%***12.9%***16.2%*** Intracranial bleed 0.2%0.6%**0.4%*0.7%** Fatal bleed 0.2%0.3%0.1%0.4% *P<0.05; **P<0.01; ***P<0.001 † requiring medical attention

23. Questions after ATLAS ACS 2 1.How do you weight the outcomes in terms of efficacy vs. safety for the 2 different rivaroxaban doses? 2.Assuming that the 2.5 mg po bid dose is approved for ACS, when would you prefer: - aspirin + clopidogrel, then PCI, then add rivaroxaban? - aspirin + prasugrel? - aspirin + ticagrelor? - aspirin + prasugrel/ticagrelor, then PCI, then switch to ASA + clopidogrel + rivaroxaban?

24. Thiele H et al. Circulation 2008;118;49-57 RCT of IC vs. IV Abciximab LIPSIAbciximab-STEMI MRI measures (day 2) (median, %LV) P=0.01 P=0.01P=0.02 154 pts with STEMI <12º undergoing PCI randomized to IC (thru guide catheter) vs. IV 0.25 mg/kg bolus abciximab followed by 12 hr infusion. 55% anterior MI, Sx-PCI ~4º, baseline TIMI 0/1 ~62%.

25. Meta-analysis of IV vs IC Bolus Abciximab (+ 12  Infusion) During Primary PCI in STEMI 6 RCTs, 1246 total pts randomized 30-Day Mortality Study or Subgroup Events Intracoronary abciximab N CICERO 2010 Crystal AMI 2010 Dominguez-Rodriguez 2009 EASY-MI 2010 Iversen 2011 Thiele 2008 Total (95% CI) Total events Heterogeneity: Chi 2 =1.88, df=3 (P=0.60); 1 2 =0% Test for overall effect: Z=2.11 (P=0.03) 5000229271252553185776361.4%71009320263232552170776103.3%33.7%7.4%44.8%14.1%100.0% Odds Ratio M-H, Fixed 95% CI Events Intravenous abciximab NWeight Favors IC 0.69 (0.22, 2.19) 0.29 (0.01, 7.59) Not estimable 0.20 (0.04, 0.92) 0.66 (0.11, 4.05) 0.43 (0.20, 0.94) Odds Ratio M-H, Fixed 95% CI Favors IV 0.01 0.1 1 10 100 Navarese EP et al. Platelets 2011:On-line

26. AIDA STEMI: Study Design and Flow 8 technical PCI-problems 7 exclusion criteria detected 2065 patients with suspected STEMI - Symptoms <12 h; planned primary PCI - No contraindication for abciximab UFH 50-70 IU/kg Aspirin 500 mg, Clopidogrel 600 mg or Prasugrel 60 mg Abciximab bolus 0.25 mg/kg plus 12 h infusion 0.125 µg/kg/min 1032 patients randomized to IC abciximab 1002 patients PCI started 995 patients abciximab bolus given; PCI completed 935 patients with 90 day follow-up 1033 patients randomized to IV abciximab 1001 patients PCI started 993 patients abciximab bolus given; PCI completed 932 patients with 90 day follow-up 64 withdrawal informed consent 32 lost to follow-up 25 incomplete information 62 patients not PCI eligible: - 46 STEMI not confirmed - 13 emergency CABG - 3 exclusion criteria LAD IRA ~43% Sx-PCI~3.2 hrs 20% thrombectomy Thiele H. AHA 2011

27. AIDA STEMI: Primary Outcomes IC Abcx (n=935) IV Abcx (n=932) OR (95% CI) P value Death, ReMI, or new CHF65 (7.0%)71 (7.6%)0.91 (0.91-1.28)0.58 - Death42 (4.5%)34 (3.6%)1.24 (0.78-1.97)0.36 Cardiac3533 Non-cardiac71 - Reinfarction17 (1.8%) 1.0 (0.51-1.96)0.99 - New CHF22 (2.4%)38 (4.1%)0.57 (0.33-0.97)0.04 Thiele H. AHA 2011

28. AIDA STEMI: Early ST-Segment-Resolution (%) IV Abciximab IC Abciximab Frequency p=0.37 Thiele H. AHA 2011

29. AIDA STEMI: Infarct Size – CK-AUC Time IV Abciximab IC Abciximab Median creatine kinase [μmol//s*l] p=0.74 Thiele H. AHA 2011

30. INFUSE-AMI Trial PI: Gregg W. Stone; Co-PI: C. Michael Gibson Primary endpoint: Infarct size at 30 days (MRI) 2º endpoints: TIMI flow, blush, ST-resolution, MACE (30d, 1 yr) 452 pts with anterior STEMI Anticipated sx to PCI <5 hrs, TIMI 0-2 flow in prox or mid LAD PCI with bivalirudin IC abcx bolus (ClearWay) PCI with bivalirudin Standard of care R 1:1 Aspiration(Export) No aspiration Aspiration(Export) R 1:1 R 1:1

31. Why might this trial have been negative (other than the hypothesis was wrong)? Why might this trial have been negative (other than the hypothesis was wrong)? What lessons can be learned from AIDA STEMI regarding What lessons can be learned from AIDA STEMI regarding  The level of evidence that is required before new therapies are adopted?  The utility of meta-analysis? Questions after AIDA STEMI