446670

2012
TAK631753944712446670M Singh, T ShahTherapeutic Advances in Cardiovascular Disease

Therapeutic Advances in Cardiovascular Disease Original Research

Safety and efficacy of intracoronary Ther Adv Cardiovasc Dis

(2012) 6(3) 101­–114

adenosine administration in patients DOI: 10.1177/

1753944712446670

with acute myocardial infarction

© The Author(s), 2012.
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coronary intervention: a meta-analysis

of randomized controlled trials
Mukesh Singh, Tejaskumar Shah, Kavia Khosla, Param Singh,
Janos Molnar, Sandeep Khosla and Rohit Arora

Abstract:  Correspondence to:

Mukesh Singh, MD
Background: Studies evaluating intracoronary administration of adenosine for prevention of Department of Cardiology,
microvascular dysfunction and ischemic-reperfusion injury in patients with acute myocardial Chicago Medical School,
3333, Green Bay Road,
infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) have yielded North Chicago, IL 60068,
USA
mixed results. Therefore, we performed a meta-analysis of these trials to evaluate the safety and drmukeshsingh@yahoo.
efficacy of intracoronary adenosine administration in patients with AMI undergoing primary PCI. com

Methods: A total of seven prospective randomized controlled trials were analyzed. Tejaskumar Shah, MD,
Kavia Khosla,
The endpoints extracted were post-procedure residual stent thrombosis (ST) segment Param Singh, MD,
Janos Molnar, MD,
elevation and ST segment resolutions (STRes), difference in peak creatine kinase (CK- Sandeep Khosla, MD
MB) concentration, thrombolysis in myocardial infarction (TIMI) grade III flow (TIMI 3 flow), Rohit Arora, MD
Department of Cardiology,
myocardial blush grade (MBG) 3, mean difference in post-PCI ejection fraction (EF), all-cause Chicago Medical School,
North Chicago, IL, USA
mortality, cardiovascular mortality, heart failure (HF) and major adverse cardiovascular event
(MACE). Safety endpoints analyzed were bradycardia, second-degree atrioventricular block
(AVB), ventricular tachycardia (VT), ventricular fibrillation (VF) and recurrence of chest pain
(CP). The endpoints were analyzed by standard methods of meta-analysis.
Results: Intracoronary adenosine therapy led to significantly more post-PCI STRes [relative
risk (RR) 1.39, 95% confidence interval (CI) 1.01–1.90; p = 0.04] and reduction in residual ST
segment elevation (RR 0.82, CI 0.69–0.99; p = 0.04) but did not improve TIMI 3 flow (RR 1.09,
CI 0.94–1.27; p = 0.25), MBG3 (RR 1.04, CI 0.65–1.69; p = 0.88), peak CK-MB concentration
(mean difference −39.43, CI −120.223 to 41.371; p = 0.339) and post-PCI EF (mean difference
1.238, CI −5.802 to 8.277; p = 0.730). There was a trend towards improvement and MACE (RR
0.64, CI 0.40–1.03; p = 0.06), incidence of HF (RR 0.47, CI 0.19–1.12; p = 0.08) and CV mortality
(RR 0.15, CI 0.02–1.23; p = 0.08) that did not reach statistical significance but no difference
in all-cause mortality (RR 0.77, CI 0.25–2.34; p = 0.64). Safety analysis showed no significant
difference in CP events (RR 1.26, CI 0.55–2.86; p = 0.58), bradycardia (RR 2.19, CI 0.24–0.38;
p = 0.49), VT (odds ratio 0.61, CI 0.08–4.90; p = 0.64) and VF (RR 0.49, CI 0.13–1.90; p = 0.30),
but significantly more second-degree AVB (RR 7.88, CI 4.15–14.9; p < 0.01) in the adenosine
group compared with the placebo group.
Conclusion: Intracoronary adenosine administration was well tolerated and significantly
improved electrocardiographic outcomes with a tendency towards improvement in MACE,
HF and CV mortality that could not reach statistical significance.

Keywords:  Intracoronary adenosine, acute myocardial infarction.

