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results of the Melatonin Adjunct in the acute myocaRdial Infarction treated with
Sanchez5, Maria del Mar Garcia-Saiz6, Ana Aldea-Perona6, Tirso Virgos-Aller7, Agueda
Tenerife. Spain.
This article has been accepted for publication and undergone full peer review but has
not been through the copyediting, typesetting, pagination and proofreading process,
which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.1111/jpi.12374
This article is protected by copyright. All rights reserved.
(5) Hospital Universitario de Santa Lucia. Department of Cardiology, Murcia, Spain.
Tenerife. Spain.
(9) Department of Cellular and Structural Biology, University of Texas Health Science
e-mail: adrvdg@hotmail.com
ABSTRACT
The MARIA randomized trial evaluated the efficacy and safety of melatonin for the
myocardial infarction (STEMI). This was a prespecified interim analysis. A total of 146
patients presenting with STEMI within 6 hours of chest pain onset were randomized to
endpoints were changes in left ventricular volumes and ejection fraction (LVEF) at
13010 days post-PPCI and adverse events during the first year. No significant
post-PPCI, did not differ between melatonin and placebo groups (P=0.63). Infarct size
LVEF from 62 to 13010 days post-PPCI was greater in the placebo group
Accepted Article
(60.010.4% vs 53.112.5%,P=0.008). Both left ventricular end-diastolic and end-
systolic volumes were lower in the placebo group (P=0.01). The incidence of adverse
STEMI population, intravenous and intracoronary melatonin was not associated with a
reduction in infarct size and has an unfavourable effect on the ventricular volumes and
LVEF evolution. Likewise, there is lack of toxicity of melatonin with the doses used.
1 INTRODUCTION
requisite for limiting infarct size, the process of reperfusion itself causes injury
(ischaemia reperfusion injury, IRI) due, among other processes, to opening of the
reperfusion1.
such as hypertension, myocardial hyperthophy and IRI2,3. Petrosillo et al4 observed that
strong protective effect against oxidative alterations to complex I and III in isolated
mitochondria4.
In a later study, Petrosillo et al5 confirmed that melatonin protects the heart from
reperfusion injury by inhibiting MPTP opening, most likely via the prevention of
cardiolipin peroxidation. Moreover, it was found that mitochondria from aged rats
mitochondrial adaptive changes are likely of great value for the cardioprotective actions
of this indoleamine. Given that melatonin has shown efficacy in protecting human cells
and reduce infarct size in animal models of myocardial infarction, rationale exists for a
The objective of this study was to evaluate the safety, tolerability, and efficacy
the reduction of IRI among patients who present with a first STEMI undergoing primary
rationale and study design have been previously published7. Briefly, the MARIA study
placebo intravenous infusion just prior to balloon inflation. The study protocol
administered once the artery related to the infart was open, based on the study by
an animal model increased the coronary blood flow through the involvement of
MT1/MT2 receptors and nitric oxide release. The regulatory approvals were obtained
from Spanish Research Ethics Committee and European Healthcare Regulatory Agency
2.2 Patients
Patients were recruited in three centres. The study population included patients > 18
years of age with a first-time STEMI (defined as nitrate resistant chest pain 30 min,
and new ST elevation at J-point in two contiguous leads with cut-off points 0.2 mV in
Additional inclusion criteria were presentation within 6 hours of chest pain onset,
clinical decision to treat with PPCI, occlusion of culprit artery with thrombolysis in
potential. Patients were excluded if they had experienced cardiac arrest, cardiogenic
insufficiency, known history of severe renal failure, and inability to give informed
Initial written consent was obtained where possible, with the majority of patients
providing verbal agreement. Subsequently, fully informed written consent was sought.
2.3 Randomization
The randomization procedure was Web-based, with the use of permuted blocks. We
stratified randomization according to hospital, and use of melatonin (yes or no). The
minutes starting immediately before PCI and a bolus of 8.6 mol of intracoronary
melatonin given through the PCI-guiding catheter within the first 60 seconds after
restoring the blood flow to the infarct related artery. The control group received a
matching placebo formulation. Technical aspects of the PPCI procedure were left to
clinician discretion and all the patients received medical therapy in accordance with
current guidelines9.
