NAPLES Novel Approaches for Preventing or Limiting Event Study Randomised 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
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NAPLES Novel Approaches for Preventing or Limiting Event Study Randomised Comparison of Bivalirudin Monotherapy versus Unfractionated Heparin plus Tirofiban.
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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, 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
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
• 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
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.