http://tac.sagepub.com 101
Therapeutic Advances in Cardiovascular Disease 6 (3)
Background
Primary percutaneous coronary intervention
(PCI) has become the preferred reperfusion
strategy over thrombolytic therapy in patients
with stent thrombosis elevation myocardial
infarction (STEMI) [Keeley et al. 2003]. Despite
immediate reperfusion through an occluded epi-
cardial coronary artery, myocardial perfusion still
remains inadequate in 25–30% patients and
results in a larger infarct size and increased mor-
tality [van’t Hof et al. 1998]. The pathogenesis of
microvascular injury resulting in the ‘no-reflow’
phenomenon is complex and multifactorial
and is an important predictor of mortality, recur-
rent infarction and impaired ventricular func-
tion. Coronary microvascular dysfunction and
ischemic reperfusion injury have been proposed
as the potential mechanisms responsible for this
inadequate myocardial perfusion (known as a
‘no-reflow phenomenon’) [Matsumura et al.
1998; Gottlieb et al. 1994]. Coronary microvas-
cular dysfunction is related to distal embolization
of plaque material and thrombus, microvascular
spasm, myocardial edema, myocardial necrosis,
leukocyte adhesion platelet aggregation all of
which may contribute to the reperfusion injury
[Kloner et al. 1991; Ambrosio and Tritto, 1999;
Heusch et al. 2009].
Several pharmacological agents including aden-
osine have been studied in the prevention and
treatment of the ‘no-reflow’ phenomenon
[Neumann et al. 1998; De Luca et al. 2005;
Hang et al. 2005; Taniyama et al. 1997; Ito et al.
1999; Ishii et al. 2005; Garratt et al. 1998;
Mahaffey et al. 1993; Ross et al. 2005; Petronio
et al. 2005; Barcin et al. 2004]. Previous studies
comparing intravenous adenosine showed some
promising results but intracoronary injection of
medications has the advantage of allowing a
high concentration of the drug near the distal
coronary bed, with lower incidence of side
effects [Petronio et al. 2005]. Also those studies
were done in the era of thrombolytic therapy
and their relevance in the contemporary era of
primary PCI and advanced antiplatelet therapy
is unknown. Clinical studies evaluating the
role of the intracoronary adenosine in patients
with acute myocardial infarction (AMI) under-
going primary PCI have yielded mixed results.
Therefore, we performed a meta-analysis of
these trials to evaluate the safety and efficacy of
intracoronary adenosine administration in these
patients.
102 http://tac.sagepub.com
Methods
We performed this review in accordance with the
Quality of Reporting of Meta-analysis statement
and the Consolidated Standards of Reporting
Trials Group recommendations [Moher et al.
1999]. A protocol was prospectively developed,
detailing the objectives, criteria for study selec-
tion and approach to assessing the study quality,
primary outcome and methodology.
Literature search
We performed a computerized search to identify
all relevant studies published in the English lan-
guage untill May 2011 in EMBASE, CINAHL,
PubMed and the Cochrane database. The key
words used for the search were: acute myocardial
infarction, ST elevation myocardial infarction,
percutaneous coronary interventions, microvas-
cular dysfunction, no-reflow phenomenon, aden-
osine and intracoronary adenosine.
Study selection
We reviewed all titles and abstracts from the
results of our computerized search. We also went
into the related links of all relevant articles. In
addition to our computerized search, we manu-
ally reviewed the reference list of all retrieved arti-
cles to complete our search. The study selection
process is outlined in Figure 1.
Inclusion criteria
Studies had to meet all the following criteria to be
included in the analysis:
(1) Prospective randomized controlled trial
design.
(2) Include patients with AMI undergoing pri-
mary PCI
(3) Compare intracoronary adenosine with
placebo group.
(4) Report at least one of the clinical, angio-
graphic, cardiac imaging related, elec-
trocardiography (EKG) related, cardiac
biomarkers or safety-related outcomes,
including all-cause mortality, cardio-
vascular (CV) mortality, heart failure
(HF), major adverse cardiovascular
event (MACE), thrombolysis in myocar-
dial infarction (TIMI) grade III flow
(TIMI 3 flow), myocardial blush grade
(MBG) 3, mean difference in post-PCI

Figure 1.  Study selection process.
ejection fraction (EF), post-procedure
residual stent thrombosis (ST) segment
elevation and ST segment resolutions
(STRes), difference in peak creatine
kinase (CK-MB) concentration, brady-
cardia, second degree atrioventricular
block (AVB), ventricular tachycardia
(VT), ventricular fibrillation (VF) and
recurrence of chest pain (CP).
Exclusion criteria
Studies that did not meet the above criteria were
excluded.
Data abstraction
After identifying all the relevant articles, we
extracted characteristics of the study (author, year,
design, duration, sample size, study patient popu-
lation, clinical outcomes, angiographic outcomes,
http://tac.sagepub.com 103
M Singh, T Shah et al.
cardiac imaging related outcomes, EKG-related
outcomes, cardiac enzymes comparison, safety
endpoints and follow-up percentage). Two review-
ers independently extracted data and assessed
outcomes. The inter-rater agreement was 90%,
and disagreements were resolved by consensus.
Quality assessment
All the trials reported adequate concealment of
the randomized treatment sequence. In all studies,
follow up was more than 90% complete.
Statistical analysis
The statistical analysis was performed using the
Comprehensive Meta-Analysis software (Biostat,
Englewood, NJ, USA). Heterogeneity of the stud-
ies was assessed for each outcome. Studies that
were homogenous for an outcome were analyzed
by the Mantel-Haenszel fixed effect model, while
Therapeutic Advances in Cardiovascular Disease 6 (3)

Table 1.  Endpoint definitions.

Trial MACE STRes Residual ST segment Mean peak CK-MB

deviation concentration
Marzilli et al. Recurrent angina/ NA NA Blood samples
[2000] ischemia, non-fatal obtained every 8 h for
AMI, HF and CV first day and then every
mortality day until discharge
Claeys et al. Cardiac death and STRes > 50% initial Residual ST deviation NA
[2004] myocardial infarction value ≥50% initial value
Stoel et al. Cardiac death, STRes > 70% Residual ST deviation Blood sample
[2008] noncardiac death, ST > 70% or 2 mv ST after adenosine
and HF elevation persistent in administration
anterior lead and 1 mv in
a nonanterior lead
Fokkema et al. All-cause mortality, STRes >70% Residual ST deviation Blood sample obtained
[2009] reinfarction and TVR < 0.2 mv before and after PCI;
after PCI at 3, 6, 9, 12,
18, 24, 36 and 48 h
Desmet et al. NA STRes > 70% NA Blood sample obtained
[2011] before and after PCI;
after PCI at 8, 6, 9 and
24 h
Grygier et al. Death, recurrent STRes > 50% NA Blood sample obtained
[2011] MI, cardiac arrest, every 8 h for first day
cardiogenic shock, admission
cardiac arrest and HF
AMI, acute myocardial infarction; CV, cardiovascular; HF, heart failure; MACE, major adverse cardiovascular event; NA, not available;
PCI, percutaneous coronary intervention; ST, stent thrombosis; STRes, ST segment resolution; TVR, target vessel revascularization.

