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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
   I, Giuseppe De Luca
Do not have any conflict of interest
PERIPROCEDURAL MYONECROSIS / INFARCTION




                          Myocardial ischemia /
    Distal embolization
                          coronary vasospasm




    Reperfusion injury    Side branch Loss




                                      PREVENT-ICARUS
        Prevention of periprocedural
                Myonecrosis

• Glycoprotein IIb-IIIa
• Verapamil
• Nitroprussiate                  DRUGS

• Nicorandil
• Adenosine


•Distal/proximal protection devices
                                      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 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

                                           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

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.




                                         PREVENT-ICARUS
          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)
                        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.
                      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
                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.
                   Study Flow Chart
                     260 patients undergoing elective angioplasty




            IC PLACEBO                                         120-180 μg
0 h                                                           IC Adenosine
             (N = 130)
PCI                                                             (N = 130)




6 h                              Cardiac enzymes




12 h                             Cardiac enzymes




 Hospital                        Clinical outcome
discharge
                             Patients’ characteristics
           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
                              Angiographic 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
                            Procedural characteristics and results
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




                                                            PREVENT-ICARUS
                                    Primary End-point
                                                                    Adenosine

                                                                    Placebo

                               80            p = 0.69
Troponin I > 3 times ULN (%)




                               75
                                                        70
                               70          67.7
                               65
                               60
                               55
                               50
                               45
                               40
                                                             PREVENT-ICARUS
                                       Secondary End-point
                                                                        Adenosine

                                                                        Placebo


                                  60
                                                  p = 0.063
                                               54.6
                                  55
             > 10 Times ULN (%)




                                  50
                                                         43.1
Troponin I




                                  45
                                  40
                                  35
                                  30
                                  25
                                  20
                                                                PREVENT-ICARUS
                                    Secondary End-point
                                                                        Adenosine

                                                                        Placebo
CK-MB mass > 3 times ULN (%)


                               20
                               18
                               16                 p = 0.55
                               14
                                           12.3
                               12                            10
                               10
                                8
                                6
                                4
                               2
                               0
                                                                  PREVENT-ICARUS
                     Secondary End-point
                                                       Adenosine

                                                       Placebo

                20
                18                P = 0.21
                16
cTFC (Frames)




                                             13
                14         11.4
                12
                10
                 8
                 6
                 4
                 2
                 0
                                                  PREVENT-ICARUS
                           Secondary End-point
                                                             Adenosina

                                                             Placebo

                      20
PeriMI and uTVR(%)




                      18
 In-Hospital Death,




                      16                          p = 0.44
                      14                          13.1
                      12
                                                      10
                      10
                       8
                       6               p = 0.28
                       4     p = 1.0
                       2               1.5
                             0 0.8           0
                       0
                             Morte      uTVR       MACE
                                                       PREVENT-ICARUS
                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)

								
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