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NAPLES III Novel Approaches in Preventing or Limiting Event III TriaL Randomised Comparison of Bivalirudin versus Unfractionated Heparin in Patients at.

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Presentation on theme: "NAPLES III Novel Approaches in Preventing or Limiting Event III TriaL Randomised Comparison of Bivalirudin versus Unfractionated Heparin in Patients at."— Presentation transcript:

1 NAPLES III Novel Approaches in Preventing or Limiting Event III TriaL Randomised Comparison of Bivalirudin versus Unfractionated Heparin in Patients at High Risk of Bleeding Undergoing Elective Coronary Stenting thought the Femoral Approach Carlo Briguori, MD, FACC, FSCAI Clinica Mediterranea, Naples, Italy

2 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

3 Background  Major bleeding and blood transfusion after PCI have been strongly associated with increased rates of in- hospital and late mortality, myocardial infarction (MI) and repeat revascularization 1-2  Unfractionated heparin (UFH) is the most commonly used anticoagulant drug during PCI in order to prevent thrombotic complications  Limitations of UFH include 4-5  inability to inactivate clot-bound thrombin,  the indirect mechanism of thrombin inhibition via anti-thrombin-III activation,  the nonspecific protein binding  Non-linear pharmacokinetic, requiring a continuous monitoring of the effect in order to confirm the optimal anticoagulation regimen and, on the contrary, avoid a high bleeding risk 1 Doyle BJ et al. J Am Coll Cardiol 2009;53: Rao SV. et al. Am Heart J 2008;155: Young E, et al. Thrombosis and Haemostasis 1992; 67: Sobel M et al. J Vasc Surg 2001;33:587-94

4 Background  Bivalirudin (The Medicine’s Co., Parsippany, NJ) is a synthetic direct thrombin inhibitor approved for patients with stable and unstable coronary syndromes undergoing PCI 1.  Favorable properties of bivalirudin include:  its ability to inhibit both circulating and clot-bound thrombin,  an inherent anti-platelet effect by inhibition of thrombin-induced platelet activation,  a short half-life, which may minimize bleeding.  direct binding to thrombin without co-factors and no binding to plasma proteins.  linear kinetics, resulting in predictable serum concentrations Levine GN et al. J Am Coll Cardiol 2011;58:e44 2. Stone GW et al. JAMA 2007;298: Stone GW, et al. N Engl J Med 2008;358: Lincoff AM et al. JAMA 2003;298;853

5 Background  The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR- REACT) 3 trial 1 showed that bivalirudin led to a net clinical outcome comparable with that achieved with UFH. However:  an high (140 U/Kg) single bolus dose of UFH was used  Not specifically designed for high-risk bleeding patients  The ISAR-REACT 3A 2 showed that, in biomarker negative patients, a low dosing regimen (100 U/Kg) of UFH represents a simple and safe method of lowering the bleeding peri-procedural risk without compromise the risk of ischemic complications. However:  Single-arm prospective study  Not specifically designed for high-risk bleeding patients 1. Kastrati et al. N Engl J Med 2008;359: Schultz S et al. Eur Heart J 2010;31:582-7

6 High risk bleeding patients Age > 75 years0 for ≤55 years Add 4 for every 10 years over 55 Female gender3 Anemia2 LMWH within 48 h pre-PCI2 eGFR <60 mlmin1.73 m 2 2 Risk Score Risk of Major Bleeding % % %  10 ≥5% Eur Heart J Nikolski E et al Eur Heart J 2007; 28:

7 Background  At present there is a lack of prospective clinical trial assessing the safety and the efficacy of bivalirudin compared with UFH in the subset of patients exposed to high risk of bleeding.

8 Purpose  We performed a prospective, randomized, double-blind, single center, investigator- initiated study comparing the 2 different strategies in high-risk bleeding patients:  Unfractionated heparin (UFH Group)  Bivalirudin (Bivalirudin Group)

9 NAPLES III trial DESIGN: Prospective, randomized, double-blind single center, investigator-initiated clinical study Elective PCI in biomarker negative patients at high risk of bleeding (risk score ≥10) In-hospital major bleeding Bivalirudin group UFH group

10 Hypothesis: — Reduction in the primary endpoint from >5% 1-3 in the UFH group to <3% 2-3 in the Bivalirudin group Sample size : –A total of 830 patients (415 each group) will be necessary to gave the study 80% power and a significance level <0.05 Sample size 1. Nikolski E et al. Eur Heart J 2007; 28: Kastrati A et al. N Engl J Med 2008;359: Schultz S et al. Eur Heart J 2010;31:582-7

11 Inclusion criteria  Age  18 y  Bleeding risk score ≥10  Procedure planned through the femoral approach  Angiographic evidence of de novo or restenotic lesions requiring revascularization  Stable or unstable angina or documented silent ischemia  Negative biomarkers of myocardial injury  Double antiplatelet therapy  Stable hemodynamic conditions

