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, PhDLaboratoy 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: 27672 Topol EJ. et al. Lancet 1999; 354: 20193 Bhatt DL. et al. JACC 2000; 35: 9224 Ryden L. et al. Eur Heart J 2007; 28: 885 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 plateletso is able to interfere with both circulating and clot-bound

thrombino 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: 272 Lev EI. et al. Thrombosis and Haemostasis 2006; 95: 4413 Sibbing D. et al. Eur Heart J 2008; 29: 15044 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: 19322 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 PatientsElective PCI

Biomarker negative

UFH + Tirofiban Bivalirudin alone

ASAClopidogrel

(loading dose 300 mg the day before procedure)

Elective PCI

30 day endpointsDeath, 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 group1

• 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 <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

Study Medications

0.75 bolus iv3

1.75/h infusion iv4

12 iv bolus0.15/min iv2

70 1mg/kg

Bivalirudin#

g/Kg

Tirofiban*

U/Kg

UF Heparin

1 Additional 20 U/Kg bolus if ACT <250 seconds2 Discontinued at 12 hours following the procedure3 Additional 0.3 mg/kg bolus if ACT < 250 seconds4 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

• Non-Q wave MI:o Periprocedural = CKMB 3X ULNo 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 consent25 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 10.312 (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 4.134.1

65.0 9.8

Bivalirudin alone(N=167)

0.360.340.690.531.000.930.730.52

0.570.53

0.890.82

0.52

P value

35 (35.1%)CKD*

28.7 4.6BMI (kg/m2)

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 DiabetesOral agentsInsulin

35.7Female, %

65.6 8.3

UFH +Tirofiban(N=168)

Age, yrs (mean SD)

* Estimated glomerular filtration rate <60 mL/min/1.73 m2

Clinical Characteristics

138 (82.6%)7.6 1.7

46 (27.8%)102 (60.8%)19 (11.4%)

Bivalirudin alone(N=167)

1.000.56

0.17

P value

139 (82.7%)Statin treatment7.4 1.4HbA1c, % (mean SD)

38 (22.8%)98 (58.6%)31 (18.5%)

UFH +Tirofiban(N=168)

SymptomsAsymptomaticStable anginaUnstable 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 0.691.15 0.4143 (25.8%)22 (13.2%)

167 (100%)135 (80.8%)

6 (3.6%)0

Bivalirudin alone(N=167)

0.840.110.25

0.380.110.650.100.87

0.94

P value

33 (19.4%)Direct stenting

70 (32.8%)Calcified lesions36 (17.2%)Bifurcation lesions

1.26 0.48No. treated lesion/patient1.13 0.36No. treated vessel/patient

138 (65.1%)Complex (B2/C) lesions

80 (42.2%)55 (28.9%)52 (27.6%)

3 (1.3%)

Target vesselLADCxRCALM

21 (12.5%)Multivessel stenting

168 (100%)141 (84.1%)

6 (3.6%)1 (0.6%)

UFH +Tirofiban(N=168)

Procedure strategyStentDESRotablatorDCA

Angiographic & Procedural Characteristics

0.204 (2.4%)7 (4.2%)Radial approach

0.620.13

0.0130.57

3.04 0.563.14 0.75

2 52.65 0.59

3.02 0.592.92 0.64

3 82.52 0.71

Postprocedural QCARVD, mmMLD, mmDS, %Acute gain, mm

8 (4.8%)1.00 0.19

15 423.2 12.0

1.4 0.9

2.89 0.530.48 0.33

85 818.9 9.2

Bivalirudin alone(N=167)

0.800.45

0.340.460.57

0.850.06

0.0130.45

P value

24.5 11.6Stent length, mm

1.02 0.14BA ratio

15 4Max inflation pressure, atm

7 (4.2%)Angiographic complications1

1.3 0.8Stent/patient

2.88 0.600.41 0.39

87 919.7 9.3

UFH +Tirofiban(N=168)

Preprocedural QCARVD, mmMLD, mmDS, %Lesion length, mm

1 Intraprocedural slow-flow, residual dissection, coronary rupture, side branch closure or compromise

Bleeding risk score*

10.7 12

31.534.1

31.7

38.1

19.622.2

0

10

20

30

40

50

UFH & Tirofibanmean risk score = 4.3±3.9

Bivalirudinmean risk score = 4.5±4.2

1risk ≤1.3%

2-6risk ≤1.8%

7-9risk ≤2.7%

10risk ≥5.0%

p = 0.68

* According to Nikolsky E. et al. Eur Heart J 2007; 28: 1936-45

% of case

30-day outcome

00Q-wave MI

0.6117 (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)

0.0180.6230.035

13 (7.7%)3 (1.8%)10 (6%)

BleedingMajorMinor

0Unplanned revasc

0.6121 (12.5%)MI

0Death

0.038

P value

35 (20.8%)

UFH +Tirofiban(N=168)

Net clinical outcome

P = 0.038

P = 0.035

P = 0.606

UFH plus tirofiban(n = 168)

Bivalirudin(n = 167)

OR, 0.517 95% CI, 0.284-0.940

OR, 0.793 95% CI, 0.402-1.564

OR, 0.21895% CI, 0.061-0.780

Risk score < 7n = 227 (67.8%)

Risk score ≥ 7n = 108 (32.2%)

UFH plus tirofiban(n = 168)

Bivalirudin(n = 167)

P= 0.472

P= 0.007

OR, 0.49895% CI, 0.436-0.569

OR, 0.73695% CI, 0.413-1.311

6.8%(n=8/117)

0%(n= 0/110)

9.8%(n=5/57)

5.3%(n=3/51)

0

2

4

6

8

10

12

14

%

Low Risk Moderate - 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.