Diapositiva 1

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PRevEntion of cardiac and Vascular pEriprocedural
complications in patients undergoiNg coronary
angiography or angioplasTy IntraCoronary
Adenosine administration to prevent
peRiprocedUral myonecrosiS in elective coronary
angioplasty. A prospective double-blind
randomized trial (PREVENT ICARUS) trial.
ClinicalTrials.gov NCT01148147
Giuseppe De Luca, MD, PhD Aggregate Professor of
Cardiology Chief Interventional
Cardiology Eastern Piedmont University Novara
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I, Giuseppe De Luca

• Do not have any conflict of interest

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PERIPROCEDURAL MYONECROSIS / INFARCTION
Myocardial ischemia / coronary vasospasm
Distal embolization
Reperfusion injury
Side branch Loss
PREVENT-ICARUS
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• Prevention of periprocedural Myonecrosis
• Glycoprotein IIb-IIIa
• Verapamil
• Nitroprussiate
• Nicorandil
• Adenosine
• Distal/proximal protection devices

DRUGS
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Adenosine Receptor A1 Responsible for AV
block Receptor A2A Microcirculation
Vasodilatation Receptor A2B Broncospasm Recepto
r A3 Inhibiton of neutrophil degranulation
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• Pharmacological effects of Adenosine
• Inhibition of platelet aggregation and thrombus
  formation
• Inhibition of activation and accumulation of
  neutrophils, and their adhesion to endothelial
  cells
• Reduction of calcium overloading and formation
  of Oxigen free radicals
• Vasodilatation of microcirculation
• Ischemic preconditioning

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• Previous trials in elective patients
• Desmet et al Pilot study ADELINE, 28 pts
  adenosine ev -gt Reduction in CK-MB
• Lee et al Randomized trials with 62 pts ic
  Bolus (50 µg) of adenosine before elective
  angioplasty -gt significant reduction in
  myonecrosis (39 vs 13)
• Limitation
• 1) Open label design
• 2) Small dimension
• 3) Low-dose intracoronary adenosine
• 4) No overall difference in periprocedural MI as
  defined by 3 times increase in CK-MB

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Aim of the Study
To evaluate the adjunctive benefits of high-dose
intracoronary adenosine administration as
compared to placebo to prevent periprocedural
myonecrosis in patients undergoing elective
coronary angioplasty.
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METHODS
This is a single center, double blind randomized
trial. Patients undergoing elective coronary
angioplasty were randomly assigned (11) through
sealed envelops to Placebo or Adenosine
administrated intracoronary through the guiding
catheter.
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Exclusion criteria

• Marked Bradycardia (lt 40 bpm)
• Previous allergy to adenosine
• Inability to sign the informed consent
• Asthma
• Elevated cardiac enzymes (troponin I o CK-MB)

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METHODS
After knowing the treatment arm, a nurse not
involved in the revascularization procedure
prepared adenosine (diluted to 10 ml with 0.9
NaCl solution, at a concentration of 60 ug/ml) or
placebo (10 ml 0.9 NaCl solution), both
contained in a 10 cc syringe. Study drug
(Adenosine) or placebo were administrated
intracoronary through the guiding catheter at the
dose of 120 ug (2 ml) (right coronary artery) and
180 ug (3 ml) (left coronary artery),
respectively. In case of chronically occluded
vessel, randomization was performed after initial
dilatation, with al least antegrade TIMI 2 flow.
Patients were clinically followed from hospital
admission up to discharge.
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• Study Endpoints
• Primary study endpoint
• Periprocedural increase in troponin I (gt 3 times
  the upper normal limit).
• Secondary study endpoints
• Angiographic coronary flow, as evaluated by
  corrected TIMI frame count
• 2) Increase in Troponin I gt 10 times ULN
• 3) Increase in CK-MB mass gt 3 times ULN
• 4) Cumulative in-hospital incidence of death,
  periprocedural MI, urgent target-vessel
  revascularization.
• Safety endpoint
• Incidence of bradycardia and ventricular
  arrhythmias during study drug administration.

