NAPLES Novel Approaches for Preventing or Limiting Event Study Randomised Comparison of Bivalirudin

1
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

2
Disclosure Statement of Financial Interest

• 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.

3
Background

• 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

1 Roffi M. et al. Circulation 2001 104 2767 2
Topol EJ. et al. Lancet 1999 354 2019 3 Bhatt
DL. et al. JACC 2000 35 922 4 Ryden L. et al.
Eur Heart J 2007 28 88 5 King SB. et al. JACC
2008 51 172
4
Background

• 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

1 Keating FK. et al. Thrombosis research 2004
113 27 2 Lev EI. et al. Thrombosis and
Haemostasis 2006 95 441 3 Sibbing D. et al. Eur
Heart J 2008 29 1504 4 Anand SX. et al. Am J
Cardiol 2007 100 417
5
Background

• 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

1 Gurm HS. et al. JACC 2005 45 1932 2 Feit F.
et al. JACC 2008 51 1645
6
Purpose

• 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

7
NAPLES

• DESIGN Prospective, randomized, double-arm,
  single-center clinical study

Diabetic Patients Elective PCI Biomarker negative
ASA Clopidogrel (loading dose 300 mg the day
before procedure)
Bivalirudin alone
UFH Tirofiban
Elective PCI
30 day endpoints Death, MI, IUR, ACUITY major
bleeding (net clinical outcome)
8
Sample size

• 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 lt0.05

1 REPLACE-2 trial - Lincoff AM, et al. JAMA 2003
289 853
9
Inclusion criteria

• Diabetes mellitus treated by insulin and/or oral
  agents
• Age ?18 y
• De novo lesion in a native coronary artery
• Elective PCI

10
Exclusion criteria

• Primary or rescue PCI
• ACS with elevated cardiac markers
• Pregnancy
• Recent (lt1 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 lt125.000/mm3
• History of heparin-induced thrombocytopenia
• Creatinine gt3.0 mg/dL or dialysis
• Recent (lt6 h) UFH or (lt12 h) GP IIb/IIIa use
• Oral anticoagulant use

11
Study Medications
Bivalirudin
Tirofiban
UF Heparin
mg/kg
?g/Kg
U/Kg
0.75 bolus iv3 1.75/h infusion iv4
12 iv bolus 0.15/min iv2
70 1
1 Additional 20 U/Kg bolus if ACT lt250 seconds 2
Discontinued at 12 hours following the
procedure 3 Additional 0.3 mg/kg bolus if ACT lt
250 seconds 4 Discontinued at end of PCI In eGFR
lt30 ml/kg/1.73 m2 the dose was halved In eGFR
lt30 ml/kg/1.73 m2 , the infusion rate was reduced
to 1 mg/kg/h
12
Definitions

• 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 gt5cm, Hgb drop gt3g/dL with source or
  gt4g/dL without source, transfusion gt2 units of
  packed red blood cells pr whole blood
• Minor bleeding
• Clinically overt bleeding not meeting criteria
  for major bleeding.