sequences endorsed by the ESC10. Endocardial and epicardial borders were delineated at
deviations above average, obtained from the remote healthy myocardium, and
normalized by the left ventricular mass. All MRI measurements were taken by
The primary outcome was the difference in infarct size (expressed as a percentage of
left ventricular myocardial mass) between the active and placebo groups at early MRI
The secondary outcomes were the incidence of major adverse cardiac events,
defined as a composite of death, heart failure, re-infarction, and angina at 360 days and
differences between groups of MRI data in the infarct size, left ventricular ejection
adjudicated by a Clinical Event Committee that included two cardiologists who were
The sample size was based on a previous study that tested the cardioprotective effect of
interventions in acute STEMI, data loss from randomized patients were high12. In our
study, sample size was inflated by 30% to account for loss of primary outcome data
to detect the anticipated effect size with 80% power at the 5% alpha level7. We planned
Accepted Article
in this trial an interim efficacy analysis in the first 50% of patients enrolled. The interim
analyses was conducted for the primary measure of efficacy as well as safety to
determine if there is strong evidence of efficacy, clear lack efficacy, or safety concerns
Discrete variables have been described with counts and percents, continuous
with means and deviations or medians and quartiles depending on if its distribution
independent test for discrete variables and U- Mann Whitney independent non-
parametric test for non- parametric continuous variables and t-Student independent test
for continuous variables. All efficacy analyses were performed according to the
groups were evaluated with Cox-Mantel log-rank test. For all analyses, statistical
significance was assumed when the 2-tailed P < 0.05. Statistical analysis was performed
with the Statistical Package for the Social Sciences (SPSS, IBM) version 23.0.
3 RESULTS
One hundred and forty six patients were randomized to receive intravenous and
intracoronary melatonin (n=73) or placebo (n=73). Three patients (2%) were not
scheduled for MRI because not enzymatic evidence of infarction. Of patients scheduled
for MRI, 18 (12%) did not undergo MRI because of poor clinical status (n=10),
claustrophobia (n=7), or technical problems with the magnet (n=1). Patients with poor
clinical status not undergoing MRI included 6 patients in the melatonin group (all with
refractory heart failure). Thus, 125 patients (63 receiving intravenous and intracoronary
Accepted Article
melatonin and 62 control subjects) had MRI data available for primary analysis. A
Figure 1.
Groups were well balanced for age, gender, cardiovascular risk factors and chest
pain onset-to-balloon time (Table 1). All patients showed a TIMI flow grade 0-1 before
PPCI. All patients received the standard anti-platelet therapy pre-PPCI, 60% received
PPCI. There were no significant differences between melatonin and placebo groups in
differences at hospital discharge medications. Patients showing partial (30 to < 70%)
The primary outcome data of MRI at 6 2 days post-PPCI were obtained from 55 of 63
(87%) participants in the melatonin and 53 of 62 (85%) in the placebo group. The
reason for not obtaining primary outcome data was unreadable scans (17 in total). The
0.06). Overall no significant differences were found between groups in the percentage
The secondary outcome data of MRI at 130 10 days post-PPCI were obtained from 44
statistically significant differences between melatonin and placebo groups (Table 4).
Accepted Article
However, the recovery of LVEF from baseline to 130 10 days post-PPCI was greater
in the placebo group (P = 0.008). Moreover, both left ventricular end-diastolic and end-
systolic volumes were lower in the placebo group (Table 4 and Figure 2).
Melatonin infusion was generally safe and well tolerated. At 12 months follow up there
62 participants (19%) in the placebo group. No deaths occurred in either group. Table 5
shows the clinical composite endpoint at 30 and 360 days. No significant differences
were observed with respect to death, congestive heart failure, reinfarction or occurrence
of angina.
4 DISCUSSION
intravenous and intracoronary during PPCI for STEMI, melatonin, had an acceptable
safety and tolerability profile. In this study, however, melatonin did not appear to exert
a significant effect on myocardial infarct size measured by MRI. Moreover, it may have
a detrimental effect after STEMI, mainly because it might facilitate left ventricular
remodelling.
Multiple therapeutic strategies have aimed at reducing infarct size in the setting
events16. In contrast to MITOCARE, the EMBRACE STEMI study tested the MPTP-
131 in patients with large anterior STEMIs which was not associated with a decrease in
immunosuppresant that prevents T cells activity, also directly inhibits the opening of
MPTP and could have a potential role in reducing infarct size. Thus, cyclosporine has
been used in two small pilot trials18,19. However, the Cycloposporine and Prognosis in
Acute MI Patients (CIRCUS) trial that included 791 patients recently demonstrated that
cyclosporine did not improve 1-year clinical outcome after STEMI. Specifically, the
treatment failed to reduce the incidence of both single and composite outcomes
and a rapid increase of reactive oxygen species production. These factors contribute to
increase of MPTP opening in the early minutes of reperfusion. The use of antioxidants
to prevent IRI, via MPTP inhibition, appears to be a logical measure to improve the
variety of reactive oxygen and nitrogen species including the hydroxyl radical, peroxyl
dismutase and glutathione peroxidase and acts synergistically with other endogenous
virtually impossible since the onset of a STEMI is totally unpredictable. Therefore, the
Accepted Article
only option available in patients presenting with a STEMI is to administer the drug just
thereby optimising the antioxidant capacity needed for a possible modification of the
oxidative stress response and the degree of IRI24. In the present study, the patients
This dose causes approximately 12,000 times blood level with respect to the highest
melatonin given through the PCI-guiding catheter after restoring the blood flow to the
infarct related artery. Melatonin was well tolerated in this study. Previous studies have
response studies for assessment of the optimal dose of melatonin for cardioprotection
during myocardial reperfusion have been done. In a clinical study on lower body
ischemia and reperfusion during abdominal aortic repair a total dose of 50 mg plus a
coronary artery bypass graft surgery, whose participants were randomly allocated into 3
study groups: placebo, low dose melatonin treatment group (10 mg capsule once daily)
and high dose melatonin treatment group (20 mg capsule once daily). They
size24. In our trial, the median pain-to-balloon time (200 minutes) was so long that it
indicating that reperfusion-induced myocardial salvage rapidly decreases after the first
Accepted Article
120 minutes of ischemia29. Identifying the best timing for melatonin administration for
attaining cardioprotection has implications for the chain of care for STEMI patients.
