1. Carlo Briguori, MD, FACC, FSCAI Clinica Mediterranea, Naples, Italy
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. 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.
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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 revascularization1-2
Unfractionated heparin (UFH) is the most commonly used anticoagulant drug during PCI in order to prevent thrombotic complications
Limitations of UFH include4-5
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:
2 Rao SV. et al. Am Heart J 2008;155:369-74
3.Young E, et al. Thrombosis and Haemostasis 1992; 67:
4. 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 PCI1.
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 concentrations2-4
1. Levine GN et al. J Am Coll Cardiol 2011;58:e44
2. Stone GW et al. JAMA 2007;298:2497
3. Stone GW, et al. N Engl J Med 2008;358:2218
4. 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 trial1 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 3A2 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
1. Kastrati et al. N Engl J Med 2008;359:688-96
2. Schultz S et al. Eur Heart J 2010;31:582-7

6. High risk bleeding patients
Score
Risk of Major Bleeding
0-1
1.3%
2-6
1.8%
7-9
2.3%
10
≥5%
Age > 75 years
0 for ≤55 years
Add 4 for every 10 years over 55
Female gender 3
Anemia 2
LMWH within 48 h pre-PCI
eGFR <60 mlmin1.73 m2
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)
UFH group
Bivalirudin group
In-hospital major bleeding

10. Sample size Hypothesis: Sample size:
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
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1. Nikolski E et al. Eur Heart J 2007; 28:
2. Kastrati A et al. N Engl J Med 2008;359:688-96
3. Schultz S et al. Eur Heart J 2010;31:582-7 10

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 < /mm3

13. NAPLES III trial UFH group Bivalirudin group 70 U/Kg i.v. prior to
start the procedure
Additional bolus 20 U/Kg
in case ACT <250 sec
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

14. Endpoints 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
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15. Endpoints 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
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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)
Enrollement
Randomized (n = 837)
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)
Allocation
Patients lost at follow-up (n = 0)
Discontinued treatment (n = 0)
Patients lost at follow-up (n = 0)
Discontinued treatement (n = 0)
Follow-up
Analysis
Patients analized ( n = 418)
Patients excluded from analysis (n = 0)
Patients analized ( n 419)
Patients excluded from analysis (n = 0) 16

17. Clinical Characteristics
Bivalirudin group
(N= 418)
UFH Group
(N=419) P
Age, yrs (mean  SD)
78  4
0.89
Female, %
210 (50.5%)
186 (44.5%)
0.09
BMI (kg/m2)
28 4
27  4
0.25
LVEF, % (mean  SD)
49  9
50  8
0.07
Prior MI
Prior PCI
Prior CABG
181 (42%)
143 (34%)
55 (13.2%)
158 (38%)
150 (36%)
57 (13.6%)
0.10
0.63
0.85
eGFR (ml/min/1.73 m2)
GFR <60
66±25
179 (42.8%)
64±24
204 (48.7%)
0.20
Diabetes mellitus
Insulin-treated
189 (45.2%)
88 (21%)
181 (43%)
69 (16%)
0.56
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
543
60 (11%)
204 (37.5%)
228 (42%)
51 (9.5%)
544
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%)
46 (11%)
100 (24%)
0.94
0.84
0.98
0.73
0.80
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  0.53
0.52  0.37
83  10
17  10
3.06  0.56
0.56  0.37
82  10
18  9
0.87
0.12
0.19
0.60
Post-procedural QCA
3.23  0.52
3.19  0.52
2  3
3.22 0.57
3.17  0.58
2  5
0.88
0.63
0.40
Stent/patient
1.3  0.8
1.3  0.9
0.57
Stent length, mm
29  18
30  18
0.24
Max inflation pressure, atm
18  5
19  5
0.44
BA ratio
1.02  0.14
1.00  0.19
0.45

21. Procedural Characteristics
Bivalirudin group
(N= 418)
UFH Group
(N=419) P
Radial approach
2 (0.5%)
0.99
Glycoprotein IIbIIIa inhibitors
5 (1.3%)
0.22
Volume of contrast media (ml)
177  83
170  79
0.26
Peak ACT value (seconds)
<250 seconds
483±187
10 (2.4%)
305±77
68 (16.2%)
<0.001
0.002

22. Primary endpoint Odds ratio = 1.28; 95% CI= 0.58-2.86 p = 0.54 3.3%
14/418
3,5
3,0
2.6%
14/418
2,5
11/419
2,0
16/146 %
1,5
1,0
0,5
0,0
UFH group
Bivalirudin group

23. Primary endpoint Major bleeding Bivalirudin group (N= 14/418)
UFH Group
(N= 11/419) P
Intracranial -
Intraocular
Retroperitoneal
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 % Entry-site Non entry-site UFH group
2,5
p = 0.80
2.1%
2,0
p = 0.10
7/418
9/419
1.7%
1.7%
7/418
7/418
1,5 %
1,0
0.5%
0,5
2/419
UFH group
Bivalirudin group
0,0
Entry-site
Non entry-site

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

26. All bleeding (major and minor)
10.0
Odds ratio = 0.88; 95% CI= ; p = 0.63
9.1%
9.0
8.1%
38/419
8.0
34/418 %
7.0
6.0
5.0
4.0
p = 1.00
6.0
5.2%
5.2%
5.0
p = 0.56
22/419
22/418
3.8%
4.0 %
16/419
2.9%
3.0
12/418
2.0
UFH group
1.0
Bivalirudin group
Entry-site
Non entry-site

27. Peak ACT & Bleeding Event yes Event no 365±151 364±150 355±141 316±86
380
365±151
364±150
355±141
360
340
Event yes
316±86
320
Event no
300
peak ACT (seconds)
280
260
240
220
200
Major bleeding
Major&Minor bleeding

28. Periprocedural Myocardial Infarction (TnI >5x ULN)25
21.5
21.8 20
90/419
91/418 % 15 10 5
UFH group
Bivalirudin group

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%)
0.50
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