those studies that were heterogeneous for an out-
come were analyzed by the random effect model.
For each categorical variable, such as CV death or
MACE, the common relative risk (RR) was, while
for continuous variables, such as EF or CK-MB,
the common mean differences between the
adenosine and placebo groups were computed.
A two-sided α error of less than 0.05 was considered
to be statistically significant (p < 0.05).
Results
Literature search
A total of 92 articles were identified of which
41 were potentially relevant studies and screened
for retrieval. After title and abstract screening,
28 studies were excluded and the remaining
13 studies were retrieved for a more detailed eval-
uation. Out of these 13 studies, 6 were excluded;
out of these 6 excluded studies, 1 study had no
control groups [Lim et al. 2004], 4 studies had
different study population [Assali et al. 2000;
Quintana et al. 2003; Kim et al. 2011; Pepine et
al. 2010] and 1 study had different endpoints
[Tsao et al. 2009]. Thus, a total of seven clinical
trials were included in the final analysis [Marzilli
et al. 2000; Claeys et al. 2004; Hendler et al. 2006;
Stoel et al. 2008; Fokkema et al. 2009; Desmet
et al. 2011; Grygier et al. 2011].
Endpoints
Table 1 lists the endpoint definitions used in the
individual studies included in this meta-analysis.
Out of seven trials, six [Marzilli et al. 2000;
Claeys et al. 2004; Stoel et al. 2008; Fokkema et al.
2009; Desmet et al. 2011; Grygier et al. 2011]
had clinical and EKG-related outcomes as their
endpoints. Four trials had TIMI 3 flow as end-
points [Marzilli et al. 2000; Fokkema et al. 2009;
Desmet et al. 2011; Grygier et al. 2011]. The
angiographic outcome TIMI 3 flow was graded
using a TIMI study criterion which was meas-
ured either at the end of the balloon dilation pro-
cedure [Marzilli et al. 2000; Grygier et al. 2011]
or after primary PCI with stenting [Fokkema
et al. 2009; Desmet et al. 2011]. Another
angiographic outcome, MBG3, was defined as
a normal myocardial blush or contrast density,

104 http://tac.sagepub.com

comparable with that obtained during angiography
of a non-infarct-related coronary artery territory
[van’t Hof et al. 1998]. Three trials provided
data on MBG3 outcomes [Fokkema et al. 2009;
Desmet et al. 2011; Grygier et al. 2011]. Cardiac
imaging related outcome (mean difference in
post-PCI EF) which was assessed by either
echocardiography [Hendler et al. 2006; Grygier
et al. 2011] or magnetic resonance imaging
[Desmet et al. 2011]. All clinical trials had safety
events as one of their endpoints, except one trial
[Hendler et al. 2006].
Overview of study and patient characteristics
The trials included in this meta-analysis consisted
of a total of 1030 patients (placebo group, n = 570;
treatment group, n = 460). Study design was
similar in all seven trials: comparison between a
placebo arm and an intracoronary adenosine arm.
Intra coronary administration protocol was either
as boluses or continuous infusion during primary
PCI. The results of the meta-analysis are shown in
Figures 2–7. Baseline characteristics of individual
trials are given in Tables 2 and 3.
Figure 2.  All-cause mortality (upper panel) and cardiovascular mortality (lower panel). CI, confidence interval.
http://tac.sagepub.com 105
M Singh, T Shah et al.
Clinical outcomes
There was no significant difference in the all-cause
mortality [RR 0.77, 95% confidence interval (CI)
0.25–2.34; p = 0.64], or between the two groups
(Figure 2). Proportionately more MACE were
noted in the placebo group and there was a trend
towards benefit with intracoronary adenosine ther-
apy but it could not reach statistical significance
[27 (6.85%) events in the adenosine group versus
48 (9.49%) in the placebo group with RR 0.64, CI
0.40–1.03; p = 0.06] (Figure 3). A similar trend
was noted for HF events (RR 0.47, CI 0.19–1.12;
p = 0.08), and CV mortality (RR 0.15, CI 0.02–1.23;
p = 0.08) (Figures 2 and 3).
Electrocardiography and creatine kinase
A total of 225 (58.75%) subjects in the adenosine
group had post-PCI STRes compared with 217
(43.23%) subjects in the placebo group. Analysis
revealed significant post-PCI STRes (RR 1.39,
CI 1.01–1.90; p = 0.04) and reduction in residual
ST segment elevation (RR 0.82, CI 0.69–0.99;
p = 0.04) in the adenosine group compared with
the placebo group (Figure 4). However, mean
Therapeutic Advances in Cardiovascular Disease 6 (3)

Figure 3.  Heart failure (upper panel) and major adverse cardiovascular event (lower panel). CI, confidence
interval.

Figure 4.  Stent thrombosis segment resolutions (STRes) (upper panel) and residual ST elevation (lower
panel). CI, confidence interval.

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 M Singh, T Shah et al.

Figure 5.  Cardiac biomarkers (upper panel) and mean difference in post percutaneous coronary intervention
ejection fraction (PCI EF) (lower panel). CI, confidence interval; CK, creatine kinase.

Figure 6.  Thrombolysis in myocardial infarction (TIMI) grade 3 flow (upper panel) and myocardial blush grade
3 (lower panel). CI, confidence interval.

