prevention of cardiac and vascular periprocedural complications in patients undergoing coronary...
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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.
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.
Giuseppe De Luca, MD, PhD
Aggregate Professor of CardiologyChief Interventional Cardiology
Eastern Piedmont UniversityNovara
ClinicalTrials.gov NCT01148147
I, Giuseppe De Luca
Do not have any conflict of interest
Distal embolization
Side branch LossReperfusion injury
Myocardial ischemia /
coronary vasospasm
PERIPROCEDURAL MYONECROSIS / INFARCTION
PREVENT-ICARUS
Prevention of periprocedural Myonecrosis
• Glycoprotein IIb-IIIa
• Verapamil
• Nitroprussiate
• Nicorandil
• Adenosine
•Distal/proximal protection devices
DRUGS
PREVENT-ICARUS
Adenosine
Receptor A1 :Responsible for AV block
Receptor A2A: Microcirculation Vasodilatation
Receptor A2B: Broncospasm
Receptor A3: Inhibiton of neutrophil
degranulation
PREVENT-ICARUS
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
PREVENT-ICARUS
Previous trials in elective patients
• Desmet et al: Pilot study ADELINE, 28 pts; adenosine ev -> Reduction in CK-MB
•Lee et al: Randomized trials with 62 pts; ic Bolus (50 μg) of adenosine before elective angioplasty -> significant reduction in myonecrosis (39% vs 13%)
Limitation 1) Open label design2) Small dimension 3) Low-dose intracoronary adenosine 4) No overall difference in periprocedural MI as defined by 3 times increase in CK-MB
PREVENT-ICARUS
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.
PREVENT-ICARUS
METHODS
PREVENT-ICARUS
This is a single center, double blind randomized trial.
Patients undergoing elective coronary angioplasty were randomly assigned (1:1) through sealed
envelops to Placebo or Adenosine administrated intracoronary through the guiding catheter.
Exclusion criteria
1) Marked Bradycardia (< 40 bpm) 2) Previous allergy to adenosine 3) Inability to sign the informed consent 4) Asthma 5) Elevated cardiac enzymes (troponin I o
CK-MB)
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.
METHODS
Study Endpoints
Primary study endpoint: Periprocedural increase in troponin I (> 3 times the upper normal limit).
Secondary study endpoints:1) Angiographic coronary flow, as evaluated by corrected TIMI frame
count; 2) Increase in Troponin I > 10 times ULN; 3) Increase in CK-MB mass > 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.
PREVENT-ICARUS
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.
Study Hypothesis
260 patients undergoing elective angioplasty
IC PLACEBO(N = 130)
0 hPCI
12 h
6 h
120-180 μgIC Adenosine
(N = 130)
Cardiac enzymes
Cardiac enzymes
Study Flow Chart
Hospital discharg
e
Clinical outcome
Variable ADENOSINE (N = 130)
PLACEBO (N = 130)
p value
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 0.13
Stable angina (%) 43.1 37.7
CMPD o Valvular heart disease (%)
6.9 14.6
ACS (%) 50 47.7
Patients’ characteristics
Variable ADENOSINE (N = 130)
PLACEBO (N = 130)
p value
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
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
Patients’ characteristics
Variable ADENOSINE (N = 130) PLACEBO (N = 130)
p value
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
Angiographic characteristics
Variable ADENOSINE (N = 130) PLACEBO (N = 130) p value
Preprocedural TIMI flow (%) 0.038
TIMI 3 (%) 95.2 90.9
TIMI 2 (%) 3 1.2
TIMI 1 (%) 0 1.8
TIMI 0 (%) 1.8 6.1
GP IIb-IIIa Inhibitors (%) 35.2 40.6 0.36
Clopidogrel loading dose > 4h (%) 43.4 41.7 0.79
Stenting 0.2
No (%) 1.2 4.2
Direct (%) 31.5 26.7
Predilatation (%) 67.3 69.1
DES (%) 52.8 51.3 0.79
Max balloon dilatation (atm) 20.6 + 3.5 20.5 + 3.5 0.71
Postdilatation (%) 77.6 75.8 0.7
n° stent / patients 1.3 + 0.64 1.23 + 0.26 0.66
Multiple overlapping stent (%) 14.5 13.3 0.75
Total stent lenght 23.6 + 13.8 23.5 + 15.3 0.9
Maximum stent diameter 3.11 + 0.55 3.16 + 0.58 0.42
Residual thrombus (%) 0 0.6 1.0
Distal embolization (%) 0.6 1.2 1.0
Loss of Side brach > 2 mm 0 3 0.06
Procedural characteristics and results
Variable ADENOSINE (N = 130)
PLACEBO (N = 130)
p value
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 <0.00001
Procedural characteristics and results
PREVENT-ICARUS
40
45
50
55
60
65
70
75
80
Tro
pon
in I
> 3
tim
es U
LN
(%
)
67.770
p = 0.69
Adenosine
Placebo
Primary End-point
PREVENT-ICARUS
20
25
30
35
40
45
50
55
6054.6
43.1
p = 0.063
Adenosine
Placebo
Tro
pon
in I
> 1
0 T
imes
UL
N (
%)
Secondary End-point
PREVENT-ICARUS
0
2
4
6
8
10
12
14
16
18
20
12.310
p = 0.55
CK
-MB
mas
s >
3 t
imes
UL
N (
%)
Adenosine
Placebo
Secondary End-point
PREVENT-ICARUS
0
2
4
6
8
10
12
14
16
18
20
11.413
P = 0.21
cTF
C (
Fra
mes
)
Adenosine
Placebo
Secondary End-point
PREVENT-ICARUS
In-H
osp
ital
Dea
th,
Per
iMI
and
uT
VR
(%)
0
2
4
6
8
10
12
14
16
18
20
Morte uTVR
0.8 1.500
p = 1.0
13.1
10
MACE
Adenosina
Placebo
Secondary End-point
PREVENT-ICARUS
p = 0.28
p = 0.44
Safety Profile
13 cases (10%) of transient (2-4 seconds) AV block, clinically irrilevant (p < 0.001 vs placebo).
PREVENT-ICARUS
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.
PREVENT-ICARUS
However beautiful the strategy,
you should occasionally look at the results
(Winston Churcill)