Bivalirudin is Superior to Heparin for ACS Patients Gregg W. Stone, MD Columbia University Medical Center NewYork-Presbyterian Hospital Cardiovascular Research Foundation

Disclosures None

Comparison 1 Bivalirudin vs. Heparin + routine GPI in STEMI

Meta-analysis: UFH ± Abciximab in Primary PCI 8 RCTs, 3,949 pts with STEMI w/i 12 undergoing primary (7) or rescue (1) PCI randomized to UFH + abciximab vs. UFH alone OR [95%CI] = 0.72 [0.55,0.94] P=0.01 OR [95%CI] = 0.63 [0.54,0.73] P<0.001 De Luca G et al. JAMA 2005;293:1759–1765

CADILLAC (n=2,082) Subacute thrombosis: Impact of abciximab Stone GW et al. NEJM 2002;346:957–66 4

Kandzari DE et al. AHJ 2004;147:457–62 4 RCTs of Abciximab vs. Control in Primary PCI (N=3,266): Safety Events OR [95%CI) = 1.45 (1.04–2.02) OR [95%CI) = 1.74 (1.11–2.72) OR [95%CI) = 2.13 (0.78–5.76) OR [95%CI) = 0.75 (0.26–2.13) Kandzari DE et al. AHJ 2004;147:457–62

HORIZONS-AMI + EUROMAX Pooled 30-day results (n=5,800) Heparin ± GPI (N=2911) Bivalirudin (N=2889) Relative risk (95% CI) P Value Death 90 (3.1%) 69 (2.4%) 0.77 (0.57-1.05) 0.10 Cardiac 85 (2.9%) 59 (2.0%) 0.70 (0.50-0.97) 0.03 Non‑cardiac 5 (0.2%) 10 (0.4%) 2.01 (0.69-5.88) 0.19 Reinfarction 42 (1.4%) 53 (1.8%) 1.27 (0.85-1.90) 0.24 Stent thrombosis (ARC) 40 (1.4%) 60 (2.1%) 1.51 (1.01-2.24) 0.04 Acute 6 (0.2%) 36 (1.2%) 6.04 (2.55-14.31) <0.0001 Sub‑acute 34 (1.2%) 25 (0.9%) 0.74 (0.44-1.23) MACE (death, MI, IDR, or stroke) 161 (5.5%) 163 (5.6%) 1.02 (0.83-1.26) 0.85 Protocol major bleeding 226 (7.8%) 120 (4.2%) 0.53 (0.43-0.66) Blood transfusion 110 (3.8%) 62 (2.1%) 0.57 (0.42-0.77) 0.0002 Acquired thrombocytopenia 77 (2.9%) 37 (1.4%) 0.48 (0.33-0.71) NACE (MACE or major bleeding) 346 (11.9%) 253 (8.8%) 0.74 (0.63-0.86) Breslow-Day test for study heterogeneity non-significant: P ≥0.11 for all variables Stone GW et al. JACC 2015;65:27–38 6

Comparison 2 Bivalirudin vs. Heparin + bailout GPI in STEMI

Bivalirudin vs. Heparin Monotherapy During Primary PCI in STEMI: Three major RCTs EUROMAX HEAT PPCI BRIGHT N centers 65 1 82 N patients 2,198 1,812 2,194 - Bivalirudin 1,089 905 735 - Heparin 460 907 729 - Heparin + GPI 649 - 730 Heparin mono bolus 60 IU/kg 70 IU/kg 100 IU/kg Bival infusion Low or high dose Median 4 hrs No High dose Median 3 hrs GPI bailout, Biv vs. Hep 7.9% vs. 25.4% 13.5% vs. 15.5% 4.4% vs. 5.6% Prasugrel/ticagrelor 59% 89% 0% Radial 47% 81% 79% non-rand rand

EUROMAX: Treatment According to Routine GPI Use 1:1 UFH (91.3%*)/LMWH ± GPI Per standard practice (n=1,109) BIVALIRUDIN (provisional GPI only) (n=1,089) 58.5% (n=649) Routine GPI 41.5% (n=460) No GPI 3.9% (n=42) Routine GPI* 96% (n=1047) No GPI Note: Non-randomized, non-stratified * Median 60 U/kg received in both arms * Protocol Deviation 25.4% (n=117) Bailout GPI 7.9% (n=83) Bailout GPI Zeymer U et al. EHJ 2014:on-line

