Download Putting Out the Fire Shadwan Alsafwah, MD Staff Support: Dr. Richard Davis

Putting Out the Fire
Shadwan Alsafwah, MD
The University of Tennessee at Memphis
Staff Support: Dr. Richard Davis
Introduction
• Over the past three decades, the adoption of highly
effective new pharmacological and mechanical reperfusion
treatments has improved survival for patients who
experience acute MI
• Unfortunately, reperfusion, although it relieves or reduces
ischemia and necrosis, is followed by morphological and
functional changes that ultimately result in tissue damage
known as reperfusion injury
• Myocardium that is viable at the end of the ischemic
period may therefore lose viability during reperfusion
• Conversely, the extent of myocardial necrosis
correlates with the severity and duration of
myocardial ischemia
• The net effects of reperfusion are usually
beneficial, but strategies or interventions that
could prevent its negative counterparts would
optimize myocardial salvage and improve
functional recovery
Reperfusion Injury
• Reperfusion injury, occurring with restoration of blood
flow to ischemic tissue, is associated with myocardial cell
death and apoptosis, microvascular injury, myocardial
stunning, and arrhythmias—all of which can result in
mortality and morbidity, including heart failure
• Reperfusion injury can occur after percutaneous coronary
intervention (PCI) or thrombolysis for acute myocardial
infarction (MI) as well as after coronary blood flow is
halted for 30 min or longer during coronary artery bypass
graft (CABG) surgery
Kloner RA, et al. Circulation 104 (2001)2981–9
Reperfusion Injury During CABG
• In the controlled ischemia/reperfusion setting of
coronary revascularization bypass graft surgery,
where the myocardium must be made ischemic, an
estimated 3% to 20% of patients experience MI
associated with reperfusion after bypass grafting
• Up till very recently, no effective pretreatment to
prevent or lessen the loss of viable myocardium
has been effective
Mangano, DT. West J Med 161 (1994), 87–9
Approaches to Prevent from Reperfusion Injury
• Numerous studies evaluating the use of pharmacologic and
mechanical therapies to mitigate reperfusion injury have
proven unsuccessful not only in CABG surgery but in PCI
as well
• These approaches have focused on oxygen free radicals,
neutrophil accumulation and activation, intracellular Ca2+
overload via sodium-hydrogen exchange (NHE) inhibition,
complement activation, hypothermia, hyperbaric
oxygenation, and distal embolic protection devices
Stone GW, et al. JAMA 293 (2005), pp. 1063–72
• In each of these approaches, specific mechanisms of
reperfusion injury were targeted
• Their disappointing results might reflect the inherent
limitations of therapies that target specific mechanisms
or cell types involved in the pathophysiology of
reperfusion injury, perhaps because they fail to address
the full spectrum of its complexity
The Cellular Mechanisms of
Ischemia-reperfusion
Injury
During Ischemia
•
Cessation of oxygen supply in ischaemia leads to a loss
of ATP production and an increase of reactive oxygen
species (ROS) in the mitochondria
•
Reduced activity of the ATP consuming Na+-K+-pump
leads to Na+ accumulation in the myocyte and the resting
membrane potential is lowered
•
With the development of acidosis, the Na+-H+exchanger (NHX) further increases intracellular Na+
•
Under these conditions the Na+-Ca2+-exchanger (NCX)
operates in the reverse mode, letting Ca2+ into the cell
•
Ca2+ also enters through the sarcolemmal L-type
voltage-gated Ca2+-channel (L) as the resting membrane
potential is low
•
The increased Ca2+ is taken up into the sarcoplasmic
reticulum (SR) by the SR Ca2+-pump SERCA2 (P) and
