NAPLES Novel Approaches for Preventing or Limiting Event Study Randomised Comparison of Bivalirudin Monotherapy versus Unfractionated Heparin plus Tirofiban in Diabetic Patients Undergoing Elective Coronary Stenting Carlo Briguori, MD, PhD Laboratoy of Interventional Cardiology Clinica Mediterranea, Naples - Italy

I, Carlo Briguori DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. Disclosure Statement of Financial Interest

In diabetic patients undergoing PCI the use of platelet glycoprotein (Gp) IIb/IIIa inhibitors reduce short- and long-term mortality 1-3 Contemporaty guidelines recommend platelet Gp IIb/IIIa inhibitors administration in diabetic patients undergoing elective and urgent PCI 4-5 Background 1 Roffi M. et al. Circulation 2001; 104: Topol EJ. et al. Lancet 1999; 354: Bhatt DL. et al. JACC 2000; 35: Ryden L. et al. Eur Heart J 2007; 28: 88 5 King SB. et al. JACC 2008; 51: 172

Bivalirudin is a direct thrombin inhibitor that demonstrated antiplatelet and anti-inflammatory properties similar to the combination of unfractionated heparin (UFH) plus Gp IIb/IIIa inhibitors 1-2 Unlike UFH, bivalirudin 3-4 o does not activate platelets o is able to interfere with both circulating and clot-bound thrombin o when added to clopidogrel, it achieves additional inhibition of platelet function decreasing platelet surfage coverage Background 1 Keating FK. et al. Thrombosis research 2004; 113: 27 2 Lev EI. et al. Thrombosis and Haemostasis 2006; 95: Sibbing D. et al. Eur Heart J 2008; 29: Anand SX. et al. Am J Cardiol 2007; 100: 417

Few data exist comparing bivalirudin with UFH plus GP IIb/IIIa inhibitors in diabetic patients o Post-hoc analysis of REPLACE-2 and ACUITY 1-2  no difference in short and long-term ischemic events  lower rate of major bleeding Background 1 Gurm HS. et al. JACC 2005; 45: Feit F. et al. JACC 2008; 51: 1645

To compare the acute and 1-month safety, tolerability and efficacy of Bivalirudin alone as compared to unfractionated heparin (UFH) plus tirofiban in diabetic patients undergoing elective PCI Purpose

NAPLES DESIGN: Prospective, randomized, double- arm, single-center clinical study Diabetic Patients Elective PCI Biomarker negative UFH + Tirofiban Bivalirudin alone ASA Clopidogrel (loading dose 300 mg the day before procedure) Elective PCI 30 day endpoints Death, MI, IUR, ACUITY major bleeding (net clinical outcome)

Hypothesis:  Riduction in the primary composite endpoint from 38% in the UFH plus tirofiban group to 23.5% in the Bivalirudin alone group 1 Sample size : o A total of 316 patients (158 each group) will be necessary to gave the study 80% power and a significance level <0.05 Sample size 1 REPLACE-2 trial - Lincoff AM, et al. JAMA 2003; 289: 853

Inclusion criteria Diabetes mellitus treated by insulin and/or oral agents Age  18 y De novo lesion in a native coronary artery Elective PCI

Exclusion criteria Primary or rescue PCI ACS with elevated cardiac markers Pregnancy Recent (<1 month) previous PCI Restenotic lesion SVG or LIMA treatment Active bleeding or bleeding diathesis, trauma or gastrointestinal or genitourinary tract bleeding Prior intracranial bleeding Platelets < /mm 3 History of heparin-induced thrombocytopenia Creatinine >3.0 mg/dL or dialysis Recent (<6 h) UFH or (<12 h) GP IIb/IIIa use Oral anticoagulant use

Study Medications 0.75 bolus iv /h infusion iv 4 12 iv bolus 0.15/min iv mg/kg Bivalirudin#  g/Kg Tirofiban* U/Kg UF Heparin 1 Additional 20 U/Kg bolus if ACT <250 seconds 2 Discontinued at 12 hours following the procedure 3 Additional 0.3 mg/kg bolus if ACT < 250 seconds 4 Discontinued at end of PCI *In eGFR <30 ml/kg/1.73 m 2 the dose was halved # In eGFR <30 ml/kg/1.73 m2, the infusion rate was reduced to 1 mg/kg/h

Non-Q wave MI: o Periprocedural = CKMB  3X ULN o Within 30-day = CKMB  2X ULN Q wave MI: o CKMB  2X ULN with new significant Q waves in  2 contiguous leads Major bleeding: o intracranial, intraocular, or retroperitoneal hemorrhage, access site with intervention, hematoma >5cm, Hgb drop >3g/dL with source or >4g/dL without source, transfusion >2 units of packed red blood cells pr whole blood Minor bleeding: o Clinically overt bleeding not meeting criteria for major bleeding. Definitions

Patients assessed for eligibility (n=366) Excluded (n=31) 6 withdrew consent 25 did not meet the inclusion criteria 335 patients randomized 168 allocated to UFH plus tirofiban group 167 allocated to Bivalirudin group

