ARNO TRIAL (Antithrombotic Regimens aNd Outcome)

1
ARNO TRIAL (Antithrombotic Regimens aNd
Outcome)
A RANDOMIZED TRIAL COMPARING BIVALIRUDIN WITH
UNFRACTIONED HEPARIN IN PATIENTS UNDERGOING
ELECTIVE PCI
David Antoniucci, TCT 2008, Washington DC
2
Discolusure Information David Antoniucci Nothing
to Disclose
3
ARNO TRIAL
STUDY ORGANIZATION Steerin
g committee D. Antoniucci (PI), G. Parodi, A.
Migliorini, R. Valenti Sponsors Antithrombotic
Regimen aNd Outcome (ARNO) trial
Investigators Site Division of Cardiology,
Careggi Hospital, Florence, Italy Clinical event
committee G. Moschi, U. Signorini, B.
Bellandi Data safety monitoring board G.
Cerisano, P. Buonamici. This trial is registered
with Clinical Trials.gov (NCT00448461).
4
ARNO TRIAL

• BACKGROUND (1)
• Three large randomized trials comparing
  bivalirudin with unfractionated heparin plus
  routine use of GPI have shown that bivalirudin
  may decrease bleeding complications without
  significant increase in ischemic complications
  resulting in a better net clinical outcome.
• These studies however did not compare directly
  the 2 anticoagulant drugs, but 2 different
  antithrombotic strategies that included in the
  heparin arms the routine use of GPI with the
  associated and expected increase in bleeding
  complications.

5
ARNO TRIAL

• BACKGROUND (2)
• As compared to heparin, bivalirudin has 2 major
  advantages in terms of bleeding risk, a highly
  predictable anticoagulant effect at a
  standardized dose, and the short duration of the
  anticoagulant effect. The latter can be cancelled
  by the neutralization of heparin by protamine at
  the end of the procedure.
• It is unknown if bivalirudin is still superior
  to unfractionated heparin plus protamine in
  patients undergoing elective PCI.

6
ARNO TRIAL

• The aim of this randomized study is to determine
  if bivalirudin is still superior to
  unfractionated heparin plus protamine in
  patients undergoing elective PCI.
• All patients undergoing PCI and pretreated with
  aspirin (325 mg), and a 600 mg loading dose of
  clopidogrel at least 6 hours before PCI were
  considered eligible for enrolment.

7
ARNO TRIAL

• EXCLUSION CRITERIA
• PCI of chronic total occlusion.
• Renal insufficiency
• (GFR lt 30 ml/min or baseline creatinine value gt
  3 mg/dl).
• Known allergy to the study medications (aspirin,
  clopidogrel, unfractionated heparin, bivalirudin,
  protamine).
• Others (active bleeding, bleeding diathesis,
  recent bleeding, severe comorbid conditions,
  relevant baseline hematological deviations, age lt
  18 yrs, pregnancy).

8
ARNO TRIAL

• 
  TREATMENTS
• Aspirin (325 mg) and clopidogrel (600 mg loading)
  at least 6 hours
• before PCI in all patients. Abciximab on a
  provisional basis.
• Heparin group 100 IU per kg of body weight with
  or without
• additional boluses to achieve an ACT of 250 to
  300 seconds. Protamine 0.5 mg per 100 IU of
  heparin utilized.
• Bivalirudin group bolus of 0.75 mg/kg followed
  by infusion of
• 1.75 mg/kg per hour for the duration of the
  procedure.
• Immediate post-PCI sheath removal and routine use
  of closure
• devices in all patients.

9
ARNO TRIAL

• END POINTS
• Primary in-hospital major bleeding
• (REPLACE 2 definition).
• Secondary 1) 30-day composite of death, MI,
  TVR.
• 2) 30-day net clinical
  outcome
  (death/MI/TVR or major bleeding).
• 3) 30-day minor bleeding.
• 4) Vascuular
  complications.
• 5) Six-month outcome.

10
ARNO TRIAL

• SAMPLE SIZE
• Hypothesis bivalirudin is superior to
  unfractionated heprin in terms of major bleeding
  in elective PCI.
• Assumptions Major bleedingg in heparin group 6
• Major bleeding in the
  bivalirudin group 2
• Power 90 with an
  a-level of 0.05
• Needed number of patients 850 (425 for each
  group).

11
ARNO TRIAL
BASELINE CHARACTERISTICS
(1)
Bivalirudin Heparin
p
(n425) (n425)
value Age, yrs
68.7 10.6 69.1 10.6
NS Male
77.4 75.1
NS Diabetes
21.5 22.2 NS
Hypertension 58.9
61.2 NS Smoker
18.0
16.9 NS Previous MI
40.7
38.1 NS Prior CABG
9.9 7.7
NS LVEF
48 12 46 12
NS BMI, Kg/m2 26.5
3.1 26.1 3.4
NS Creatinine, mg/dL 0.99 0.62
1.02 0.76 NS
12
ARNO TRIAL
BASELINE CHARACTERISTICS
(2)
Bivalirudin Heparin
p
(n425) (n425)
value Stable angina 44.7
40.2 NS Unstable angina 27.5
26.3 NS Raised troponin I
14.6 18.6 NS MVD
53.1 58.5 NS
13
ARNO TRIAL
PROCEDURAL
CHARACTERICS
Bivalirudin Heparin
p
(n425)
(n425) value Femoral access
98.3 97.6
NS No. lesion/patients 1.6 0.9
1.6 0.9 NS Stenting
84.7 87.8
NS No. stent/patient 1.5 1.2
1.6 1.1 NS IABP
0.7
0.5 NS Abciximab
14.6 27.6
0.0001 Closure device 90.9
90.1 NS
14
ARNO TRIAL

• ONE-MONTH OUTCOME - BLEEDING
• 
  
• 
  Bivalirudin Heparin
  p
• 
  (n425) (n425)
  value
• Major bleeding
• in-hospital 2 (0.5)
  9 (2.1) 0.033
• one-month 4 (0.9)
  12 (2.8) 0.043
• gt 3gr/dL overt source, n 2
  3
• gt 4gr/dL, n
  0 3
• blood transfusion, n
  2 6
• Minor bleeding 2.4
  2.4 NS

15
ARNO TRIAL
ONEMONTH OUTCOME

Bivalirudin Heparin
p
(n 425) (n 425)
value Death/MI/TVR 12 (2.8)
27 (6.4) 0.014 Death
1 (0.2) 6
(1.4) 0.057 MI
11 (2.4) 20 (4.5)
0.098 Q-wave 1
1 TVR
2 (0.4) 3 (0.7)
0.411 NCO 14
(3.3) 33 (8.0) 0.004 Definite
stent thrombosis 2 (0.5) 1 (0.3)
acute 1
0 subacute
1 1
16
Study 30-Day End Points
Bivalirudin
UFH
Incidence ()
P 0.004
P 0.014
P 0.043
17
ARNO TRIAL
CONCLUSIONS In this
randomized trial of patients undergoing elective
PCI and pre-treated with aspirin and clopidogrel,
bivalirudin compared to unfractionated heparin
plus protamine resulted in a significant
reduction of major bleeding, of the composite of
death, MI, TVR, and in a better net clinical
outcome.