12 Exclusion criteria Bleeding risk score <10 Pregnancy  Ongoing or recent (<48 h) episode of STEMI or NSTEMI  Negative biomarkers of myocardial injury  Chronic dialysis and/or history or previous dialysis  Hemodynamic instability requiring inotropic support or IABP  Ongoing or recent (<7 days) treatment with glycoprotein IIb/IIIa inhibitors  Ongoing or recent (6 months) bleeding or bleeding diathesis.  Recent (within 6 months) stroke  History of heparin-induced thrombocitopenia  Platelet count < /mm 3

13 Bivalirudin group NAPLES III trial Bolus of 0.75 mg/kg i.v. prior to the start of the procedure, followed by infusion of 1.75 mg/kg per hour for the duration of the procedure Additional bolus 0.3mg/Kg in case ACT <250 sec 70 U/Kg i.v. prior to start the procedure Additional bolus 20 U/Kg in case ACT <250 sec UFH group

14 Primary endpoint: –Rate of in-hospital major bleeding, defined according the REPLACE 2 criteria: –intracranial, –intraocular, –retroperitoneal, –access-site haemorrhage requiring intervention, –clinically overt blood loss resulting in a decrease in haemoglobin by ≥3 g/dl, –any decrease in haemoglobin ≥4 g/dl, –transfusion of ≥2 units of packed cells or whole blood Endpoints

15 Secondary endpoints: –Rate of in-hospital major and minor bleeding, defined according the REPLACE 2 criteria –Rate of in-hospital, 30-day and 1-year major adverse cardiac events, defined as death, non-fatal myocardial infarction, repeat revascularization –Rate of stent thrombosis, according to the ARC criteria –Rate of major bleeding according to other criteria Endpoints

16 Assessed for eligibility ( n= 1859) Exclusion (n = 1021) Not meeting inclusion/exclusion criteria (n = 998) Radial access (n = 275) Acute myocardial infarction (n = 219) End-stage renal disease = 238) IIbIIIa inhibitors (n = 211) Recent bleeding (n = 55) Refused to partecipate (n = 23) Randomized (n = 837) Patients lost at follow-up (n = 0) Discontinued treatment (n = 0) Patients allocated in the Bivalirudin Group (n = 418) Received allocated treatment (n = 418) Did not receive the allocated treatment (n =0) Patients allocated in the UFH group (n = 419) Received allocated treatment (n = 419) Did not receive the allocated treatment (n= 0) Patients analized ( n = 418) Patients excluded from analysis (n = 0) Patients lost at follow-up (n = 0) Discontinued treatement (n = 0) Patients analized ( n 419) Patients excluded from analysis (n = 0) Enrollement Allocation Follow-up Analysis

17 Clinical Characteristics Bivalirudin group (N= 418) UFH Group (N=419) P Age, yrs (mean  SD)78  Female, %210 (50.5%)186 (44.5%)0.09 BMI (kg/m 2 ) 28  427  LVEF, % (mean  SD)49  950  Prior MI Prior PCI Prior CABG 181 (42%) 143 (34%) 55 (13.2%) 158 (38%) 150 (36%) 57 (13.6%) eGFR (ml/min/1.73 m 2 ) GFR <60 66± (42.8%) 64± (48.7%) Diabetes mellitus Insulin-treated 189 (45.2%) 88 (21%) 181 (43%) 69 (16%) Hypertension, %350 (84%)349 (83%)0.86 Symptoms Silent ischemia Stable angina Unstable angina 77 (18%) 244 (68.4%) 97 (23.2%) 76 (18%) 250 (69.6%) 93 (22.4%) 0.98

18 Procedural Characteristics Bivalirudin group (N= 418) UFH Group (N=419) P CASS 1-vessel 2-vessel 3-vessel 78 (18.5%) 140 (33.5%) 200 (48%) 92 (22%) 149 (35.5%) 178 (42.5%) 0.20 Target vessel (not mutually exclusive) LAD LCX RCA LM SVG 155 (37%) 118 (28%) 120 (28.5%) 20 (4.5%) 10 (2%) 156 (37% 115 (27%) 121 (29%) 18 (4%) 14 (3%) 0.63 Lesion site Ostial Proximal Middle Distal (11%) 204 (37.5%) 228 (42%) 51 (9.5%) (11%) 207 (38%) 223 (41%) 54 (10%) 0.84

19 Procedural Characteristics Bivalirudin group (N= 418) UFH Group (N=419) P Procedure Stent DES Rotablator Direct stenting Multivessel stenting 417 (99.8%) 338 (81%) 26 (6.5%) 42 (10%) 96 (23%) 417 (99.5%) 352 (84%) 26 (6.5%) 46 (11%) 100 (24%) Complex lesions (B2/C) 247(59%)256 (61%)0.51 CTO 40 (9.5%) 31 (7.5%) 0.24 Bifurcation lesion 77 (18.5%)84 (20%)0.63 Thrombus 17 (4%)14 (3%)0.56 Calcified lesion 171 (41%) 0.96

