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)