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Received Date : 17-Aug-2016

Revised Date : 06-Oct-2016


Accepted Article
Accepted Date : 10-Oct-2016

Article type : Original Manuscript

Effect of intravenous and intracoronary melatonin as an adjunct to primary

percutaneous coronary intervention for acute ST-elevation myocardial infarction:

results of the Melatonin Adjunct in the acute myocaRdial Infarction treated with

Angioplasty (MARIA) trial.

Alberto Dominguez-Rodriguez1,2, Pedro Abreu-Gonzalez3, Jose M de la Torre-

Hernandez4, Julia Gonzalez-Gonzalez1, Tamara Garcia-Camarero4, Luciano Consuegra-

Sanchez5, Maria del Mar Garcia-Saiz6, Ana Aldea-Perona6, Tirso Virgos-Aller7, Agueda

Azpeitia8, Russel J Reiter9. On behalf of the MARIA investigators++.

(1) Hospital Universitario de Canarias. Department of Cardiology. Santa Cruz de

Tenerife. Spain.

(2) Facultad de Ciencias de la Salud. Universidad Europea de Canarias. La Orotava.

Santa Cruz de Tenerife. Spain.

(3) Departamento de Ciencias Mdicas Bsicas (Unidad de Fisiologa), Universidad de

La Laguna. Santa Cruz de Tenerife. Spain.

(4) Hospital Universitario Marques de Valdecilla. Department of Cardiology.

Santander, Cantabria. 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.

(6) Hospital Universitario de Canarias. Department of Pharmacology. Santa Cruz de


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Tenerife. Spain.

(7) Hospital Universitario de Canarias. Department of Pharmacy. Santa Cruz de

Tenerife. Spain.

(8) onmedic Networks. Barcelona. Spain.

(9) Department of Cellular and Structural Biology, University of Texas Health Science

Center, San Antonio, TX, USA.

(++) Natalia Caballero-Estevez*, Alejandro de la Rosa*, Julia Nazco-Casariego*, Teresa

Gimnez Poders**, Ignacio Laynez-Cerdea*, Francisco Bosa-Ojeda*, Alejandro

Sanchez-Grande*, Geoffrey Yanes-Bowden*, Manuel Vargas-Torres*, Antonio Lara-

Padrn*, Pablo Perez-Jorge*, Lucio Diaz-Flores*, Jorge Lopez*, Juan Lacalzada-

Almeida*, Amelia Duque*, Miguel Bethencourt*, Mariela Izquierdo*, Ruben Juarez-

Prera*, Gabriela Blanco-Palacios*, Antonio Barragan-Acea*, Julio Ferrer-Hita*, Belen

Mar-Lopez*, Marta Padilla*, Esther Gonzalez*, Marta Martin-Cabeza*, Corabel

Mendez-Vargas*, Patricia Barrios*, Carima Belleyo-Belkasem*, Miguel Leiva*, Ivan

Betancor*, Julio Miranda*, Federico Soria-Arcos, Lourdes Martinez.

* Hospital Universitario de Canarias. Santa Cruz de Tenerife. Spain.

** Hospital Universitario Marques de Valdecilla. Santander, Cantabria. Spain.

Hospital Universitario de Santa Luca, Murcia. Spain.

Running title: Melatonin and acute myocardial infarction.

This article is protected by copyright. All rights reserved.


Corresponding author: Dr. Alberto Dominguez-Rodriguez. Hospital Universitario de

Canarias, Department of Cardiology, Ofra s/n La Cuesta E-38320, Tenerife, Spain.


Accepted Article
Telephone: +34 922679040

Fax: +34 922 677284

e-mail: adrvdg@hotmail.com

Keywords: melatonin; acute myocardial infarction; infarct size; mitochondria; primary

angioplasty, heart ischemia-reperfusion injury.