released from there via two types of release channels
(RYR) and the (IP3R), leading to contraction
Zaugg M, et al. BJA 93 (2004), 21-33
During the First Minutes of Reperfusion
•
Reoxygenation during reperfusion restores
ATP production with a further boost of ROS
•
Reactivation of the Na+-K+-pump by ATP
slowly restores the sodium gradient leading to
normal cation fluxes with the NCX eventually
extruding the excess of cytosolic Ca2+
•
During the early reperfusion phase when the
intracellular Ca2+ level is still high,
myocardial contracture (supercontraction of
myocytes) may develop
•
When contracture affects the entire heart as it
may occur after global ischaemia, it has been
termed the ‘stone heart’ phenomenon
Zaugg M, et al. BJA 93 (2004), 21-33
During the Subsequent Hours of Reperfusion
• With the resumption of blood flow, the endothelial
lining of blood vessels subjected to ischemiareperfusion becomes permeable, thus causing interstitial
edema
• Endothelial cells in reperfused myocardium assume an
activated state in which they express adhesion proteins,
release cytokines, and reduce production of NO
• This promotes adherence, activation, and accumulation
of neutrophils and monocytes in the ischemic-reperfused
tissue
Piper HM, et al. Ann Thorac Surg 75 (2003), 644-8
• The release of reactive oxygen species and proteolytic
enzymes from these activated leukocytes can contribute to
the damage of myocytes and vascular cells
• Vascular plugging by adherent leukocytes and aggregated
platelets can also promote a slow- or no-reflow
phenomenon, already favored by tissue contracture and
increased pressure of interstitial edema
• It seems that these additional reperfusion-induced noxes
contribute to infarct development predominantly during the
first 2 hours of reperfusion, as myocardial necrosis almost
reaches its final size during this period
Piper HM, et al. Ann Thorac Surg 75 (2003), 644-8
Adenosine
• Adenosine, an endogenous purine
nucleoside, is an anti-injury
autocoid that targets a broad
spectrum of the pathophysiology
of ischemia/reperfusion injury
• It has been shown to improve
post-ischemic ventricular function
and prevent myocardial necrosis
and apoptosis
Adenosine
Gruber HE, et al. Circulation 80 (1989), 1400–11
Adenosine Anti-inflammatory
Effects
• Inhibits neutrophil activation, adhesion to
endothelium, and migration into the myocardium
• Inhibits cytokine release from mononuclear cells
• Inhibits release of oxygen radicals from
granulocytes
• Inhibits cardiomyocyte apoptosis
• Prevents endothelial damage
Gruber HE, et al. Circulation 80 (1989), 1400–11
Gruber HE, et al. Circulation 80 (1989), 1400–11
Other Protective Effects
• Adenosine also has an anti-platelet effect that may have a role in
maintaining infarct artery patency
• Increases coronary collateral blood flow during ischemia
• In isolated, perfused rat hearts, adenosine given at reperfusion
increases glucose oxidation and inhibits glycolysis, reduces tissue
lactate levels, and increases ATP levels. These effects tend to decrease
cellular acidosis and Ca2+ overload and are associated with beneficial
effects on mechanical function
• Most importantly, adenosine has been shown to be a powerful inducer
of ischemic preconditioning
Gottlieb RA, et al. J Clin Invest 97 (1996), pp. 2391–8
Adenosine Role in Ischemic Preconditioning
•
Stimulation of G-protein coupled
receptors by primary messengers
activates phospholipases (PL)
•
PL in turn produce two second
messengers originating from
phosphatidylinositol bisphosphate
(PIP2), namely inositol trisphosphate
(IP3) and diacylglycerol (DAG)
•
DAG activates different protein kinase C
(PKC) isoforms
•
PKC isoforms translocate to their