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Therapeutic Advances in Cardiovascular Disease 6 (3)
Figure 7.  Safety analysis. AV, atrioventricular; CI, confidence interval; CP, chest pain; VF, ventricular
fibrillation.
difference in peak CK-MB concentration did
not differ significantly between the two groups
(mean difference –39.43, CI –120.223 to 41.371;
p = 0.339) (Figure 5).
Post-percutaneous coronary intervention
ejection fraction change
Intracoronary adenosine treatment did not lead
to improvement in post-PCI EF (mean difference
1.238, CI –5.802 to 8.277; p = 0.730) compared
with the placebo group (Figure 5).
Angiographic outcomes
Post-procedure TIMI 3 flow rate was similar
between the two groups (RR 1.09, CI 0.94–1.27;
p = 0.25) (Figure 4). Similar results were
obtained for achievement of MBG3 with adeno-
sine therapy (RR 1.04, CI 0.65–1.69; p = 0.88)
(Figure 6).
108 http://tac.sagepub.com
Safety analysis
Overall there was no significant difference in CP
events (RR 1.26, CI 0.55–2.86; p = 0.58), brady-
cardia (RR 2.19, CI 0.24–0.38; p = 0.49), VT
(odds ratio 0.61, CI 0.08–4.90; p = 0.64) and VF
(RR 0.49, CI 0.13–1.90; p = 0.30) between the
two groups. However, the incidence of second
degree AVB was significantly higher in the aden-
osine group (RR 7.88, CI 4.15–14.9; p < 0.01)
compared with the placebo group (Figure 7).
Discussion
Angiographic evidence of impaired tissue perfu-
sion, known as the ‘no-reflow’ or ‘slow-reflow’
phenomenon, is a serious complication associ-
ated with STEMI in patients undergoing primary
PCI [Forman et al. 2006, 2008]. Various mecha-
nisms implicated in the pathogenesis of the no-
reflow phenomenon include oxygen-derived free
radicals, distal embolization to micovascular bed,
 M Singh, T Shah et al.

Table 2.  Study characteristics.

Trial Design Study population Intracoronary adenosine Endpoints studied

administration
Marzilli et al. RCT AMI undergoing Adenosine (4 mg) randomly • All-cause mortality, CV mortality,
[2000] primary PCI administered distal to PCI site HF and MACE, TIMI 3 flow
• Difference in peak CK-MB
concentration
• Bradycardia, second degree AVB,
VT, VF and recurrence of CP
Claeys et al. RCT STEMI Adenosine (60 μg/min for the • MACE, post-procedure residual ST
[2004] undergoing RCA and 90 μg/min for the LCA) segment deviation and STRes
primary PCI just before and during PCI for • Difference in peak CK-MB
a 20 min intracoronary infusion concentration
at catheter site
Hendler et al. RCT STEMI Adenosine(60–120 μg) •  Mean difference in post PCI EF
[2006] undergoing injection randomly • Bradycardia, second degree AVB,
primary PCI administered to catheter site VT, VF and recurrence of CP
Stoel et al. RCT STEMI Adenosine (6 mg/ml) • All-cause mortality, CV mortality,
[2008] undergoing administered for 5–10 min HF and MACE, post-procedure
primary PCI as intracoronary infusion at residual ST segment deviation and
catheter site STRes, difference in peak CK-MB
concentration
• Bradycardia, second degree AVB,
VT, VF and recurrence of CP
Fokkema RCT STEMI Adenosine (120 μg in 20 ml • All-cause mortality and MACE,
et al. [2009] undergoing NaCl) TIMI 3 flow, MBG 3, post-procedure
primary PCI two bolus injections at catheter residual ST segment deviation and
site; first bolus after thrombus STRes
aspiration and the second after • Difference in peak CK-MB
stenting of the infarct-related concentration
artery • Bradycardia, second degree AVB,
VT, VF and recurrence of CP
Desmet et al. RCT STEMI Adenosine (4 mg) • All-cause mortality, TIMI 3 flow,
[2011] undergoing randomly administered distal MBG 3, mean difference in post PCI
primary PCI to target lesion site EF and STRes, difference in peak
CK-MB concentration
• Bradycardia, second degree AVB,
VT, VF and recurrence of CP
Grygier et al. RCT STEMI Adenosine (1 mg for RCA and 2 • HF and MACE, TIMI 3 flow, MBG 3,
[2011] undergoing mg of LCA) mean difference in post PCI EF,
primary PCI two bolus injections at STRes, difference in peak CK-MB
catheter site; first bolus concentration
crossing guide wire and the • Bradycardia, second degree AVB,
second after balloon inflation VT, VF and recurrence of CP
of occlusion site
AMI, acute myocardial infarction; AVB, atrioventricular nodal block; CP, chest pain; CV, cardiovascular; EF, ejection fraction; HF, heart failure;
MACE, major adverse cardiovascular event; MBG, myocardial blush grade; PCI, percutaneous coronary intervention; RCT, randomized control
trial; ST, stent thrombosis; STEMI, elevation myocardial infarction; STRes, ST segment resolution; TIMI, thrombolysis in myocardial infarction; VF,
ventricular fibrillation; VT, ventricular tachycardia; LCA, left coronary artery; RCA, right coronary artery.

inflammatory marker mediated myocardial dys-
function and myocardial edema, localized neutro-
phil activation and platelet activity, amplification
of the local release of serotonin and potent vaso-
constrictor endothelin-1 by stent insertion, and
angioplasty and activation of the sympathetic
nervous and renin–angiotensin systems [Gech
et al. 1996; Stone et al. 2005; Meldrum, 1998;
Kerins et al. 1989; Leosco et al. 1999; Taylor et al.
2004; Gibson and Schomig, 2004]. Adenosine
has been postulated to have strong vasodilator
activity, anti-inflammatory, antiplatelet and

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Therapeutic Advances in Cardiovascular Disease 6 (3)

Table 3.  Characteristics of study population.

