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Carlo Briguori, MD, PhD Laboratoy of Interventional Cardiology

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

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Carlo Briguori, MD, PhD Laboratoy of Interventional Cardiology

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  1. NAPLES Novel Approaches for Preventing or Limiting Event StudyRandomised 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

  2. Disclosure Statement of Financial Interest 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.

  3. Background 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 PCI4-5 1 Roffi M. et al.Circulation 2001; 104: 2767 2 Topol EJ. et al.Lancet 1999; 354: 2019 3 Bhatt DL. et al.JACC 2000; 35: 922 4 Ryden L. et al.Eur Heart J 2007; 28: 88 5 King SB. et al.JACC 2008; 51: 172

  4. Background 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, bivalirudin3-4 does not activate platelets is able to interfere with both circulating and clot-bound thrombin when added to clopidogrel, it achieves additional inhibition of platelet function decreasing platelet surfage coverage 1 Keating FK. et al.Thrombosis research 2004; 113: 27 2 Lev EI. et al.Thrombosis and Haemostasis 2006; 95: 441 3 Sibbing D. et al.Eur Heart J 2008; 29: 1504 4 Anand SX. et al.Am J Cardiol 2007; 100: 417

  5. Background Few data exist comparing bivalirudin with UFH plus GP IIb/IIIa inhibitors in diabetic patients Post-hoc analysis of REPLACE-2 and ACUITY 1-2 no difference in short and long-term ischemic events lower rate of major bleeding 1 Gurm HS. et al.JACC 2005; 45: 1932 2 Feit F. et al.JACC 2008; 51: 1645

  6. Purpose 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

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

  8. Sample size Hypothesis: Riduction in the primary composite endpoint from 38% in the UFH plus tirofiban group to 23.5% in the Bivalirudin alone group1 Sample size: A total of 316 patients (158 each group) will be necessary to gave the study 80% power and a significance level <0.05 1 REPLACE-2 trial - Lincoff AM, et al.JAMA 2003; 289: 853

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

  10. 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 <125.000/mm3 • 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

  11. Study Medications UF Heparin Tirofiban* Bivalirudin# U/Kg g/Kg mg/kg 70 1 12 iv bolus 0.15/min iv2 0.75 bolus iv3 1.75/h infusion iv4 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 m2 the dose was halved # In eGFR <30 ml/kg/1.73 m2 , the infusion rate was reduced to 1 mg/kg/h

  12. Definitions Non-Q wave MI: Periprocedural = CKMB 3X ULN Within 30-day = CKMB 2X ULN Q wave MI: CKMB 2X ULN with new significant Q waves in 2 contiguous leads Major bleeding: 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: Clinically overt bleeding not meeting criteria for major bleeding.

  13. 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

  14. UFH + Tirofiban (N=168) Bivalirudin alone (N=167) P value Clinical Characteristics Age, yrs (mean  SD) 65.6  8.3 65.0  9.8 0.52 Female, % 35.7 34.1 0.82 BMI (kg/m2) 28.7 4.6 28.7  4.1 0.89 Family history for CAD 39 (23.2%) 44 (26.3%) 0.53 Treatment of Diabetes Oral agents Insulin 116 (69%) 52 (31%) 126 (75.4%) 41 (24.6%) 0.57 Hypertension, % 131 (78%) 125 (74.9%) 0.52 Hyperlipidemia, % 109 (64.9%) 105 (62.9%) 0.73 Current smoker, % 35 (20.8%) 34 (20.4%) 0.93 Prior MI, % 75 (44.6%) 75 (44.9%) 1.00 Prior PCI, % 41 (24.4%) 46 (27.5%) 0.53 Prior CABG, % 15 (8.9%) 12 (7.2%) 0.69 LVEF, % (mean  SD) 55.9  10.0 54.9  10.3 0.34 CKD* 35 (35.1%) 67 (40.4%) 0.36 * Estimated glomerular filtration rate <60 mL/min/1.73 m2

  15. Clinical Characteristics UFH + Tirofiban (N=168) Bivalirudin alone (N=167) P value Symptoms Asymptomatic Stable angina Unstable angina 38 (22.8%) 98 (58.6%) 31 (18.5%) 46 (27.8%) 102 (60.8%) 19 (11.4%) 0.17 HbA1c, % (mean  SD) 7.4  1.4 7.6  1.7 0.56 Statin treatment 139 (82.7%) 138 (82.6%) 1.00