myocardial infarct size in those patients with a short ischaemic time (< 2.5 h).
On the other hand, we showed that melatonin had a detrimental effect on left
mechanical scaffold on which myocytes are arrayed for coordinated and synergistic
into the coronary circulation using doses causing 10,000 times higher values than
nocturnal blood levels. The question arises whether high doses of melatonin into the
coronary circulation might have deleterious effects on scar formation favouring the left
ventricular remodeling.
because we aimed to obtain plasma melatonin concentrations within the effective range,
previously have been suggested in studies with other molecules33. With our clinical
trial, we raised important questions of the dose and timing of the administration of
This investigation has some limitations. During the course of this trial, the
primary endpoint was changed from enzymatic infarct size to infarct size measured by
MRI, since the infarct size could be studied more precisely with MRI. A possible
limitation of our trial is that 26% of the recruited patients population did not undergo
MRI for primary end-point evaluation. Compared with similar studies, our loss of data
was modest12,13. Moreover, we evaluated the infarct size based on the peak value of
troponin I measured every 8 h for 24 h, and this may not have provided sufficient
accuracy to estimate infarct size compared with more frequent sampling or measuring
the area under the curve. Late MRI was not done in all patients with available early
MRI because ot the limitations in two of the centers. The sample size was clearly
underpowered for clinical events and no conclusions can be drawn in this regard.
5 CONCLUSION
that intravenous infusion and intracoronary bolus of melatonin in patients with first
acute STEMI is safe but does not reduce infarct size and has an unfavourable effect on
ACKNOWLEDGEMENTS
We would like thank our patients and the staff of the cardiology and radiology/cardiac
The MARIA trial was a noncommercial trial. This study was supported by Institute
Accepted Article
Carlos III (ISCIII) (PI15 / 01260), General Branch Evaluation and Research Promotion,
State Plan of Scientific and Technical Research and Innovation 2013-2016 and
European Regional Development Fund Health - FEDER-, which relates to the topic of
this study.
DISCLOSURES
A.D-R and P.A-G have a patent to the use of melatonin in ST-elevation myocardial
AUTHORS' CONTRIBUTIONS
A.D-R. coordinated the study, interpreted the results and contributed to the manuscript;
A.D-R. handled funding and supervision; A.D-R., P.A-G and R.J.R. conceived and
designed the research; A.D-R., P.A-G., J.M.T-H., J.G-G., T.G-C., L.C-S., M.M.G-S., A.
A-P., T.V-A. and N.C-E. contributed to recruitment, data collection including follow-up
statistical analysis of the data. A.D-R., P.A-G., J.M.T-H., J.G-G., T.G-C., L.C-S.,
M.M.G-S., A. A-P., T.V-A., N.C-E. and A.A. drafted the manuscript. R.J.R. made
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2010;55:1200-1205.
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FIGURE LEGENDS
(N=63) (N=62)
Discharge medication
Values are counts (%) and means standard deviation or median (interquartile range).
CAD, coronary artery disease; LAD, left anterior descending artery; LCx, left circunflex
artery; LV, left ventricular; PCI, percutaneous coronary intervention; RCA, right
(N=63) (N=62)
(N = 55) (N = 53)
(N = 55) (N = 53)
(N = 44) (N = 43)
(N = 55) (N = 53)
Infarct size (proportion of LV mass) (%) 12.1 (6.0-23.2) 13.1 (5.5-18) 0.63
(N = 54) (N = 52)
(N = 54) (N = 52)
(N = 44) (N = 47)
(N = 44) (N = 47)
(N = 40) (N = 44)
(N = 44) (N = 47)
(N = 44) (N = 45)
(N = 44) (N = 45)
(N=63) (N=62)
Reinfarction
Angina re-hospitalization
30 7 days
Reinfarction
Angina re-hospitalization
12 1.5 months