appropriate target sites, activating the
sarcolemmal and mitochondrial ATPdependent potassium channels (K) and
initiating distinct gene expression in the
cell nucleus
Zaugg M, et al. BJA 93 (2004), 21-33
Beneficial Effects of Intracoronary
Adenosine as an Adjunct to Primary
Angioplasty in Acute Myocardial
Infarction
Methods
• 54 patients with AMI undergoing primary PTCA were
randomized to either intracoronary adenosine or saline
(27 patients in each)
• Inclusion criteria:
Patients referred for PTCA within 3 hours from the
onset of AMI underwent diagnostic coronary
angiography. If the culprit lesion was suitable for
PTCA and presented with a TIMI flow from 0 to 2, the
patient was included in the study and randomized
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
• Exclusion criteria:
-History of bronchospasm
-Therapy with theophylline derivatives
-Patients who had received thrombolytics in
ER
• The 2 groups were similar for age, sex, and
infarct location
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
Clinical and Angiographic Characteristics
Adenosine (n=27)
Saline (n=27)
P
58.5±11
61.9±9
NS
Age, y
Male
22 (81)
21 (78)
NS
Previous MI
3 (11)
4 (15)
NS
Time from pain onset to PTCA, min
106±81
126±69
NS
Systolic blood pressure at admission, mm Hg
116±28
109±22
NS
Heart rate at admission, bpm
85±22
83±17
NS
Site of infarction
Anterior
14 (52)
16 (59)
Inferior
8 (30)
8 (30)
Inferolateral
5 (18)
3 (11)
LAD
13 (48)
15 (56)
RCA
9 (33)
7 (26)
LCx
2 (7)
3 (11)
Marginal
1 (4)
2 (7)
Diagonal
2 (7)
0 (0)
Multivessel disease
16 (59)
16 (59)
NS
Infarct-related artery
NS
NS
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
Treatment Regimen
•
The obstruction of the infarct-related artery was crossed with a 0.014-in
guidewire
•
Over-the-wire balloon catheter was positioned at the level of the
obstruction
•
The wire was pulled out, and diluted contrast was injected through the
central lumen of the catheter to confirm positioning of the catheter tip and
to assess patency of the distal vessel
•
The balloon was inflated, and either adenosine (4 mg in 2 mL saline) or
saline (2 mL) was hand-injected into the distal vascular bed
•
The rate of injection was such as to complete treatment in 1 minute
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
• The guidewire was then readvanced into the distal vessel, and the
balloon was deflated to initiate reperfusion of the ischemic
territory. The dilatation procedure was completed according to
standard technique
• Stenting of the dilated coronary segment was performed only for
suboptimal balloon results or flow-limiting dissections
• After completion of the dilation procedure, patients were observed
in the catheterization room for 30 minutes. The final angiogram
was then obtained, and the patient was transferred to ICU
• Technically, the drug was administered distal to the coronary
obstruction and before the onset of reperfusion
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
End Points
• The primary end points of this study were
feasibility and safety of intracoronary adenosine
administration in the setting of primary PTCA and
its effect on coronary blood flow
• As secondary end points, indexes of myocardial
damage, including left ventricular regional
function, Q-wave MI, recurrence of angina,
nonfatal MI, heart failure, and cardiac death were
evaluated
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
Results: Feasibility and Safety
• The injections of adenosine or saline in the distal coronary
bed were well tolerated and free of side effects
• No patients complained of worsening of chest pain
• No patients suffered from hemodynamic instability
• No bradyarrhythmias or tachyarrhythmias were associated