Trial Follow up Patients (n) Intracoronary Placebo

(months) adenosine

  Placebo Adenosine  
Marzilli et al. NA 27 27 Men 81% Men 78%
[2000] Previous MI 11% Previous MI 15%
Ant infarction 52% Ant infarction 59%
LAD 48% LAD 56%
Claeys et al.  1 200 79 Men 80% Men 75%
[2004] HTN 42% HTN 44%
DM 16% DM 10%
Previous MI 24% Previous MI 14%
LAD 25% LAD 84%
Hendler et al.  1 10 10 NA NA
[2006]
Stoel et al. 12 22 27 Men 63% Men 70.4%
[2008] HTN 40.7% HTN 40.9%
DM 3.7% DM 18.2%
LAD 55.6% LAD 45.5%
Fokkema  1  222 226 Men 73% Men 76.6%
et al. [2009] HTN 36.2% HTN 37.9%
DM 10.2% DM 10.1%
Previous MI 7.6% Previous MI 9.1%
LAD 42.5% LAD 36.9%
Desmet et al. 12 54 56 Men 78.6% Men 85.2%
[2011] HTN 39.3% HTN 40.7%
DM 3.6% DM 16.7%
Previous MI 0.0% Previous MI 1.9%
LAD 48.2% LAD 33.3%
Grygier et al.  1 35 35 Men 63% Men 73%
[2011] HTN 60% HTN 36.2%
DM 23% DM 10.2%
Previous MI 9% Previous MI 57.1%
LAD 48.6% LAD 42.5%
Ant infarction, anterior infarction; DM, diabetes; HTN, hypertension; LAD, left anterior descending artery;
MI, myocardial infarction, NA, not available.

postconditioning effect [Rosales et al. 2004;
Headrick et al. 2003; Kloner and Rezkalla, 2006]
which all can be of benefit in the prevention and
treatment of the no-reflow phenomenon.
The results of the present meta-analysis show
that in patients with STEMI, intracoronary
adenosine therapy leads to improvement in
post-PCI STRes. However, this did not translate
into significant improvement in angiographic or
clinical outcomes. There was a trend towards
improvement in MACE (RR 0.64, CI 0.40–1.03;
p = 0.06) but it could not reach statistical signifi-
cance. A similar but less strong trend was also
noted for HF events (RR 0.47, CI 0.19–1.12; p =
0.08) and CV mortality (RR 0.15, CI 0.02–1.23;
p = 0.08). The reason for this disconnect may be
due to small study populations, low event rates in
individual trials, or short follow-up duration.
In animal models, it has been described that lev-
els of adenosine may increase to levels producing
maximal coronary arteriolar dilatation during
ischemia [Rubio et al. 1969]. So it is possible that
because of the high level of endogenous produc-
tion of adenosine during myocardial ischemia,
maximal vasodilatation is already present in
patients with STEMI, and therefore, no further
improvement is seen due to the absence of
vasodilatory reserve during and after reperfusion
by PCI. This may explain the absence of
improvement in TIMI 3 flow with intracoronary

110 http://tac.sagepub.com
 M Singh, T Shah et al.

Table 4.  Heterogeneity testing.

Outcome Q value df (Q) p value I2 Result

All-cause mortality 3.2 3 0.359 6.8 Homogenic
CV mortality 0.3 1 0.611 0.0 Homogenic
Heart failure 0.2 2 0.896 0.0 Homogenic
MACE 6.1 4 0.195 34.0 Homogenic
TIMI 3 flow 11.0 3 0.012 72.8 Heterogenic
MBG 3 7.7 2 0.022 73.9 Heterogenic
Mean difference in post-PCI EF 11.0 2 0.004 81.7 Heterogenic
Residual ST deviation 3.3 2 0.196 38.7 Homogenic
STRes 14.3 4 0.006 72.0 Heterogenic
CK-MB 23.4 4 0.000 82.9 Heterogenic
Bradycardia 9.8 1 0.002 89.8 Heterogenic
Second degree AVB 1.5 1 0.217 34.4 Homogenic
VT 0.3 1 0.617 0.0 Homogenic
VF 0.0 1 0.980 0.0 Homogenic
Recurrence of CP 1.5 2 0.480 0.0 Homogenic
p < 0.1 indicates heterogeneity, I2 indicates the percentage of variability that is due to heterogeneity.
AVB, atrioventricular nodal block; CK, creatine kinase; CP, chest pain; CV, cardiovascular; EF, ejection fraction; MACE,
major adverse cardiovascular event; MBG, myocardial blush grade; PCI, percutaneous coronary intervention; ST, stent
thrombosis; STRes, ST segment resolution; TIMI, thrombolysis in myocardial infarction; VF, ventricular fibrillation; VT,
ventricular tachycardia.

adenosine as seen in the present meta-analysis.
Moreover, the optimum dosing regimen for
intracoronary adenosine is unknown. The differ-
ence in dosing regimen may be a critical factor in
obtaining a good versus a neutral response due to
the very short half life of this molecule. The
amount of drug, timing of drug delivery, and the
site of drug delivery are all critically important
factors that need to be defined. Five studies in
our analysis involved bolus injections [Marzilli
et al. 2000; Hendler et al. 2006; Fokkema et al.
2009; Desmet et al. 2011; Grygier et al. 2011]
while two involved infusion of adenosine [Claeys
et al. 2004; Stoel et al. 2008]. Similarly the timing
and site of drug delivery were different, which
may have affected the results (Table 2).
Recently MBG has been demonstrated superior
in predicting microcirculatory flow and tissue
perfusion [Forman et al. 2006]. We did not find
any beneficial effects of intracoronary adenosine
on MBG. Our analysis of MBG3 included three
clinical trials but only one out of these trials
[Fokkema et al. 2009] allowed for manual
thrombus aspiration while the study protocol of
the other two trials [Desmet et al. 2011; Grygier
et al. 2011] was designed before the era of
thrombectomy and the distal protection device,
which may decrease the distal emobilization
responsible for poor MBG3. Thus it is possible
that the contemporary treatment of patients
with STEMI with thrombus aspiration and the
administration of the glycoprotein IIb/IIIa
inhibitor abciximab during primary PCI may
result in an improvement in myocardial reperfu-
sion [Svilaas et al. 2008; De Luca et al. 2005].
Postprocedural elevations of cardiac biomarkers
like CK-MB and troponins are shown to be
related to infarct size, late mortality and recurrent
infarction [Antman et al. 1996; Cavallini et al.
2005]. In our analysis, the level of peak CK-MB
was no different between the two arms, indicating
no obvious benefit of intracoronary adenosine
(Figure 5). This combined with the above find-
ings can explain the lack of benefit seen in clinical
outcomes. However, the only cardiac biomarker
assessed was CK-MB because no data were
available for troponins, which are more sensitive
and specific markers.
The safety endpoint analysis demonstrated that
intracoronary adenosine administration was asso-
ciated with approximately a 17–18-fold higher
rate of second degree AVB than placebo. However,
simultaneously there was no increase in chest