Clinical Characteristics 67 (40.4%) 54.9  (7.2%) 46 (27.5%) 75 (44.9%) 34 (20.4%) 105 (62.9%) 125 (74.9%) 126 (75.4%) 41 (24.6%) 44 (26.3%) 28.7   9.8 Bivalirudin alone (N=167) P value 35 (35.1%)CKD* 28.7  4.6 BMI (kg/m 2 ) 39 (23.2%)Family history for CAD 55.9  10.0LVEF, % (mean  SD) 15 (8.9%)Prior CABG, % 41 (24.4%)Prior PCI, % 109 (64.9%)Hyperlipidemia, % 131 (78%)Hypertension, % 75 (44.6%)Prior MI, % 35 (20.8%)Current smoker, % 116 (69%) 52 (31%) Treatment of Diabetes Oral agents Insulin 35.7Female, % 65.6  8.3 UFH + Tirofiban (N=168) Age, yrs (mean  SD) * Estimated glomerular filtration rate <60 mL/min/1.73 m 2

Clinical Characteristics 138 (82.6%) 7.6  (27.8%) 102 (60.8%) 19 (11.4%) Bivalirudin alone (N=167) P value 139 (82.7%)Statin treatment 7.4  1.4HbA1c, % (mean  SD) 38 (22.8%) 98 (58.6%) 31 (18.5%) UFH + Tirofiban (N=168) Symptoms Asymptomatic Stable angina Unstable angina

Angiographic & Procedural Characteristics 79 (33.9%) 54 (23.3%) 139 (59.7%) 90 (46.8%) 55 (28.8%) 42 (21.9%) 5 (2.6%) 1.39   (25.8%) 22 (13.2%) 167 (100%) 135 (80.8%) 6 (3.6%) 0 Bivalirudin alone (N=167) P value 33 (19.4%)Direct stenting 70 (32.8%)Calcified lesions 36 (17.2%)Bifurcation lesions 1.26  0.48 No. treated lesion/patient 1.13  0.36 No. treated vessel/patient 138 (65.1%)Complex (B2/C) lesions 80 (42.2%) 55 (28.9%) 52 (27.6%) 3 (1.3%) Target vessel LAD Cx RCA LM 21 (12.5%)Multivessel stenting 168 (100%) 141 (84.1%) 6 (3.6%) 1 (0.6%) UFH + Tirofiban (N=168) Procedure strategy Stent DES Rotablator DCA

Angiographic & Procedural Characteristics (2.4%)7 (4.2%)Radial approach         0.71 Postprocedural QCA RVD, mm MLD, mm DS, % Acute gain, mm 8 (4.8%) 1.00         9.2 Bivalirudin alone (N=167) P value 24.5  11.6 Stent length, mm 1.02  0.14 BA ratio 15  4 Max inflation pressure, atm 7 (4.2%)Angiographic complications  0.8 Stent/patient 2.88     9.3 UFH + Tirofiban (N=168) Preprocedural QCA RVD, mm MLD, mm DS, % Lesion length, mm 1 Intraprocedural slow-flow, residual dissection, coronary rupture, side branch closure or compromise

Bleeding risk score* UFH & Tirofiban mean risk score = 4.3±3.9 Bivalirudin mean risk score = 4.5±4.2  1 risk ≤1.3% 2-6 risk ≤1.8% 7-9 risk ≤2.7%  10 risk ≥5.0% p = 0.68 * According to Nikolsky E. et al. Eur Heart J 2007; 28: % of case

30-day outcome 00Q-wave MI (10.2%)21 (12.5%)Non Q-wave MI 3 (1.8%) 1 (0.6%) 2 (1.2%) 0 17 (10.2%) 0 20 (12%) Bivalirudin alone (N=167) (7.7%) 3 (1.8%) 10 (6%) Bleeding Major Minor 0Unplanned revasc (12.5%)MI 0Death P value 35 (20.8%) UFH + Tirofiban (N=168) Net clinical outcome

P = P = P = UFH plus tirofiban (n = 168) Bivalirudin (n = 167) OR, % CI, OR, % CI, OR, % CI,

Risk score < 7 n = 227 (67.8%) Risk score ≥ 7 n = 108 (32.2%) UFH plus tirofiban (n = 168) Bivalirudin (n = 167) P= P= OR, % CI, OR, % CI, % (n=8/117) 0% (n= 0/110) 9.8% (n=5/57) 5.3% (n=3/51) % Low RiskModerate - High Risk

Conclusions In diabetic patients undergoing elective PCI the antithrombotic strategy of bivalirudin monotherapy compared with unfractionated heparin plus tirofiban is safe and feasible. Antithrombotic regimen with bivalirudin alone suppresses adverse 30-day ischaemic events to a similar extent as does unfractionated heparin plus tirofiban. Bivalirudin administration compared with unfractionated heparin plus tirofiban is associated with a reduction of bleeding. Bivalirudin administration, compared with unfractionated heparin plus tirofiban, results in a significant decrease of the composite end-point of 30-day death, urgent revascularization, myocardial infarction and bleeding.