with this protocol, including adenosine injection into the
RCA
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
Results: Angiographic Results
Effect of adenosine (ADO) on coronary
blood flow:
Intracoronary adenosine was
associated with higher incidence of
TIMI 3 flow and with a significant
reduction in prevalence of no-reflow
phenomenon
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
Results: The Clinical Events
Adenosine (n=27)
Saline (n=27)
P
Recurrent angina and/or ischemia
3 (11)
2 (7)
NS
Nonfatal AMI
0 (0)
1 (4)
NS
Heart failure
2 (7)
5 (18)
NS
Cardiac death
0 (0)
5 (18)
0.02
Cumulative clinical end points
5 (18)
13 (48)
0.03
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
Results: Clinical Course
Effect of adenosine (ADO) on clinical
Course:
In adenosine group, a significant
reduction of death, Q-wave MI,
and major adverse cardiac events
(MACE) was observed
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
Results: Left Ventricular Function
Percentage of initially abnormal segments
showing worsening (remodeling) or recovery at
1 week:
Adenosine (ADO) adjunct to direct PTCA was
associated with early recovery of wall motion
Marzilli M, et al. Circulation 101 (2000), pp. 2154–9
A Randomized, Double-Blinded,
Placebo-Controlled Multicenter Trial of
Adenosine as an Adjunct to Reperfusion
in the Treatment of Acute Myocardial
Infarction (AMISTAD-II)
Design
• Double-blinded, placebo-controlled, randomized
study conducted in 13 countries (390 sites) and
enrolled 2,118 patients between June 1999 and
December 2000
• Objectives: to determine the effect of intravenous
adenosine on clinical outcomes and infarct size in
ST-segment elevation myocardial infarction
(STEMI) patients undergoing reperfusion therapy
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
Methods
• Enrollment required age over 18 years,
reperfusion therapy (fibrinolysis or percutaneous
intervention) within 6 h of onset of ischemic type
pain (≥30 min), and electrocardiographic evidence
of anterior STEMI
• Electrocardiographic requirements were either ≥2
mm of ST-segment elevation in at least two
contiguous precordial leads or new left bundle
branch block
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
Exclusion Criteria:
All Patients
1. Initiation of reperfusion therapy (thrombolysis or mechanical reperfusion) before initiation of study drug
2. MI precipitated by a condition other than atherosclerotic coronary artery disease (e.g., arrhythmia, severe anemia,
hypoxia, thyrotoxicosis, cocaine, severe valvular disease, hypotension)
3. Systolic blood pressure <90 mm Hg (including cardiogenic shock) not responsive to intravenous fluids
4. Sustained bradycardia (<55 beats/min for >10 min)
5. Clinical evidence of significant reactive airway disease (e.g., asthma)
6. Greater than first-degree AV block without functional pacemaker
7. Received dipyridamole within 24 h of randomization
8. Coexistent condition associated with a limited life expectancy (e.g., advanced cancer, end-stage pulmonary disease)
9. Participation in another clinical research study involving the evaluation of another investigational drug or device within 7
days of randomization
Patients Who Were to Receive Thrombolytic Therapy as Initial Reperfusion Strategy
10. Active internal bleeding or history of hemorrhagic diathesis (including heparin-induced thrombocytopenia)
11. Previous hemorrhagic stroke at any time or any stroke within 1 year
12. Major surgery or trauma within the previous 6 weeks
13. Recent non-compressible vascular puncture
14. Severe uncontrolled hypertension (blood pressure ≥180/110 mm Hg determined from a reliable measurement before
randomization