ABSTRACT

The MARIA randomized trial evaluated the efficacy and safety of melatonin for the

reduction of reperfusion injury in patients undergoing revascularization for ST-elevation

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

receive intravenous and intracoronary melatonin (n=73) or placebo (n=73) during

primary pecutaneous coronary intervention (PPCI). Primary endpoint was myocardial

infarct size as assessed by magnetic resonance imaging (MRI) at 62 days. Secondary

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

differences in baseline characteristics were observed between groups. MRI was

performed in 108 patients(86.4%). Myocardial infarct size by MRI evaluated 62 days

post-PPCI, did not differ between melatonin and placebo groups (P=0.63). Infarct size

assessed by MRI at 13010 days post-PPCI, performed in 91 patients(72.8%), did not

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show statistically significant differences between groups(P=0.27). The recovery of

LVEF from 62 to 13010 days post-PPCI was greater in the placebo group
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(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

events at 1 year was comparable in both groups (P=0.150). Thus, in a non-restricted

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

Heart failure is a common long-term complication of acute myocardial infarction. While

prompt reperfusion in acute ST-elevation myocardial infarction (STEMI) is a pre-

requisite for limiting infarct size, the process of reperfusion itself causes injury

(ischaemia reperfusion injury, IRI) due, among other processes, to opening of the

mitochondrial permeability transition pore (MPTP) occurring 3 minutes after

reperfusion1.

Melatonin has significant beneficial effects in several cardiovascular conditions,

such as hypertension, myocardial hyperthophy and IRI2,3. Petrosillo et al4 observed that

reperfusion of the ischemic heart significantly altered several mitochondrial parameters,

while melatonin treatment had a strong protective effect by attenuating these

perturbations. The beneficial actions of melatonin in these situations appear to be due, at

least in part, to melatonin's ability to limit reactive oxygen species damage to

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cardiolipin, which plays a pivotal role in mitochondrial bioenergetics. The prevention of

mitochondrial dysfunction was associated with an improvement in the postischemic


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hemodynamic function of the heart. In addition to cardiolipin, melatonin also had a

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

displayed an increased susceptibility to Ca2-induced MPTP opening, which was

associated with an elevated release of cytochrome c; melatonin treatment counteracted

both of these processes6. Therefore, these results emphasize that melatonin-induced

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

clinical study in humans.

The objective of this study was to evaluate the safety, tolerability, and efficacy

of intravenous and intracoronary administration of melatonin as an adjunct therapy for

the reduction of IRI among patients who present with a first STEMI undergoing primary

percutaneous coronary intervention (PPCI).

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2 METHODS

2.1 Study design


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Between May 2013 and March 2015, we conducted the MARIA trial, which is a phase

IIa, prospective, multicentre, randomized, double-blind, placebo-controlled study. The

rationale and study design have been previously published7. Briefly, the MARIA study

randomized patients with a first-time acute STEMI undergoing PPCI to melatonin or

placebo intravenous infusion just prior to balloon inflation. The study protocol

recommended the use of an intravenous infusion and an intracoronary bolus,

administered once the artery related to the infart was open, based on the study by

Grossini et al in 20118 that showed that the intracoronary administration of melatonin in

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

(EudraCT number 2005-000821-49). The study was registered (NCT00640094) and

overseen by trial steering and data monitoring committees7.

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

men or 0.15 mV in women in leads V2V3 and/or 0.1 mV in other leads).

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

myocardial infarction (TIMI) basal flow grade 01 and being of non-child-bearing

potential. Patients were excluded if they had experienced cardiac arrest, cardiogenic

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shock, previous coronary artery disease, prehospital fibrinolytic therapy, had a

pacemaker implanted, concurrent inflammatory condition, infectious, or malignant


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disease, severe concurrent illness with reduced short-term prognosis, hepatic

insufficiency, known history of severe renal failure, and inability to give informed

consent and participation in another study within the past 30 days.

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

company responsible for this procedure was "onmedic Network"

(http://www.onmedic.com). The investigational product was a formulation of melatonin

in polyethylene glycol solution (Farma Mediterrnea, S.L. Barcelona, Spain). Patients

randomised to melatonin received a dose of 51.7 mol given by a time period of 60

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.