http://tac.sagepub.com 111
Therapeutic Advances in Cardiovascular Disease 6 (3)
pain, bradycardia, VT or VF events. However, these
were transient events due to the short half life of
adenosine.
Adenosine is an important component of the
interventional cardiologist's toolbox and plays a
useful role in patients with slow flow or no reflow.
Studying the effects of adenosine in these patients
alone is likely to establish a benefit but may be a
difficult study to do as few operators would be
willing to randomize these patients to placebo.
The trend towards MACE benefit that was seen
in all patients with myocardial infarction should
therefore not be minimized. In sufficient numbers
this would likely have shown a benefit. Transient
AVBs are expected with adenosine and should be
appropriately minimized.
As with any meta-analysis, one of the limitations
of our study is the difference in the definitions
of the endpoints in the component trials. Baseline
characteristics between two groups cannot be
compared completely in most meta-analyses
because of differences in the study protocols
across the component trials. Also, there is a
potential for publication bias but the trials in
our analysis had different results which should
reduce this potential risk.
Conclusion
Our results provide evidence that intracoronary
adenosine may be a useful therapy as indicated
by improvement in EKG findings. A trend
towards improvement was noted in MACE and
HF events but at present there are not enough
data to reach strong conclusions on clinical out-
comes. This also underscores the importance of
conducting further long-term studies with
larger numbers of patients to evaluate the clini-
cal endpoints. Moreover, this meta-analysis
highlights the gaps in the available literature
about the optimum dose, timing and site of
intracoronary adenosine administration which
need further investigation.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in
preparing this article.
112 http://tac.sagepub.com
References
Ambrosio, G. and Tritto, I. (1999) Reperfusion
injury: experimental evidence and clinical
implications. Am Heart J 138: S69–S75.
Antman, E.M., Tanasijevic, M.J., Thompson, B.,
Schactman, M., McCabe, C.H., Cannon, C.P. et al.
(1996) Cardiac-specific troponin I levels to predict
the risk of mortality in patients with acute coronary
syndromes. N Engl J Med 335: 1342–1349.
Assali, A.R., Sdringola, S., Ghani, M., Denkats, A.E.,
Yepes, A., Hanna, G.P. et al. (2000) Intracoronary
adenosine administered during percutaneous
intervention in acute myocardial infarction and
reduction in the incidence of ‘no reflow’ phenomenon.
Catheter Cardiovasc Interv 51: 27–31.
Barcin, C., Denktas, A.E., Lennon, R.J., Hammes,
L., Higano, S.T., Holmes, D.R. Jr et al. (2004)
Comparison of combination therapy of adenosine and
nitroprusside with adenosine alone in the treatment
of angiographic no-reflow phenomenon. Catheter
Cardiovasc Interv 61: 484–491.
Cavallini, C., Savonitto, S., Violini, R., Arraiz,
G., Plebani, M., Olivari, Z. et al. (2005) Italian
‘Atherosclerosis, Thrombosis, and Vascular
Biology’ and ‘Society for Invasive Cardiology-GISE’
Investigators. Impact of the elevation of biochemical
markers of myocardial damage on long-term mortality
after percutaneous coronary intervention: results of the
CK-MB and PCI study. Eur Heart J 26:1494–1498.
Claeys, M.J., Bosmans, J., De Ceuninck, M., Beunis,
A., Vergauwen, W., Vorlat, A. et al. (2004) Effect
of intracoronary adenosine infusion during coronary
intervention on myocardial reperfusion injury in
patients with acute myocardial infarction. Am J
Cardiol 94: 9–13.
De Luca, G., Suryapranata, H., Stone, G.W.,
Antoniucci, D., Tcheng, J.E., Neumann, F.J.
et al. (2005) Abciximab as adjunctive therapy to
reperfusion in acute ST-segment elevation myocardial
infarction: a meta-analysis of randomized trials.
JAMA 293: 1759–1765.
Desmet, W., Bogaert, J., Dubois, C., Sinnaeve, P.,
Adriaenssens, T., Pappas, C. et al. (2011) High-dose
intracoronary adenosine for myocardial salvage in
patients with acute ST-segment elevation myocardial
infarction. Eur Heart J 32: 867–877.
Fokkema, M.L., Vlaar, P.J., Vogelzang, M., Gu, Y.L.,
Kampinga, M.A., de Smet, B.J. et al. (2009) Effect
of high dose intracoronary adenosine administration
during primary percutaneous coronary intervention in
acute myocardial infarction. A randomized controlled
trial. Circ Cardiovasc Interv 2: 323–329.
Forman, M.B., Hou, D. and Jackson, E.K. (2008)
Treating acute ‘no-reflow’ with intracoronary

