naples novel approaches for preventing or limiting event study randomised comparison of bivalirudin...
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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.