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
Treatment Regimen
• Patients selected for reperfusion therapy were
randomly assigned to adenosine, 70 μg/kg/min or
50 μg/kg/min (utilized to evaluate dose-related
responses), or to placebo in a 1:1:1 scheme
• Study drug infusion (3 h) had to be started within
15 min either of the start of fibrinolysis or before
coronary intervention
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
End Points
• The primary end point was new congestive heart
failure (CHF) beginning >24 h after
randomization, or the first re-hospitalization for
CHF, or death from any cause within six months
• Infarct size was measured in a subset of 243
patients by technetium-99m sestamibi tomography
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
Results: Infarct Size
Infarct size measured as a percent of the LV by technetium-99m SPECT
in the 243 patients in the infarct size substudy:
Only the higher adenosine dose group showed a significant reduction in
median infarct size relative to placebo (p = 0.023)
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
Infarct size measured as a percent of the LV by technetium-99m SPECT in the 28 patients
in the infarct size substudy who suffered a primary end point compared with the 215
patients who did not have an end point:
The group with a primary end point had larger infarcts than did those without (p < 0.001)
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
Results: Primary End Points
• There was no difference in the primary end point between
placebo (17.9%) and either the pooled adenosine dose groups
(16.3%) or, separately, the 50-μg/kg/min dose and 70μg/kg/min groups (16.5% vs. 16.1%, respectively, p = 0.43)
• likely explanation for failure of the trial to demonstrate a
clinical benefit was that it was underpowered:
-The sample size calculation was based on a reduction of
events in the pooled adenosine group by 25% compared with
placebo. The reduction observed was only 11%
-This result in part reflects the modest infarct size reduction
in the 50% of patients receiving the lower adenosine dose
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
Adverse Events by Treatment Groups
Placebo
Adenosine 50 μg/kg/min
Adenosine 70 μg/kg/min
n
692
690
702
Hypotension (%)
14.0
19.4
18.4
Bradycardia (%)
2.3
2.7
2.7
Ventricular tachycardia (%)
3.6
1.9
4.3
Second-degree AV block (%)
0.01
0
0.03
Third-degree AV block (%)
0
0.01
0.04
Nausea/vomiting (%)
6.9
7.1
7.8
Premature drug discontinuation (%)
3.6
6.4
5.1
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
AMISTAD-II Results: Conclusion
• A 3-h adenosine infusion at 70 μg/kg/min (but not
at the lower 50-μg/kg/min dose) reduces infarct
size in anterior MI patients when given in
conjunction with reperfusion therapy
• The major limitation of this study was that the
sample size was too small to confirm that the
observed adenosine-related reduction in the
combined clinical end point was statistically
significant
Ross AM , et al. J Am Coll Cardiol 45 (2005), pp. 1775–80
Acadesine
• Acadesine was first isolated
from a culture medium of
sulfonamide inhibited
Eschericia coli in 1952
• During studies in cultured
human lymphoblasts it was
found that Acadesine could
augment adenosine release
from cells under certain
conditions
Acadesine
5-Aminoimidazole-4-carboxamide-1-b-riboside
• Acadesine represents the prototype of a new
class of Adenosine regulating agents (ARAs)
that substantially increase endogenous
adenosine, but importantly, only in ischemic
tissue and only under conditions of adenosine
triphosphate (ATP) catabolism
• The exact mechanism of action for increased
extracellular adenosine during ATP catabolism