2.4 Magnetic resonance imaging

Magnetic resonance imaging (MRI) was planned to be performed at 5 to 7 days

(baseline) and 4 months (chronic) post-PPCI using internationally standardized

sequences endorsed by the ESC10. Endocardial and epicardial borders were delineated at

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end-systole and end-diastole with short-axis views to quantify volumes, function and

left ventricle mass. Quantification of the infarcted myocardium was assessed by


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delineating the enhanced areas in the late enhancement sequences, with 5 standard

deviations above average, obtained from the remote healthy myocardium, and

normalized by the left ventricular mass. All MRI measurements were taken by

experienced researchers unaware of the study group assignment.

2.5 Outcomes and follow-up

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

post- infarct assessed by the extent of late gadolinium enhancement on 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

fraction (LVEF) and ventricular volumes from baseline to follow-up. STEMI

cardiovascular complications and suspected unexpected serious adverse reaction were

adjudicated by a Clinical Event Committee that included two cardiologists who were

not participants in the study.

2.6 Statistical analysis

The sample size was based on a previous study that tested the cardioprotective effect of

adenosine in STEMI-patients11. In previous published studies of conditioning

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

due to death, contraindication to or failure to proceed to MRI or inadequate MRI

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quality13. Therefore, the proposed sample size of 272 (136 in each group) was required

to detect the anticipated effect size with 80% power at the 5% alpha level7. We planned
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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

for the active treatment.

Discrete variables have been described with counts and percents, continuous

with means and deviations or medians and quartiles depending on if its distribution

could be assumed as normal. Univariate comparisons were performed by chi square

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

intention-to-treat principle. Differences in the occurrence of adverse events between

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

3.1 Characteristics of the study population

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

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refractory heart failure) compared with 4 patients in the control group (all patients with

refractory heart failure). Thus, 125 patients (63 receiving intravenous and intracoronary
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melatonin and 62 control subjects) had MRI data available for primary analysis. A

CONSORT (Consolidated Standards of Reporting Trials) flow diagram is shown in

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

glycoprotein IIb-IIIa inhibitors, and 95% received unfractionated heparin pre/during

PPCI. There were no significant differences between melatonin and placebo groups in

the infarct size expressed as peak troponin I at 24 h. There were no significant

differences at hospital discharge medications. Patients showing partial (30 to < 70%)

ST-segment resolution 24 h post-PPCI were numerically higher in the melatonin group

(P = 0.06) (Table 2).

3.2 Primary outcome of MRI

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

left ventricular end-diastole volume tended to be higher in the melatonin group (P =

0.06). Overall no significant differences were found between groups in the percentage

of total necrotic myocardial mass as determined by enhancement on MRI (Table 3).

3.3 Secondary outcome of MRI

The secondary outcome data of MRI at 130 10 days post-PPCI were obtained from 44

of 55 (80%) participants in the melatonin and 47 of 53 (88%) in the placebo group.

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Reasons for incomplete data included logistic problems. The infarct size did not show

statistically significant differences between melatonin and placebo groups (Table 4).
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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).

3.4 Safety data and follow-up

Melatonin infusion was generally safe and well tolerated. At 12 months follow up there

were 13 events in 11 of 63 participants (17%) in the melatonin group, 13 events in 12 of

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

We have demonstrated in this first-in-human study that, when administered via

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

of STEMI and have failed. Experimental evidence suggests that pharmacological

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treatments designed to prevent MPTP opening at the onset of myocardial reperfusion

are capable of reducing myocardial infarct size by 30-50%14,15. Modulators of


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mitochondrial function such as the peptide TRO40303, tested in the MITOCARE trial,

failed to reduce IRI also inducing a nonnegligible number of adjudicated safety

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

myocardial infarct size assessed by myocardial enzyme release17. Cyclosporine, an

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

including recurrent infarction, unstable angina and stroke20.