adenosine in 4 patients during percutaneous coronary
intervention. Tex Heart Inst J 35: 439–446.
Forman, M.B., Stone, G.W. and Jackson, E.K.
(2006) Role of adenosine as adjunctive therapy in
acute myocardial infarction. Cardiovasc Drug Rev
24: 116–147.
Garratt, K.N., Holmes, D.R. Jr, Molina-Viamonte,
V., Reeder, G.S., Hodge, D.O., Bailey, K.R.
et al. (1998) Intravenous adenosine and lidocaine
in patients with acute mycocardial infarction.
Am Heart J 136: 196–204.
Gech, E.D., Dodd, N.J., Jackson, M.J., Morrison,
W.L., Faragher, E.B. and Ramsdale, D.R. (1996)
Evidence for free radical generation after primary
percutaneous transluminal coronary angioplasty
recanalization in acute myocardial infarction.
Am J Cardiol 77: 122–127.
Gibson, C.M. and Schomig, A. (2004) Coronary and
myocardial angiography: angiographic assessment of
both epicardial and myocardial perfusion. Circulation
109: 3096–3105
Gottlieb, R.A., Burleson, K.O., Kloner, R.A., Babior,
B.M. and Engler, R.L. (1994) Reperfusion injury
induces apoptosis in rabbit cardiomyocytes. J Clin
Invest 94: 1621–1628.
Grygier, M., Araszkiewicz, A., Lesiak, M., Janus, M.,
Kowal, J., Skorupski, W. et al. (2011) New method
of intracoronary adenosine injection to prevent
microvascular reperfusion injury in patients with
acute myocardial infarction undergoing percutaneous
coronary intervention. Am J Cardiol 107: 1131–1135.
Hang, C.L., Wang, C.P., Yip, H.K., Yang,
C.H., Guo, G.B., Wu, C.J. et al. (2005) Early
administration of intracoronary verapamil improves
myocardial perfusion during percutaneous coronary
interventions for acute myocardial infarction. Chest
128: 2593–2598.
Headrick, J.P., Hack, B. and Ashton, K.J. (2003)
Acute adenosinergic cardioprotection in ischemic-
reperfused hearts. Am J Physiol Heart Circ Physiol
285: H1797–H1818.
Hendler, A., Aronovich, A., Kaluski, E., Zyssman,
I., Gurevich, Y., Blatt, A. et al. (2006) Optimization
of myocardial perfusion after primary coronary
angioplasty following an acute myocardial infarction.
Beyond TIMI 3. J Invasive Cardiol 18: 32–36
Heusch, G., Kleinbongard, P., Böse, D., Levkau,
B., Haude, M., Schulz, R. et al. (2009) Coronary
microembolization. From bedside to bench and back
to bedside. Circulation 120: 1822–1836.
Ishii, H., Ichimiya, S., Kanashiro, M., Amano, T.,
Imai, K., Murohara, T. et al. (2005) Impact of a
single intravenous administration of nicorandil before
http://tac.sagepub.com 113
M Singh, T Shah et al.
reperfusion in patients with ST-segment-elevation
myocardial infarction. Circulation 112: 1284–1288.
Ito, H., Taniyama, Y., Iwakura, K., Nishikawa, N.,
Masuyama, T., Kuzuya, T. et al. (1999) Intravenous
nicorandil can preserve microvascular integrity and
myocardial viability in patients with reperfused
anterior wall myocardial infarction. J Am Coll Cardiol
33: 654–660.
Keeley, E., Boura, J. and Grines, C. (2003) Primary
angioplasty versus intravenous thrombolytic therapy
for acute myocardial infarction: a quantitative review
of 23 randomised trials. Lancet 361: 13–20.
Kerins, D.M., Roy, L., FitzGerald, G.A. and
Fitzgerald, D.J. (1989) Platelet and vascular function
during coronary thrombolysis with tissue-type
plasminogen activator. Circulation 80: 1718–1725.
Kim, S.J., Kim, W., Woo, J.S., Ha, S.J., Kang,
W.Y., Hwang, S.H. et al. (2011) Effect of
myocardial protection of intracoronary adenosine
and nicorandil injection in patients undergoing
non-urgent percutaneous coronary intervention: a
randomized controlled trial. Int J Cardiol 20 January
(epub ahead of print).
Kloner, R.A., Giacomelli, F., Alker, K.J., Hale,
S.L., Matthews, R. and Bellows, S. (1991) Influx
of neutrophils into the walls of large epicardial
coronary arteries in response to ischemia/reperfusion.
Circulation 84: 1758–1772.
Kloner, R.A. and Rezkalla, S.H. (2006)
Preconditioning, postconditioning and their application
to clinical cardiology. Cardiovasc Res 70: 297–307.
Leosco, D., Fineschi, M., Pierli, C., Fiaschi, A.,
Ferrara, N., Bianco, S. et al. (1999) Intracoronary
serotonin release after high-pressure coronary
stenting. Am J Cardiol 84: 1317–1322.
Lim, S.Y., Bae, E.H., Jeong, M.H., Kang, D.G., Lee,
Y.S., Kim, K.H. et al. (2004) Effect of combined
intracoronary adenosine and nicorandil on no-reflow
phenomenon during percutaneous coronary
intervention. Circ J 68: 928–932.
Mahaffey, K.W., Puma, J.A., Barbagelata, N.A.,
DiCarli, M.F., Leesar, M.A., Browne, K.F. et al.
(1999) Adenosine as an adjunct to thrombolytic
therapy for acute myocardial infarction: results of a
multicenter, randomized, placebo-controlled trial:
The Acute Myocardial Infarction Study of Adenosine
(AMISTAD) trial. J Am Coll Cardiol 34: 1711–1720.
