Transcript Use of Adenosine for AMI Patients Undergoing Reperfusion Therapy

Information Storage
Information Retrieval
(Purine base in DNA)
(Purine base in RNA)
Intracellular
Signaling
Energy Metabolism
(ATP/ADP)
NH2
(cAMP)
N
N
Adenosine
N
N
HO
O
H
H
OH
OH
H
H
Communications
(Adenosine importantly directs cell-to-cell
signaling with significant consequences for
organ function.)
Adenosine Receptors: Signal
Transduction Mechanisms
(Low affinity)
A2B
A3
A1
A2A
(Very high affinity)
Gq/11
Gi/o
beta/gamma
alphai
Gs
(High affinity)
alphas
alphaq/11
K+
PLC
2+
Ca
Channels
Channels
(KATP)
AC
Subtypes have distinct, but
overlapping, cellular distribution
and are widely expressed in
most cells/tissues/organs
of the body.
Adenosine Production:
During A Crisis Event
CELL
ATP
ATP
ADP
ADP
AMP
AMP
ADO
ADO
Adenosine Production:
Constitutive
CELL
SAM
SAH
ADO
ADO
Adenosine Production: Regulated
CELL
cAMP
AMP
ADO
Autocrine
Paracrine
Heart: Protection from
reperfusion injury
Mervyn B. Forman, MD, PhD, FACC
Atlanta Cardiovascular Associates
1,000,000 Americans suffer a heart attack (AMI) annually
200,000 (20%) die during or soon after AMI
Survivors: up to 15-fold greater risk of death
Survivors: 22% of males and 46% of females
are disable by heart failure
TOO MUCH HEART DAMAGE
IN AFTERMATH OF AMI!!
Myocardial Reperfusion Injury
Angioplasty
(with or without stenting)
Thrombolytic
Therapy
Myocardial Reperfusion Injury
• Definition:
Conversion of reversibly injured
endothelial and myocardial cells to
irreversibly injured cells during the
peri-reperfusion period.
Not synonymous with entity of
acceleration of necrosis of cells that
are already irreversibly injured.
Myocardial Reperfusion Injury
• Experimental Evidence of
Reperfusion Injury
• MRI evidence of time-related infarct
extension after reperfusion
• Enhanced myocardial salvage with
therapeutic agents administered after
reperfusion
• Differential histology between reperfused
and non-reperfused myocardium
Vascular Changes
with Reperfusion
Mechanisms of Myocardial Reperfusion
Injury and Effects of Adenosine
Reperfusion
TxA2, PAF,
Ang II, NE, ET-1
Platelets
A2A
Platelet
Aggregation
A2A
Vasoconstriction
Leukocytes
A1/3
A1/3
A2A
MPO
Proteases
Oxygen
Calcium
Cellular Calcium
Overload
Oxygen
Free
Radicals
Vascular
Plugging
No Reflow
Cell Death
ADENOSINE
A2A/2B
Angiogenesis
Vasculogenesis
Effect of IV Adenosine at Reperfusion
on Infarct Size in a Dog Model of AMI
Implanted LAD snare in 22 dogs;
5-7 days later, 90-min LAD occlusion in closed-chest dogs;
0.15 mg/kg/min adenosine IV for 150 min starting at reperfusion;
AN/AR at 72 hrs post-AMI (Mallory’s trichrome stain/Monastral blue)
50
Control (n=13)
40
AN/AR
30
(%)
20
35 ± 4 %
Adenosine (n=9)
17 ± 4 %
p<0.01
10
0
Transverse Myocardial Slice in
Adenosine and Control Animal
Adenosine-Treated
Control
Regional Ventricular Function in Ischemic Zone
Contrast ventriculography and calculation of radial shortening
Ischemic Zone Radial
Shortening
(%)
Control
Adenosine
25
20
*
15
*
21
20
**p<.01
**
17.3
**
11
10
5.5
5
0
-2.6
-5
Base
OCC
Rep 3H
Rep 72H
Endocardial Blood Flow (ml/min/g) in
Treated and Control Animals
CONTROL ZONE
2.0
CENTRAL ZONE
*P<0.05
**P<0.01
1.0
ENDOCARDIAL FLOW
Radioactive microspheres
ADENOSINE
ADENOSINE
Base OCC REP 1 HR 2 HR 24 HR
ADENOSINE
Base OCC REP 1 HR 2 HR 24 HR
CONTROL
Lab Bench
Bedside
Prospective clinical trials
• ATTACC STUDY (Phase 2)
• AMISTAD TRIAL (Phase 2)
• AMISTAD II TRIAL (Phase 3)
AMISTAD II
2118 Patients with
Anterior STEMI & Reperfusion
Therapy within 6 Hrs of Symptoms
Placebo
Adenosine
50 μg/Kg/min
X 3h
Fibrinolysis or PTCA
Infarct size (5 d)
(243 patients)
Follow-up for 6 months
13 Countries
390 Study Sites
Adenosine
70 μg/Kg/min
X 3h
AMISTAD II – Adverse Events
PLACEBO
ADENOSINE
ADENOSINE
50 μg/Kg/min
70 μg/Kg/min
Hypotension
14%
19%
18%
Bradycardia
2%
3%
3%
Tachycardia
4%
2%
4%
Nausea/Vomiting
7%
7%
8%
Premature Drug
Discontinuation
4%
6%
5%
Second-degree AV Block
0%
0%
0%
Third-degree AV Block
0%
0%
0%
AMISTAD II Infarct Size
Median LV Infarct Size (%)
p=0.028
40%
30%
p=0.122
26%
23%
20%
11%
10%
0%
Placebo
50 μg
70 μg
57% reduction in median infarct size with 70
μg/kg/min group relative to placebo
Primary Clinical End Points AMISTAD II: INTENT-TO-TREAT
End Point
Placebo
Pooled
Adenosine
n
703
1,414
Death
In-hospital CHF
Re-hospitalization
for CHF
83 (11.8%)
146 (10.3%)
0.29
28 (4.0%)
60 (4.2%)
0.75
30 (4.3%)
56 (4.0%)
0.81
Composite
126 (17.9%)
231 (16.3%)
0.43
JACC 2005, 45: 1775-80.