  16. Angiographic & Procedural Characteristics UFH + Tirofiban (N=168) Bivalirudin alone (N=167) P value Procedure strategy Stent DES Rotablator DCA 168 (100%) 141 (84.1%) 6 (3.6%) 1 (0.6%) 167 (100%) 135 (80.8%) 6 (3.6%) 0 0.94 Multivessel stenting 21 (12.5%) 22 (13.2%) 0.87 Direct stenting 33 (19.4%) 43 (25.8%) 0.10 No. treated vessel/patient 1.13  0.36 1.15  0.41 0.65 No. treated lesion/patient 1.26  0.48 1.39  0.69 0.11 Target vessel LAD Cx RCA LM 80 (42.2%) 55 (28.9%) 52 (27.6%) 3 (1.3%) 90 (46.8%) 55 (28.8%) 42 (21.9%) 5 (2.6%) 0.38 Complex (B2/C) lesions 138 (65.1%) 139 (59.7%) 0.25 Bifurcation lesions 36 (17.2%) 54 (23.3%) 0.11 Calcified lesions 70 (32.8%) 79 (33.9%) 0.84

  17. Angiographic & Procedural Characteristics UFH + Tirofiban (N=168) Bivalirudin alone (N=167) P value Preprocedural QCA RVD, mm MLD, mm DS, % Lesion length, mm 2.88  0.60 0.41  0.39 87  9 19.7  9.3 2.89  0.53 0.48  0.33 85  8 18.9  9.2 0.85 0.06 0.013 0.45 Postprocedural QCA RVD, mm MLD, mm DS, % Acute gain, mm 3.02  0.59 2.92  0.64 3  8 2.52  0.71 3.04  0.56 3.14  0.75 2  5 2.65  0.59 0.62 0.13 0.013 0.57 Stent/patient 1.3  0.8 1.4  0.9 0.57 Stent length, mm 24.5  11.6 23.2  12.0 0.46 Max inflation pressure, atm 15  4 15  4 0.34 Radial approach 7 (4.2%) 4 (2.4%) 0.20 BA ratio 1.02  0.14 1.00  0.19 0.45 Angiographic complications1 7 (4.2%) 8 (4.8%) 0.80 1 Intraprocedural slow-flow, residual dissection, coronary rupture, side branch closure or compromise

  18. Bleeding risk score* 1 risk ≤1.3% 2-6 risk ≤1.8% 7-9 risk ≤2.7% 10 risk ≥5.0% 50 38.1 40 34.1 31.5 31.7 30 p = 0.68 22.2 % of case 19.6 20 12 10.7 10 0 Bivalirudin mean risk score = 4.5±4.2 UFH & Tirofiban mean risk score = 4.3±3.9 * According to Nikolsky E. et al. Eur Heart J 2007; 28: 1936-45

  19. 30-day outcome UFH + Tirofiban (N=168) Bivalirudin alone (N=167) P value Net clinical outcome 35 (20.8%) 20 (12%) 0.038 Death 0 0 MI 21 (12.5%) 17 (10.2%) 0.61 Q-wave MI 0 0 Non Q-wave MI 21 (12.5%) 17 (10.2%) 0.61 Unplanned revasc 0 0 Bleeding Major Minor 13 (7.7%) 3 (1.8%) 10 (6%) 3 (1.8%) 1 (0.6%) 2 (1.2%) 0.018 0.623 0.035

  20. P = 0.038 OR, 0.517 95% CI, 0.284-0.940 P = 0.606 OR, 0.793 95% CI, 0.402-1.564 P = 0.035 OR, 0.218 95% CI, 0.061-0.780 UFH plus tirofiban (n = 168) Bivalirudin (n = 167)

  21. 14 P= 0.472 OR, 0.736 95% CI, 0.413-1.311 12 9.8% P= 0.007 (n=5/57) 10 OR, 0.498 95% CI, 0.436-0.569 8 6.8% (n=8/117) % 5.3% 6 (n=3/51) 4 2 0% (n= 0/110) 0 Low Risk Moderate - High Risk Risk score < 7 n = 227 (67.8%) Risk score ≥ 7 n = 108 (32.2%) UFH plus tirofiban (n = 168) Bivalirudin (n = 167)

  22. 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 unfractionatedheparin plus tirofiban is associated with a reduction of bleeding. • Bivalirudin administration, compared with unfractionatedheparin plus tirofiban, results in a significant decrease of the composite end-point of30-day death, urgent revascularization, myocardial infarction and bleeding.

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