13
Patients assessed for eligibility (n366)
Excluded (n31) 6 withdrew consent 25 did not
meet the inclusion criteria
335 patients randomized
168 allocated to UFH plus tirofiban group
167 allocated to Bivalirudin group
14
Clinical Characteristics
Bivalirudin alone (N167)
P value
UFH Tirofiban (N168)
65.0 ? 9.8
0.52
65.6 ? 8.3
Age, yrs (mean ? SD)
34.1
0.82
35.7
Female,
28.7 ? 4.1
0.89
28.7? 4.6
BMI (kg/m2)
44 (26.3)
0.53
39 (23.2)
Family history for CAD
126 (75.4) 41 (24.6)
0.57
116 (69) 52 (31)
Treatment of Diabetes Oral agents Insulin
125 (74.9)
0.52
131 (78)
Hypertension,
105 (62.9)
0.73
109 (64.9)
Hyperlipidemia,
34 (20.4)
0.93
35 (20.8)
Current smoker,
75 (44.9)
1.00
75 (44.6)
Prior MI,
46 (27.5)
0.53
41 (24.4)
Prior PCI,
12 (7.2)
0.69
15 (8.9)
Prior CABG,
54.9 ? 10.3
0.34
55.9 ? 10.0
LVEF, (mean ? SD)
67 (40.4)
0.36
35 (35.1)
CKD
Estimated glomerular filtration rate lt60
mL/min/1.73 m2
15
Clinical Characteristics
Bivalirudin alone (N167)
P value
UFH Tirofiban (N168)
46 (27.8) 102 (60.8) 19 (11.4)
0.17
38 (22.8) 98 (58.6) 31 (18.5)
Symptoms Asymptomatic Stable angina Unstable
angina
7.6 ? 1.7
0.56
7.4 ? 1.4
HbA1c, (mean ? SD)
138 (82.6)
1.00
139 (82.7)
Statin treatment
16
Angiographic Procedural Characteristics
Bivalirudin alone (N167)
P value
UFH Tirofiban (N168)
167 (100) 135 (80.8) 6 (3.6) 0
0.94
168 (100) 141 (84.1) 6 (3.6) 1 (0.6)
Procedure strategy Stent DES Rotablator DCA
22 (13.2)
0.87
21 (12.5)
Multivessel stenting
43 (25.8)
0.10
33 (19.4)
Direct stenting
1.15 ? 0.41
0.65
1.13 ? 0.36
No. treated vessel/patient
1.39 ? 0.69
0.11
1.26 ? 0.48
No. treated lesion/patient
90 (46.8) 55 (28.8) 42 (21.9) 5 (2.6)
0.38
80 (42.2) 55 (28.9) 52 (27.6) 3 (1.3)
Target vessel LAD Cx RCA LM
139 (59.7)
0.25
138 (65.1)
Complex (B2/C) lesions
54 (23.3)
0.11
36 (17.2)
Bifurcation lesions
79 (33.9)
0.84
70 (32.8)
Calcified lesions
17
Angiographic Procedural Characteristics
Bivalirudin alone (N167)
P value
UFH Tirofiban (N168)
2.89 ? 0.53 0.48 ? 0.33 85 ? 8 18.9 ? 9.2
0.85 0.06 0.013 0.45
2.88 ? 0.60 0.41 ? 0.39 87 ? 9 19.7 ? 9.3
Preprocedural QCA RVD, mm MLD, mm DS, Lesion
length, mm
0.62 0.13 0.013 0.57
3.04 ? 0.56 3.14 ? 0.75 2 ? 5 2.65 ? 0.59
3.02 ? 0.59 2.92 ? 0.64 3 ? 8 2.52 ? 0.71
Postprocedural QCA RVD, mm MLD, mm DS, Acute
gain, mm
1.4 ? 0.9
0.57
1.3 ? 0.8
Stent/patient
23.2 ? 12.0
0.46
24.5 ? 11.6
Stent length, mm
15 ? 4
0.34
15 ? 4
Max inflation pressure, atm
0.20
4 (2.4)
7 (4.2)
Radial approach
1.00 ? 0.19
0.45
1.02 ? 0.14
BA ratio
8 (4.8)
0.80
7 (4.2)
Angiographic complications1
1 Intraprocedural slow-flow, residual dissection,
coronary rupture, side branch closure or
compromise
18
Bleeding risk score
?1 risk 1.3
2-6 risk 1.8
7-9 risk 2.7
?10 risk 5.0
50
38.1
40
34.1
31.5
31.7
30
p 0.68
22.2
of case
19.6
20
12
10.7
10
0
Bivalirudin mean risk score 4.54.2
UFH Tirofiban mean risk score 4.33.9
According to Nikolsky E. et al. Eur Heart J
2007 28 1936-45
19
30-day outcome
Bivalirudin alone (N167)
P value
UFH Tirofiban (N168)
20 (12)
0.038
35 (20.8)
Net clinical outcome
0
0
Death
17 (10.2)
0.61
21 (12.5)
MI
0
0
Q-wave MI
0.61
17 (10.2)
21 (12.5)
Non Q-wave MI
0
0
Unplanned revasc
3 (1.8) 1 (0.6) 2 (1.2)
0.018 0.623 0.035
13 (7.7) 3 (1.8) 10 (6)
Bleeding Major Minor
20
P 0.038
OR, 0.517 95 CI, 0.284-0.940
P 0.606
OR, 0.793 95 CI, 0.402-1.564
P 0.035
OR, 0.218 95 CI, 0.061-0.780
UFH plus tirofiban (n 168)
Bivalirudin (n 167)
21
14
P 0.472
OR, 0.736 95 CI, 0.413-1.311
12
9.8
P 0.007
(n5/57)
10
OR, 0.498 95 CI, 0.436-0.569
8
6.8
(n8/117)

5.3
6
(n3/51)
4
2
0
(n 0/110)
0
Low Risk
Moderate - High Risk
Risk score lt 7 n 227 (67.8)
Risk score 7 n 108 (32.2)
UFH plus tirofiban (n 168)
Bivalirudin (n 167)
22
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.