EUROMAX: Primary Endpoint Death or Major Bleeding Log Rank P values Overall: 0.003 A vs. B: 0.18 A vs. C: 0.04 B vs. C: 0.0006 A. Heparin + Routine GPI B. Heparin Only + Bailout GPI 12 C. Bivalirudin 9.8% 10 8 7.4% major bleeding (%) Death or 6 5.1% 4 2 5 10 15 20 25 30 Days from Randomization Patients at risk: A. Heparin + Routine GPI 649 598 588 586 577 563 445 B. Hep Only + Bailout GPI 460 426 415 412 407 395 320 C. Bivalirudin 1089 1038 1024 1020 1007 899 791 Zeymer U et al. EHJ 2014:on-line 10

EuroMax A prolonged high-dose bivalirudin infusion may safely reduce acute stent thrombosis Heparin ± GPI (n=1109) Bivalirudin + 0.25 mg/kg/hr infusion* (n=670)‡ Bivalirudin + 1.75 mg/kg/hr infusion* (n=244)§ Acute ST 2 (0.2%) 11 (1.6%) 1 (0.4%) Major bleeding 57 (6.0%) 16 (2.4%) 7 (2.9%) Data on a post-PCI infusion is not available for 35 patients * Median [95%CI] infusion duration was 4.5 [4.2, 4.9] hours ‡ 659 of these received at least 2 hours infusion post-PCI §191 of these received at least 2 hours infusion post-PCI Clemmensen P et al. JACC Int 2015;8:214–20

HEAT PPCI: 30-Day MACE (n=1,812) Death, ReMI, CVA, TLR (%) Days Bivalirudin Heparin No. at risk 907 905 5 10 15 20 25 30 871 853 866 844 862 835 857 830 856 828 0% 1% 2% 3% 4% 5% 6% 7% 8% 9% 10% Bivalirudin Heparin P MACE 8.7% 5.7% 0.01 The event curves demonstrate an early separation reflecting the substantial early hazard in the PPCI setting. Shahzad A et al. Lancet 2014 12

HEAT PPCI: Stent Thrombosis ARC definite or probable stent thrombosis Bivalirudin (n=905) Heparin (n=907) Definite or probable 24 (3.4%) 6 (0.9%) - Definite 23 (3.3%) 5 (0.7%) - Probable 1 (0.1%) - Acute 20 (2.9%) - Subacute 4 (0.6%) 0 (0%) Almost all of these events were - by ARC criteria - definite events occurring in the first 24 hours after stent implantation. 2-3x higher than in other trials Shahzad A et al. Lancet 2014 13

Median activated clotting time post bolus Why were the rates of acute stent thrombosis higher in HEAT PPCI than in any other bivalirudin STEMI trial? Median activated clotting time post bolus ~239 secs w/o GPI ACT (seconds) HEAT PPCI: Actalyke XL MAX‐ACT system HORIZONS-AMI: Hemotec and Hemochron

HEAT PPCI: ACT* and GPI bailout Bivalirudin arm (n=915) Measure ACT 5-15 mins after bolus 806 (88%) 251 [229, 285] sec ACT end-procedure 771 (84%) 246 [229, 270] sec Bivalirudin rebolus anytime** 12.7% GPI bailout 13.5% ~25% <229 seconds; rebolus rate should have been ~25% *Actalyke XL MAX‐ACT system **By protocol, rebolus for ACT <225 seconds Shahzad A et al. Lancet 2014