in the presence of Acadesine remains unknown
Post-Reperfusion Myocardial Infarction
Long-Term Survival Improvement Using
Adenosine Regulation With Acadesine
Journal of the American College of
Cardiology, In Press, Corrected Proof,
Available online 11 May 2006
Design
• Multi-institutional (54 centers), prospectively designed,
randomized, placebo-controlled, and double-blinded study
that assessed the effects of acadesine versus placebo on MI
and secondarily on the combined outcome of cardiac death,
MI, or stroke assessed at 4 days after CABG surgery
• Long-term follow-up study was prospectively designed to
investigate the effects of acadesine versus placebo on 2year, all-cause mortality after perioperative MI
• Hypothesized that, assessed against placebo, acadesine
treatment improved 2-year survival among those patients
suffering post-reperfusion MI
Mangano DT, et al. JACC, in press
Methods
• 2,698 patients undergoing CABG surgery were
randomized to receive placebo (n = 1,346) or acadesine
(n = 1,352) by intravenous infusion (0.1 mg/kg/min; 7 h)
starting approximately 15 min before induction of
anesthesia, and also in cardioplegia solution (placebo or
acadesine; 5 μg/ml)
• Myocardial infarction was prospectively defined as: 1)
new Q-wave with CK-MB elevation (daily
electrocardiography; 16 serial CK-MB measurements); or
2) autopsy evidence
Mangano DT, et al. JACC, in press
Baseline Characteristics for All Patients, Patients Suffering MI, and Patients Not Suffering MI
All Patients
Placebo (n = 1,345)
Acadesine (n = 1,350)
Mean ± SD
63.2 ± 9.5
63.1 ± 9.6
Median
64.0
64.0
Gender: female
286 (21.3)
Smoking
Patients With MI
p Value
Placebo (n = 54)
Acadesine (n = 46)
63.4 ± 8.9
62.0 ± 10.1
0.58
65.0
63.5
254 (18.8)
0.11
15 (27.8)
986 (73.6)
966 (71.7)
0.28
Myocardial infarct(s)
716 (53.8)
725 (54.3)
Angina
1,269 (94.3)
Arrhythmias
234 (17.5)
Congestive heart failure
Hypercholesterolemia
Patients Without MI
p Value
Placebo (n = 1,291)
Acadesine (n = 1,304)
p Value
63.2 ± 9.6
63.1 ± 9.5
0.45
64.0
64.0
0.67
12 (26.1)
0.85
271 (21.0)
242 (18.6)
0.12
36 (66.7)
35 (76.1)
0.30
950 (73.9)
931 (71.6)
0.19
0.81
34 (64.2)
30 (65.2)
0.91
682 (53.4)
695 (53.9)
0.80
1,273 (94.3)
0.95
52 (96.3)
44 (95.7)
>0.99
1,217 (94.3)
1,229 (94.2)
0.98
234 (17.4)
0.96
12 (22.2)
4 (8.70)
0.07
222 (17.3)
230 (17.7)
0.77
182 (13.5)
169 (12.5)
0.43
8 (14.8)
5 (10.9)
0.56
174 (13.5)
164 (12.6)
0.50
693 (54.7)
722 (56.1)
0.48
33 (66.0)
27 (61.4)
0.64
660 (54.2)
695 (55.9)
0.40
Hypertension
796 (59.5)
773 (57.5)
0.30
36 (66.7)
24 (53.3)
0.18
760 (59.2)
749 (57.7)
0.43
Valvular disease
85 (6.32)
80 (5.94)
0.68
4 (7.41)
2 (4.35)
0.68
81 (6.28)
78 (6.00)
0.76
CABG
108 (8.03)
95 (7.04)
0.33
13 (24.1)
5 (10.9)
0.09
95 (7.36)
90 (6.90)
0.65
PTCA
172 (12.8)
184 (13.6)
0.52
6 (11.1)
7 (15.2)
0.54
166 (12.9)
177 (13.6)
0.59
Diabetes
350 (26.0)
351 (26.0)
0.99
13 (24.1)
8 (17.4)
0.41
337 (26.1)
343 (26.3)
0.91
Stroke
115 (8.55)
102 (7.56)
0.34
6 (11.1)
5 (10.9)
0.97
109 (8.44)
97 (7.44)
0.34
Neurologic disease
286 (21.3)
292 (21.6)
0.82
14 (25.9)
13 (28.3)
0.79
272 (21.1)
279 (21.4)
0.84
Vascular disease
418 (31.1)
384 (28.4)
0.13
15 (27.8)
12 (26.1)
0.85
403 (31.2)
372 (28.5)
0.13
Aspirin use (prior to surgery)
358 (26.6)
359 (26.6)
0.99
9 (16.7)
8 (17.4)
0.92
349 (27.0)
351 (26.9)
0.95
Beta-blockers use (prior to surgery)
765 (56.9)
774 (57.3)
0.81
33 (61.1)
31 (67.4)
0.51
732 (56.7)
743 (57.0)
0.89
Calcium channel blockers use (prior to surgery)
802 (59.6)
776 (57.5)
0.26
31 (57.4)
25 (54.3)
0.76
771 (59.7)
751 (57.6)
0.27
Lipid-lowering agents use (prior to surgery)
239 (17.8)
254 (18.8)
0.48
12 (22.2)
9 (19.6)
0.75
227 (17.6)
245 (18.8)
0.43
Age
Medical history
Preoperative medications
Results: Post-reperfusion MI