P-value
“…because animal studies demonstrate that
adenosine’s beneficial effects are lost if myocardial
ischemia occurs for more than 3 h , adenosine would
prevent reperfusion injury only in patients receiving
adenosine within the first 3 h after coronary occlusion.
Therefore, a subset analysis of the adenosine groups
who were reperfused within 3 h may yield an even
greater reduction in clinical end points.”
JACC 47, 1235, March , 2006
(letter to editor of JACC by Forman and Jackson)
European Heart Journal 27: 2400-2405, Oct., 2006
Aims The purpose of this analysis was to determine whether the efficacy of adenosine vs.
placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial
Infarction Study of Adenosine (AMISTAD-II).
Methods and Results Patients presenting with ST-segment elevation anterior AMI were
randomized toreceive placebo vs. adenosine (50 or 70 mg/kg/min) for 3 h starting within 15
min of reperfusiontherapy. In the present post hoc hypothesis generating study, the results
were stratified according to the timing of reperfusion, i.e. or , the median 3.17 h, and by
reperfusion modality. In patients receiving reperfusion <3.17 h, adenosine
compared with placebo significantly reduced 1-month mortality (5.2
vs. 9.2%, respectively, P=0.014), 6-month mortality (7.3 vs. 11.2%, P
=0.033), and the occurrence of the primary 6-month composite
clinical endpoint of death, in-hospital CHF, or rehospitalization for
CHF at 6 months (12.0 vs. 17.2%, P =0.022). Patients reperfused
beyond 3 h did not benefit from adenosine.
In this post hoc analysis, 3 h adenosine infusion
administered as an adjunct to reperfusion therapy within the first
3.17 h onset of evolving anterior ST-segment elevation AMI
enhanced early and late survival, and reduced the composite
clinical endpoint of death or CHF at 6 months.
Conclusion
DEATH AT 6 MONTHS IF
THERAPY WITHIN 3 HOURS
Adenosine: 7.3% (n=716)
Placebo: 11.2% (n=350)
P=0.033
Adenosine: 800,000/y x 0.073 = 58,400/y
Placebo: 800,000/y x 0.112 = 89,600/y
Lives Saved: 89,600/y – 58,400/y =
31,200/y
Key Points
AMI patients who undergo reperfusion therapy:
– Adenosine reduces infarct size
– Adenosine reduces risk of death
What is the “No-Reflow” Phenomenon?
The “no-reflow” phenomenon is defined as impaired
tissue perfusion despite successful treatment
of the target macrovascular lesion.
How often does the “No-Reflow”
Phenomenon Occur?
29-44% of reperfused patients
50-80% of reperfused patients with LAD lesion
Does the “No-Reflow” Phenomenon
Affect Outcome?
YES!
Correlates with infarct size, ventricular function
and early and late mortality
What is the Mechanism of the “NoReflow” Phenomenon?
Multifactorial:
Damage to the microvascular endothelium
Wash-in of potent vasoconstrictors
Neutrophil activation
Platelet activation
Why Use Adenosine to Prevent the
No-Reflow Phenomenon?
Reperfusion
TxA2, PAF,
Ang II, NE, ET-1
Platelets
A2A
Platelet
Aggregation
A2A
Vasoconstriction
Leukocytes
A1/3
A1/3
A2A
MPO
Proteases
Oxygen
Calcium
Cellular Calcium
Overload
Oxygen
Free
Radicals
Vascular
Plugging
No Reflow
Cell Death
ADENOSINE
A2A/2B
Angiogenesis
Vasculogenesis