Bellomo R et al. Crit Care Med 2009;37:3114-9 Limited external validity Implausible effect size Unequal allocation of resources Lack of blinding Numerous examples where single- center trials were “reversed” by multiple multicenter trials “What works in one location may not in others due differences in baseline risk, intercurrent care, opportunity cost, and the fidelity with which the intervention can be delivered.” “Single-center studies are valuable hypothesis-generating investigations. However, the evidence shows that.…they have typically not been confirmed by larger multicenter studies….the history of this field argues that two beneficial RCTs are necessary with at least one being a confirmatory trial. Accordingly, we should be very careful in taking single-center trials as a demonstration of a biological truth and should avoid giving them undue weight or value. .…practice guidelines should rarely, if ever, be based on evidence from single-center trials.” Bellomo R et al. Crit Care Med 2009;37:3114-9

Limitations of HEAT PPCI Suboptimal use of bivalirudin PCI performed in only 82% of patients – not a typical primary PCI cohort Study investigators did the data monitoring CEC was at the study center – not independent Data analysis was performed at the study center – not independent Reinfarction diagnosed by a “common sense” definition – new thrombus qualifies! Stent thrombosis not adjudicated by a core lab

BRIGHT: Study flow 2,194 pts with AMI randomized at 82 centers in China Aspirin and clopidogrel 86.2 % STEMI 13.8% NSTEMI 79% radial Randomization (1:1:1) Bivalirudin alone N=735 Biv 0.75 mg/kg bolus + 1.75 mg /kg/h infusion (0.3 mg/kg bolus if ACT< 225s). Bailout GPI permitted. Biv infusion (1.75 mg/kg/h) continued for at least 30 min post PCI (median 3h). 4.4% bailout tirofiban. UFH alone N=729 Heparin 100 U/kg bolus + additional dose if ACT <200 s. Bailout GPI permitted. ACT goal = 250-300. 5.6% bailout tirofiban. UFH + Tirofiban N=730 Heparin 60U/kg bolus . Tirofiban 10μg/kg bolus + 0.15 μg/kg/min infusion for 18-36 h. ACT goal = 200-250.   This is the study flowchart. Bivalirudin, unfractionated Heparin, and Tirofiban were administrated according to the protocol. Follow-up at 30 days, 6 months and 1 year Primary endpoint: NACE, including MACCE (all-cause death, reMI, TVR or stroke) and bleeding events at 30 days. Han Y et al. Submitted.

BRIGHT: Primary and Major Secondary Endpoint Events at 30 Days Bivalirudin (n=735) Heparin (n=729) Heparin + Tirofiban (n=730) Primary endpoint Biv vs. Hep, p=0.009 RR (95%CI) 0.67 (0.50-0.90), NNT=23.1 Biv vs. Hep+Tiro, p<0.001 RR (95%CI) 0.52 (0.39-0.69), NNT=12.3 Hep vs. Hep+Tiro, p=0.04 RR (95%CI) 0.78 (0.61-0.99), NNT=26.2 18 17.0 P<0.001 16 13.2 14 12.3 12 P<0.001 (%) 10 8.8 P=0.74 7.5 8 5.8 5.0 6 Primary events occurred in 8.8% of the patients receiving bivalirudin, which acquired 33% and 48% relative risk reductions compared with those of heparin monotherapy and heparin plus tirofiban, respectively, and the number need treatment were 23.1 and 12.3, respectively. The incidences of MACCE were similar among three treatment arms. Bivalirudin treatment was associated with a significantly reduced risk of overall bleeding events compared with heparin monotherapy and heparin plus tirofiban. 4.9 4.1 4 2 NACE MACCE Any Bleeding Han Y et al. Submitted. 19

BRIGHT: Stent Thrombosis at 30 Days Bivalirudin (n=735) Heparin (n=729) Heparin + Tirofiban (n=730) P=0.77 1.2 1.0 0.9% 0.7% 0.8 0.6% Stent thrombosis (%) 0.6 0.4 0.2 Stent thrombosis occurred in 0.6% of patients in bivalirudin group, similar to those of other two groups. Thrombocytopenia was significantly lower for patients received bivalidrudin compared with those received heparin plus tirofiban, with a p value of 0.02. The difference was significant when that of bivalirudin group compared with pooled populations in the other two heparin groups, with a p value of 0.04. Bivalirudin (n=735) Heparin (n=729) Heparin + Tirofiban (n=730) Han Y et al. Submitted. 20

