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

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 InterestDisclosure 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 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

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

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: 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

UF Heparin Tirofiban* Bivalirudin#

U/Kg g/Kg mg/kg

70 112 iv bolus

0.15/min iv2

0.75 bolus iv3

1.75/h infusion iv4

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: 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.

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

UFH +Tirofiban(N=168)

Bivalirudin alone(N=167)

P value

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%) 0.53Treatment of Diabetes Oral agents Insulin

116 (69%)52 (31%)

126 (75.4%)41 (24.6%)

0.57

Hypertension, % 131 (78%) 125 (74.9%) 0.52Hyperlipidemia, % 109 (64.9%) 105 (62.9%) 0.73Current smoker, % 35 (20.8%) 34 (20.4%) 0.93Prior MI, % 75 (44.6%) 75 (44.9%) 1.00Prior PCI, % 41 (24.4%) 46 (27.5%) 0.53Prior CABG, % 15 (8.9%) 12 (7.2%) 0.69LVEF, % (mean SD) 55.9 10.0 54.9 10.3 0.34CKD* 35 (35.1%) 67 (40.4%) 0.36

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

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 0.56Statin treatment 139 (82.7%) 138 (82.6%) 1.00

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%) 0.87Direct stenting 33 (19.4%) 43 (25.8%) 0.10No. treated vessel/patient 1.13 0.36 1.15 0.41 0.65No. treated lesion/patient 1.26 0.48 1.39 0.69 0.11Target 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%) 0.25Bifurcation lesions 36 (17.2%) 54 (23.3%) 0.11Calcified lesions 70 (32.8%) 79 (33.9%) 0.84

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 0.600.41 0.39

87 919.7 9.3

2.89 0.530.48 0.33

85 818.9 9.2

0.850.06

0.0130.45

Postprocedural QCA RVD, mm MLD, mm DS, % Acute gain, mm

3.02 0.592.92 0.64

3 82.52 0.71

3.04 0.563.14 0.75

2 52.65 0.59

0.620.13

0.0130.57

Stent/patient 1.3 0.8 1.4 0.9 0.57Stent length, mm 24.5 11.6 23.2 12.0 0.46Max inflation pressure, atm 15 4 15 4 0.34Radial approach 7 (4.2%) 4 (2.4%) 0.20BA ratio 1.02 0.14 1.00 0.19 0.45Angiographic complications1 7 (4.2%) 8 (4.8%) 0.80

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

% o

f ca

se

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 0Bleeding Major Minor

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

3 (1.8%)1 (0.6%)2 (1.2%)

0.0180.6230.035

12.5

10.2

7.7

1.8

20.8

12.0

0

5

10

15

20

25

30

%

Non Q-waveMI

Bleeding CompositeEnd Point

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.