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Study Hypothesis
According to an expected 15 absolute reduction
(60 relative reduction) in the incidence of
periprocedural myonecrosis with intracoronary
adenosine as compared to placebo (from 25 to
10), with an anticipated two sided test for
differences in independent binomial proportions
at the 5.0 and a statistical power of 80, a
total 112 patients per group were needed. In
order to avoid any drop out, the enrolment was
extended up to 130 patients per group.
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Study Flow Chart
Hospital discharge
Clinical outcome
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Patients characteristics
Variable ADENOSINE (N 130) PLACEBO (N 130) p value
Baseline clinical and demographic characteristics Baseline clinical and demographic characteristics Baseline clinical and demographic characteristics Baseline clinical and demographic characteristics
Age (mean SD) 68 11 69 10 0.89
Male Sex () 71.5 78.5 0.2
Diabetes () 32.3 31.8 0.93
Hypercolesterolemia () 62.3 58.5 0.53
Smoking () 21.1 31.5 0.07
Family hystory CAD () 30 30.8 0.89
Chronic Renal Failure () 20 15.4 0.33
Hypertension () 76.9 75.4 0.77
Previous MI () 29.5 31.5 0.72
Previous PCI () 30 25.4 0.41
Previous CABG () 6.9 11.5 0.2
Previous CVA () 9.2 10.1 0.82
Indication for angiography Indication for angiography Indication for angiography 0.13
Stable angina () 43.1 37.7
CMPD o Valvular heart disease () 6.9 14.6
ACS () 50 47.7
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Patients characteristics
Variable ADENOSINE (N 130) PLACEBO (N 130) p value
Biochemistry Biochemistry Biochemistry Biochemistry
Glyaceamia 137 61 131 52 0.45
Creatinin 1.14 0.64 1.1 0.34 0.52
Platelet count 216 62 213 54 0.71
WBC 7.32 1.72 7.78 5.32 0.35
Hb 13.5 1.7 13.6 1.7 0.67
Therapy at admission Therapy at admission Therapy at admission Therapy at admission
Statines () 66.2 63.8 0.7
ASA () 73.8 79.2 0.31
Nitrates () 48.5 56.2 0.21
Beta-blockers () 66.9 62 0.41
Ace-Inibitors () 44.6 47.3 0.67
ARB () 20.8 24.8 0.44
Diuretics () 33.8 29.5 0.45
Ca-antagonists () 27.1 25.4 0.75
Clopidogrel () 37.7 33.1 0.44
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Angiographic characteristics
Variable ADENOSINE (N 130) PLACEBO (N 130) p value
Target Vessel Target Vessel Target Vessel 0.46
Left main () 0.6 1.2
LAD () 37 30.3
LCx () 30.9 27.3
RCA () 27.9 34.5
AL () 1.2 2.4
GRAFT () 2.4 4.2
Multivessl disease () 60.5 57.4 0.61
2 treated lesions () 25.6 20.2 0.3
Multivessel PCI () 11.5 13.8 0.58
Type C Lesion () 15.2 22.4 0.091
Lesion lenght (mm) 18.6 10.5 18.1 11.4 0.67
stenosis (mean SD) 85.8 11.8 89.1 9.31 0.005
Reference diameter (mm) 3.05 0.78 3.21 1.44 0.24
Calcifications() 23 10.3 0.002
Bifurcation() 15.6 20.6 0.25
Thrombus visible () 3 0.6 0.21
Total Chronic occlusion () 1.2 6.1 0.035
In-stent restenosis () 7.3 9.1 0.55
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Procedural characteristics and results
Variable ADENOSINE (N 130) PLACEBO (N 130) PLACEBO (N 130) p value
Preprocedural TIMI flow () Preprocedural TIMI flow () Preprocedural TIMI flow () Preprocedural TIMI flow () 0.038
TIMI 3 () 95.2 95.2 90.9
TIMI 2 () 3 3 1.2
TIMI 1 () 0 0 1.8
TIMI 0 () 1.8 1.8 6.1
GP IIb-IIIa Inhibitors () 35.2 35.2 40.6 0.36
Clopidogrel loading dose gt 4h () 43.4 43.4 41.7 0.79
Stenting Stenting Stenting Stenting 0.2
No () 1.2 1.2 4.2
Direct () 31.5 31.5 26.7
Predilatation () 67.3 67.3 69.1
DES () 52.8 52.8 51.3 0.79
Max balloon dilatation (atm) 20.6 3.5 20.6 3.5 20.5 3.5 0.71
Postdilatation () 77.6 77.6 75.8 0.7
n stent / patients 1.3 0.64 1.3 0.64 1.23 0.26 0.66
Multiple overlapping stent () 14.5 14.5 13.3 0.75
Total stent lenght 23.6 13.8 23.6 13.8 23.5 15.3 0.9
Maximum stent diameter 3.11 0.55 3.11 0.55 3.16 0.58 0.42
Residual thrombus () 0 0 0.6 1.0
Distal embolization () 0.6 0.6 1.2 1.0
Loss of Side brach gt 2 mm 0 0 3 0.06
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Procedural characteristics and results
Variable ADENOSINE (N 130) PLACEBO (N 130) p value
Postprocedural TIMI flow () Postprocedural TIMI flow () Postprocedural TIMI flow () 0.18
TIMI 3 () 99.4 97
TIMI 2 () 0 1.8
TIMI 1 () 0 0
TIMI 0 () 0.6 1.2
IABP () 0 0.6 1
Thrombectomy() 0 0.6 1
Distal protection () 0 1.2 0.5
Procedural success () 99.4 97 0.6
Adenosine () 100 0.6 lt0.00001
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Primary End-point
Adenosine
Placebo
p 0.69
70
67.7
Troponin I gt 3 times ULN ()
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Secondary End-point
Adenosine
Placebo
p 0.063
54.6
43.1
Troponin I gt 10 Times ULN ()
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Secondary End-point
Adenosine
Placebo
p 0.55
12.3
10
CK-MB mass gt 3 times ULN ()
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Secondary End-point
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Secondary End-point
Adenosina
Placebo
p 0.44
13.1
In-Hospital Death, PeriMI and uTVR()
10
p 0.28
p 1.0
1.5
0.8
0
0
Morte
uTVR
MACE
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Safety Profile 13 cases (10) of transient
(2-4 seconds) AV block, clinically irrilevant (p
lt 0.001 vs placebo).
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CONCLUSIONS
Our randomized trial showed that preprocedural
intracoronary administration of a single
high-dose bolus of adenosine does not provide any
benefit in terms of periprocedural myonecrosis in
patients undergoing elective coronary
angioplasty.
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However beautiful the strategy, you should
occasionally look at the results (Winston
Churcill)