Comparison 3 Bivalirudin vs. Heparin GPI in STEMI in the “real world”

Impact of Bleeding Avoidance Strategies NCDR CathPCI Registry 2004-2008: PCI in 1,522,935 pts Manual compression alone, closure devices, bivalirudin, or both were used in 35%, 24%, 23%, and 18% of pts, respectively. Propensity-adjusted major bleeding Adj OR (95%CI) = 0.77 (0.73 – 0.80) NNT = 148 Adj OR (95%CI) = 0.67 (0.63 – 0.70) NNT = 118 Adj OR (95%CI) = 0.38 (0.35 – 0.42) NNT = 70 23%↓ 33%↓ 62%↓ Marso SP et al. JAMA. 2010;303:2156-64

Impact of Bivalirudin in Radial Procedures NCDR CathPCI Registry 2009-2012: PCI in 501,017 pts Femoral access with closure devices, radial access with heparin, and radial access with bivalirudin were used in 76%, 13%, 11%, and 18% of pts. Major bleeding: Propensity-adjusted Non-access bleeding Access bleeding 3.0 All pts OR (95% CI) NNT 2.7% 2.5% Radial + heparin 0.96 (0.88-1.05) 1607 2.5 2190 (0.6) P<0.0001 Radial + bival 0.79 (0.72-0.86) 138 168 (0.3) 2.0 1.8% High bleeding risk pts 114 (0.2) Radial + heparin 1.00 (0.90-1.11) 1393 1.5 Radial + bival 0.79 (0.70-0.88) 68 1.0 0.4 0.6 0.8 1.0 1.2 Bival is AC of choice 2013 Adjusted OR 0.5 8186 (2.1) 1405 (2.2) 889 (1.6) Lower than femoral + bivalirudin + VCD Higher than femoral + bivalirudin + VCD Radial access/bivalirudin combination was used less frequently in pts at highest risk for bleeding Femoral access with VCD + bivalirudin Radial access + heparin Radial access + bivalirudin Baklanov DV et al. Circ Cardiovasc Interv. 2013;6:347-53 23

Anticoagulation Regimens During PCI N = 458,448 PCI pts 2004-2008 at 299 hosps (Premier Perspective Database, ~1/5th of all US hosp discharges; bival in 41%) In-hospital events, propensity adjusted Bleeding + Transfusion Mortality OR (95% CI) OR (95% CI) Comparator OR (95% CI) P Value Comparator OR (95% CI) P Value Bivalirudin monotherapy (n=156,064) Bivalirudin monotherapy (n=156,064) 0.51 (0.48, 0.55) <0.0001 0.59 (0.54, 0.65) <0.0001 Bivalirudin + GPI (n=33,566) Bivalirudin + GPI (n=33,566) 0.96 (0.87, 1.06) 0.37 0.82 (0.72, 0.94) 0.004 Heparin alone (n=85,870) Heparin alone (n=85,870) 0.71 (0.66, 0.76) <0.0001 0.88 (0.82, 0.96) 0.003 Comparator Better 1 Heparin + GPI Better (n=182,948) 2 Comparator Better 1 Heparin + GPI Better (n=182,948) 2 Wise GR et al. J Interv Cardiol 2012;25:278–88

SCAAR (31,438 STEMIs) ARC Definite Stent Thrombosis All primary PCI patients who received a stent in Sweden from January 2007 to July 2014 Bivalirudin alone Heparin alone Heparin + GPIIb/IIIa n 16,860 3,246 11,392 ST day 0-30 0.8% (n=142) 0.9% (n=30) 0.9% (n=103) ST day 0-1 0.3% (n=55) 0.3% (n=9) 0.2% (n=25) ST day 2-30 0.5% (n=87) 0.7% (n=21) 0.7% (n=78) c/o David Erlinge

The MATRIX Trial (NCT01433627) ~8400 pts with STEMI and NSTEACS PCI ACC Monday, March 16th ~8400 pts with STEMI and NSTEACS Femoral access Radial access PCI Bivalirudin with or without a 4-hour post-PCI infusion (low dose or high dose) Unfractionated heparin + bailout GPI PI: Marco Valgimigli