20 Procedural Characteristics Bivalirudin group (N= 418) UFH Group (N=419) P Pre-procedural QCA RVD, mm MLD, mm DS, % Lesion length, mm 3.06         Post-procedural QCA RVD, mm MLD, mm DS, % 3.23       Stent/patient 1.3   Stent length, mm 29  1830  Max inflation pressure, atm 18  519  BA ratio 1.02  

21 Procedural Characteristics Bivalirudin group (N= 418) UFH Group (N=419) P Radial approach2 (0.5%) 0.99 Glycoprotein IIbIIIa inhibitors2 (0.5%)5 (1.3%)0.22 Volume of contrast media (ml) 177   Peak ACT value (seconds) <250 seconds 483± (2.4%) 305±77 68 (16.2%) <

22 Primary endpoint 16/146 Odds ratio = 1.28; 95% CI= p = % 3.3% 14/418 0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 UFH groupBivalirudin group 11/419 14/418 %

23 Primary endpoint Major bleeding Bivalirudin group (N= 14/418) UFH Group (N= 11/419) P Intracranial 00- Intraocular 00- Retroperitoneal 00- Access-site requiring intervention 7 (1.7%)2 (0.5%)0.10 Clinically overt bleeding (Hb drop >3 gr/dL) 2 (0.2%)6 (1.4%)0.29 Concealed bleeding (Hb drop >4 gr/dL) 5 (1.2%)3 (0.7%)0.50 Transfusion >2 units 4 (0.9%) 1.00

24 Primary endpoint % 0,0 0,5 1,0 1,5 2,0 2,5 Entry-siteNon entry-site 0.5% 2.1% 2/419 9/ % 7/ % 7/418 p = 0.10 p = 0.80 Bivalirudin group UFH group 7/418

25 Secondary endpoint Major bleeding Bivalirudin group (N= 418) UFH Group (N=419) P BARC 17 (4.1%)11 (2.6%)0.24 GUSTO 3 (0.7%)5 (1.2%)0.72 TIMI 2 (0.5%)3 (0.7%)0.65 CURE 5 (1.2%)7 (1.7%)0.56 PLATO 16 (3.8%)10 (2.4%)0.23

26 All bleeding (major and minor) Odds ratio = 0.88; 95% CI= ; p = % 8.1% 38/419 34/418 % Entry-siteNon entry-site 5.2% 3.8% 22/419 16/ % 22/ % 12/418 p = 1.00 p = 0.56 Bivalirudin group UFH group %

27 Peak ACT & Bleeding 316±86 p = 0.36p = Major bleeding Event yes Event no 365± ± ±150 Major&Minor bleeding peak ACT (seconds)

28 Periprocedural Myocardial Infarction (TnI >5x ULN) UFH groupBivalirudin group /41991/418 % p = 0.93

29 Secondary endpoint 30-day MACE Bivalirudin group (N= 418) UFH Group (N=419) P Major bleeding 14 (3.3%)11 (2.6%)0.58 Death 10 (2.4%)6 (1.4%)0.31 Myocardial infarction 1 (0.2%)00.50 Revascularization 5 (1.2%)3 (0.7%)0.47 Stent thrombosis 2 (0.5%) 0.99 Composite 27 (6.5%)18 (4.3%)0.17

30 Secondary endpoint 1-year MACE Bivalirudin group (N= 418) UFH Group (N=419) P Death 20 (4.8%)21 (5.0%)1.00 Myocardial infarction 6 (1.7%)2 (0.5%)0.17 Revascularization 30 (7.2%)32 (7.6%)0.89 Stent thrombosis 4 (1.0%)3 (0.7%)0.71 Composite 68 (16.3%)62 (14.8%)0.11

31 Conclusions  In patients at high risk of bleeding undergoing to elective PCI through the femoral approach, the use of bivalirudin does not reduce the rate of in-hospital major bleeding compared to UFH.  Entry-site bleeding still represent an important issue  Radial approach should be routinely used in this subgroup of patients

32 NAPLES III Investigators Inteventional Cardiologists Carlo Briguori, MD, PhD Amelia Focaccio, MD Gabriella Visconti, MD Michael Donahue, MD Laboratory of Interventional Cardiology, Clinica Mediterranea, Naples, Italy Clinical Cardiologists Bruno Golia, MD Bruno Ricciardelli, MD Coronary Care Unit and Department of Cardiology, Clinica Mediterranea, Naples, Italy Vascular surgeon Lucio Selvetella, MD Vascular Surgery, Clinica Mediterranea, Naples, Italy

33 NAPLES III Investigators Clinical Events Commitee Flavio Airoldi, MD Davide Tavano, MD Laboratory of Interventional Cardiology, IRCCS Multimedica, Milan Italy Data Monitoring & Safety Commitee Gerolama Condorelli, MD, PhD Cristina Quintavalle, PhD Department of Pathology, Federico II University, Naples, Italy Clinical Trial & Evaluation Unit Members Chiara Viviani Anselmi, PhD Laura Lapa, PhD Deparment of Cardiology IRCCS Humanitas Hospital, Milan, Italy


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