NAPLES IIINovel 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, FSCAIClinica 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

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;53:2019-272 Rao SV. et al. Am Heart J 2008;155:369-743.Young E, et al. Thrombosis and Haemostasis 1992; 67:639-43.4. Sobel M et al. J Vasc Surg 2001;33:587-94

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:e442. Stone GW et al. JAMA 2007;298:24973. Stone GW, et al. N Engl J Med 2008;358:22184. Lincoff AM et al. JAMA 2003;298;853

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 Not specifically designed for high-risk bleeding patients

1. Kastrati et al. N Engl J Med 2008;359:688-962. Schultz S et al. Eur Heart J 2010;31:582-7

High risk bleeding patients

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

2

eGFR <60 mlmin1.73 m2 2

Risk

Score

Risk of Major Bleeding

0-1 1.3%

2-6 1.8%

7-9 2.3%

10 ≥5%

Nikolski E et al Eur Heart JEur Heart J 2007; 28:1936-45

eGFR = estimated glomerular filtration rate (ml/min/1.73m2) baseline haematocrit <39% for male and <36% for female; LMWH = low molecular weight heparin

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.

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)

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 bleedingIn-hospital major bleeding

Bivalirudin group UFH group

• 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; 28:1936-452. Kastrati A et al. N Engl J Med 2008;359:688-963. Schultz S et al. Eur Heart J 2010;31:582-7

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

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 <100.000/mm3

Bivalirudin groupBivalirudin group

NAPLES III trial

Bolus of 0.75 mg/kg i.v. prior to Bolus of 0.75 mg/kg i.v. prior to the start of the the start of the procedure, procedure, followed by followed by infusion of 1.75 mg/kg per hour for the infusion of 1.75 mg/kg per hour for the

duration of the procedureduration of the procedure

Additional bolus 0.3mg/Kg Additional bolus 0.3mg/Kg in case ACT <250 secin case ACT <250 sec

70 U/Kg i.v. prior to 70 U/Kg i.v. prior to start the procedurestart the procedure

Additional bolus 20 U/Kg Additional bolus 20 U/Kg in case ACT <250 secin case ACT <250 sec

UFH groupUFH group

• 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

• 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

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)

Enro

llem

ent

Allo

catio

nFo

llow

-up

Anal

ysis

Clinical Characteristics

Bivalirudin group(N= 418)

UFH Group(N=419)

P

Age, yrs (mean SD) 78 4 78 4 0.89Female, % 210 (50.5%) 186 (44.5%) 0.09BMI (kg/m2) 28 4 27 4 0.25LVEF, % (mean SD) 49 9 50 8 0.07Prior MIPrior PCIPrior CABG

181 (42%)143 (34%)55 (13.2%)

158 (38%)150 (36%)57 (13.6%)

0.100.630.85

eGFR (ml/min/1.73 m2) GFR <60

66±25179 (42.8%)

64±24204 (48.7%)

0.200.09

Diabetes mellitus Insulin-treated

189 (45.2%)88 (21%)

181 (43%)69 (16%)

0.560.10

Hypertension, % 350 (84%) 349 (83%) 0.86Symptoms Silent ischemia Stable angina Unstable angina

77 (18%)244 (68.4%)97 (23.2%)

76 (18%)250 (69.6%)93 (22.4%)

0.98

Procedural CharacteristicsBivalirudin 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

54360 (11%)

204 (37.5%)228 (42%)51 (9.5%)

544 60 (11%)

207 (38%)223 (41%)54 (10%)

0.84

Procedural CharacteristicsBivalirudin 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%)

0.940.840.980.730.80

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%) 171 (41%) 0.96

Procedural Characteristics

Bivalirudin group(N= 418)

UFH Group(N=419)

P

Pre-procedural QCA RVD, mm MLD, mm DS, % Lesion length, mm

3.06 0.530.52 0.37

83 1017 10

3.06 0.560.56 0.37

82 1018 9

0.870.120.190.60

Post-procedural QCA RVD, mm MLD, mm DS, %

3.23 0.523.19 0.52

2 3

3.22 0.573.17 0.58

2 5

0.880.630.40

Stent/patient 1.3 0.8 1.3 0.9 0.57Stent length, mm 29 18 30 18 0.24Max inflation pressure, atm 18 5 19 5 0.44BA ratio 1.02 0.14 1.00 0.19 0.45

Procedural Characteristics

Bivalirudin group(N= 418)

UFH Group(N=419)

P

Radial approach 2 (0.5%) 2 (0.5%) 0.99

Glycoprotein IIbIIIa inhibitors 2 (0.5%) 5 (1.3%) 0.22

Volume of contrast media (ml) 177 83 170 79 0.26

Peak ACT value (seconds) <250 seconds

483±18710 (2.4%)

305±7768 (16.2%)

<0.0010.002

Primary endpoint

16/146

Odds ratio = 1.28; 95% CI= 0.58-2.86 p = 0.54

2.6%

3.3% 14/418

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

UFH group Bivalirudin group

11/419

14/418

%

Primary endpoint

Major bleedingBivalirudin group

(N= 14/418)UFH Group(N= 11/419)

P

Intracranial 0 0 -

Intraocular 0 0 -

Retroperitoneal 0 0 -

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%) 4 (0.9%) 1.00

Primary endpoint

%

0,0

0,5

1,0

1,5

2,0

2,5

Entry-site Non entry-site

0.5%

2.1%

2/419

9/4191.7%7/418

1.7%

7/418

p = 0.10

p = 0.80

Bivalirudin group

UFH group

7/418

Secondary endpoint

Major bleedingBivalirudin 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

All bleeding(major and minor)

4.0

5.0

6.0

7.0

8.0

9.0

10.0 Odds ratio = 0.88; 95% CI= 0.55-1.44; p = 0.639.1%

8.1%38/419

34/418%

0

1.0

2.0

3.0

4.0

5.0

6.0

Entry-site Non entry-site

5.2%

3.8%22/419

16/419

5.2%

22/418

2.9%12/418

p = 1.00

p = 0.56

Bivalirudin group

UFH group

%

Peak ACT & Bleeding

316±86

p = 0.36 p = 0.77

200

220

240

260

280

300

320

340

360

380

Major bleeding

Event yes

Event no

365±151355±141 364±150

Major&Minor bleeding

peak

AC

T (

seco

nds)

Periprocedural Myocardial Infarction(TnI >5x ULN)

UFH group Bivalirudin group0

5

10

15

20

25

21.5 21.8

90/419 91/418

%

p = 0.93

Secondary endpoint30-day MACE

Bivalirudin group(N= 418)

UFH Group(N=419)

P

Major bleeding14 (3.3%) 11 (2.6%) 0.58

Death10 (2.4%) 6 (1.4%) 0.31

Myocardial infarction1 (0.2%) 0 0.50

Revascularization5 (1.2%) 3 (0.7%) 0.47

Stent thrombosis2 (0.5%) 2 (0.5%) 0.99

Composite27 (6.5%) 18 (4.3%) 0.17

Secondary endpoint1-year MACE

Bivalirudin group(N= 418)

UFH Group(N=419)

P

Death20 (4.8%) 21 (5.0%) 1.00

Myocardial infarction6 (1.7%) 2 (0.5%) 0.17

Revascularization30 (7.2%) 32 (7.6%) 0.89

Stent thrombosis4 (1.0%) 3 (0.7%) 0.71

Composite68 (16.3%) 62 (14.8%) 0.11

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 issueRadial approach should be routinely used in this subgroup of patients

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

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 CardiologyIRCCS Humanitas Hospital, Milan, Italy