• Myocardial infarction occurred in 100 of the 2,695 patients enrolled
(3.7%)
• Although acadesine reduced the incidence of MI (placebo, 4.01% [54
of 1,345]; acadesine, 3.41% [46 of 1,350]), the reduction was not
statistically significant (p = 0.24)
• The occurrence of a perioperative MI conferred a 4.2-fold increased
risk in 2-year mortality:
-Among the 2,595 patients not suffering infarction, 2-year mortality
was 4.28%, versus 18.0% among the 100 patients suffering infarction
(p < 0.001)
-The primary mortality effect appeared over the first 30 days after
infarction
Mangano DT, et al. JACC, in press
Kaplan-Meier analysis of 2-year survival according to with or without
postoperative myocardial infarction (MI) among the 2,698 study patients
Mangano DT, et al. JACC, in press
• The impact of acadesine treatment on postinfarction survival was significant. Acadesine
treatment was associated with a 4.3-fold reduction
in 2-year mortality from 27.78% (15 of 54;
placebo) to 6.52% (3 of 46; acadesine) (p = 0.006)
with the principal benefit occurring over the first
30 days after MI
• The acadesine benefit was similar among diverse
subsets, including gender, race, age, and disease
acuity
Mangano DT, et al. JACC, in press
(A) Kaplan-Meier analysis of 2-year
survival according to the use or nonuse of acadesine among the 100
study patients who sustained postreperfusion MI
(B) Two-year mortality by-MI and
by-treatment
Mangano DT, et al. JACC, in press
Two-year mortality: acadesine versus placebo by patient characteristic
Mangano DT, et al. JACC, in press
Results of Multivariable Logistic Regression for 2-Year Mortality Among All Patients
Risk Factor
Odds Ratio (95%
CI)
p Value
Age > 65 yrs
2.12 (1.40–3.23)
<0.001
Female gender
1.64 (1.05–2.57)
0.03
Medical history of angina
0.44 (0.22–0.91)
0.03
Medical history of congestive heart failure
1.98 (1.25–3.13)
0.003
Medical history of hypercholesterolemia
0.52 (0.34–0.78)
0.002
Medical history of vascular disease
2.81 (1.88–4.20)
<0.001
Previous CABG surgery
2.45 (1.41–4.27)
0.002
Inotrope use on remaining day of reperfusion
2.43 (1.62–3.64)
<0.001
Post-reperfusion renal failure
3.18 (1.38–7.35)
0.007
Post-reperfusion stroke
8.48 (4.04–17.78)
<0.001
Aspirin use (post surgery)
0.51 (0.33–0.77)
0.002
Post-reperfusion MI vs. no MI: placebo-treated
patients
11.92 (5.48–25.95)
<0.001
Post-reperfusion MI vs. no MI: acadesine-treated
patients
0.95 (0.26–3.52)
0.94
Acadesine vs. placebo: patients with postreperfusion MI
0.10 (0.02–0.41)
0.002
Acadesine vs. placebo: patients without postreperfusion MI
1.21 (0.79–1.83)
0.38
Mangano DT, et al. JACC, in press
Study Conclusion
• Post-reperfusion MI conferred a four-fold increased risk of
long-term mortality
• Importantly, acadesine treatment was associated with a
four-fold reduction in 2-year mortality after perioperative
post-reperfusion, acute MI
• It is the first study of this size to demonstrate an important
reduction in mortality associated with reperfusion-induced
MI in any setting of clinical revascularization and the first
to show a sustained benefit over the long term
Mangano DT, et al. JACC, in press
Summary
• Reperfusion injury, occurring with restoration of blood
flow to ischemic tissue, is associated with myocardial cell
death and apoptosis result in increased mortality and
morbidity
• Adenosine and adenosine agonists are myocardial
protectants. Their mechanisms of action include mainly
anti-inflammatory effects and ischemic preconditioning
• The therapeutic approach of safely increasing endogenous
adenosine at the site of ischemia enables reduction of
reperfusion injury and post-infarction mortality
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