Marzilli, M., Orsini, E., Marraccini, P. and Testa, R.
(2000) Beneficial effects of intracoronary adenosine as
an adjunct to primary angioplasty in acute myocardial
infarction. Circulation 101: 2154–2159.
Matsumura, K., Jeremy, R.W., Schaper, J. and
Becker, L.C. (1998) Progression of myocardial
Therapeutic Advances in Cardiovascular Disease 6 (3)
necrosis during reperfusion of ischemic myocardium.
Circulation 97: 795–804.
Meldrum, D.R. (1998) Tumor necrosis factor in the
heart. Am J Physiol 274: R577–R595.
Moher, D., Cook, D.J., Eastwood, S., Olkin, I.,
Rennie, D. and Stroup, D.F. (1999) Improving the
quality of reports of meta-analyses of randomised
controlled trials: the QUOROM statement. Quality of
Reporting of Meta-analyses. Lancet 354: 1896–1900.
Neumann, F.J., Blasini, R., Schmitt, C., Alt, E.,
Dirschinger, J., Gawaz, M. et al. (1998) Effect of
glycoprotein IIb/IIIa receptor blockade on recovery
of coronary flow and left ventricular function after
the placement of coronary-artery stents in acute
myocardial infarction. Circulation 98: 2695–2701.
Pepine, C.J., Anderson, R.D., Sharaf, B.L., Reis,
S.E., Smith, K.M., Handberg, E.M. et al. (2010)
Coronary microvascular reactivity to adenosine
predicts adverse outcome in women evaluated for
suspected ischemia results from the National Heart,
Lung and Blood Institute WISE (Women's Ischemia
Syndrome Evaluation) study. J Am Coll Cardiol 55:
2825–2832.
Petronio, A.S., De Carlo, M., Ciabatti, N., Amoroso,
G., Limbruno, U., Palagi, C. et al. (2005) Left
ventricular remodeling after primary coronary
angioplasty in patients treated with abciximab or
intracoronary adenosine. Am Heart J 150: 1015.
Quintana, M., Hjemdahl, P., Sollevi, A., Kahan,
T., Edner, M., Rehnqvist, N. et al. (ATTACC
Investigators) (2003) Left ventricular function and
cardiovascular events following adjuvant therapy with
adenosine in acute myocardial infarction treated with
thrombolysis, results of the Attenuation by Adenosine
of Cardiac Complications (ATTACC) study. Eur J
Clin Pharmacol 59: 1–9.
Rosales, O.R., Eades, B. and Assali, A.R. (2004)
Cardiovascular drugs: adenosine role in coronary
syndromes and percutaneous coronary interventions.
Catheter Cardiovasc Interv 62: 358–363.
Ross, A.M., Gibbons, R.J., Stone, G.W., Kloner, R.A.
and Alexander, R,W. (AMISTAD-II Investigators)
Visit SAGE journals online (2005) A randomized, double-blinded, placebo-
http://tac.sagepub.com
controlled multicenter trial of adenosine as an adjunct
SAGE journals to reperfusion in the treatment of acute myocardial
114 http://tac.sagepub.com
infarction (AMISTAD-II). J Am Coll Cardiol
45: 1775–1780.
Rubio, R., Berne, R.M. and Katori, M. (1969)
Release of adenosine in reactive hyperemia of the dog
heart. Am J Physiol 216: 56–62.
Stoel, M.G., Marques, K.M., de Cock, C.C.,
Bronzwaer, J.G., von Birgelen, C. and Zijlstra, F.
(2008) High dose adenosine for suboptimal
myocardial reperfusion after primary PCI: a
randomized placebo-controlled pilot study. Cath
Cardiovasc Interv 71: 283–289.
Stone, G.W., Webb, J., Cox, D.A., Brodie, B.R.,
Qureshi, M., Kalynych, A. et al. Enhanced Myocardial
Efficacy and Recovery by Aspiration of Liberated
Debris (EMERALD) Investigators (2005) Distal
microcirculatory protection during percutaneous
coronary intervention in acute ST-segment elevation
myocardial infarction: a randomized controlled trial.
JAMA 293: 1063–1072.
Svilaas, T., Vlaar, P.J., van der Horst, I.C., Diercks,
G.F., de Smet, B.J., van den Heuvel, A.F. et al.
(2008) Thrombus aspiration during primary
percutaneous coronary intervention. N Engl J Med
358: 557–567
Taniyama, Y., Ito, H., Iwakura, K., Masuyama, T.,
Hori, M., Takiuchi, S. et al. (1997) Beneficial effect
of intracoronary verapamil on microvascular and
myocardial salvage in patients with acute myocardial
infarction. J Am Coll Cardiol 30: 1193–1199.
Taylor, A.J., Bobik, A., Richards, M., Kaye, D.,
Raines, G., Gould, P. et al. (2004) Myocardial
endothelin-1 release and indices of inflammation
during angioplasty for acute myocardial infarction and
stable coronary artery disease. Am Heart J 148: e10.
Tsao, T.P., Cheng, S.M., Cheng, C.C. and Yang, S.P.
(2009) Comparison of intracoronary adenosine and
isosorbide dinitrate on no-reflow/slow flow during
rotational atherectomy. Acta Cardiol 64: 225–230.
van’t Hof, A.W., Liem, A., Suryapranata, H.,
Hoorntje, J.C., de Boer, M.J. and Zijlstra, F. (1998)
Angiographic assessment of myocardial reperfusion
in patients treated with primary angioplasty for
acute myocardial infarction: myocardial blush
grade. Zwolle Myocardial Infarction Study
Group. Circulation 97: 2302–2306.