In a reperfusion process, there is an increased release of Ca2+ into mitochondria

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

myocyte survival21. Melatonin, an endogenously produced circadian hormone of the

pineal gland, is a potent direct and indirect antioxidant in physiological as well as

pharmacological concentrations3,22,23. Melatonin is a potent radical scavenger of a wide

variety of reactive oxygen and nitrogen species including the hydroxyl radical, peroxyl

radical, hydrogen peroxide and radical derivatives of nitric oxide24. Moreover,

melatonin stimulates the intracellular antioxidant enzymes including superoxide

dismutase and glutathione peroxidase and acts synergistically with other endogenous

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antioxidants25. Pretreatment with melatonin in patients at the beginning of STEMI is

virtually impossible since the onset of a STEMI is totally unpredictable. Therefore, the
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only option available in patients presenting with a STEMI is to administer the drug just

before reperfusion. In our study, we administered intravenous infusion of melatonin just

before performing PCI to establish supraphysiologic levels of plasma melatonin,

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

received 12 mg of melatonin intravenously as a continuous infusion for 60 minutes.

This dose causes approximately 12,000 times blood level with respect to the highest

nocturnal blood levels. In addition, we administered a bolus of 2 mg of intracoronary

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

demonstrated the lack of toxicity of intravenous melatonin in human26. No dose

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

postoperative dose of 30 mg was sufficient to attenuate oxidative stress and reduce

myocardial damage27. Recently, Dwaich et al in patients who were undergoing elective

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

demonstrated that melatonin supplementation can ameliorate the degree of myocardial

ischemic-reperfusion injury, which these effects were dose-dependent28.

Experimental studies in animals have proven that melatonin limits infarct

size24. In our trial, the median pain-to-balloon time (200 minutes) was so long that it

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likely negated the benefits of melatonin in reducing lethal IRI. There is evidence

indicating that reperfusion-induced myocardial salvage rapidly decreases after the first
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120 minutes of ischemia29. Identifying the best timing for melatonin administration for

attaining cardioprotection has implications for the chain of care for STEMI patients.

Therefore, a post hoc analysis might reveal if there is a significant reduction in

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

ventricular remodelling, characterized by a progressive increase in both left ventricular

end-diastolic and end-systolic volumes. The early hypertrophic remodeling of the

remote non-infarcted myocardium is considered an adaptive response to preserve

cardiac performance. The myocardial extracellular matrix, an interwoven meshwork of

proteins, glycoproteins, proteoglycans, and glycosaminoglycans serves as the

mechanical scaffold on which myocytes are arrayed for coordinated and synergistic

force transduction30. Recently, Drobnik et al demonstrated that the collagen and

glycosaminoglycans accumulation in the myocardium of the infarcted heart is

augmented by melatonin31,32. In our study, a part of melatonin was locally administered

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.

In our study, a continuous infusion and intracoronary bolus were chosen,

because we aimed to obtain plasma melatonin concentrations within the effective range,

but too high plasma concentrations possibly leading to loss of cardioprotection as

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

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melatonin in relation to reperfusion and the therapeutic options available in the clinical

setting of PPCI. These issues should be answered in future research on the


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cardioprotective effects of melatonin

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

This multicentre, randomized, double blind, placebo-controlled phase 2 trial showed

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

the ventricular volumes and LVEF evolution.

ACKNOWLEDGEMENTS

We would like thank our patients and the staff of the cardiology and radiology/cardiac

MRI departments at all sites.

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FUNDING INFORMATION

The MARIA trial was a noncommercial trial. This study was supported by Institute
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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

infarction (P 201400743). The other authors report no conflict of interest.

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

assessments, data interpretation, and contributed to the manuscript; A.A., performed

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

critical revision of the manuscript for key intellectual content.

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FIGURE LEGENDS

FIGURE 1. CONSORT diagram. MRI, magnetic resonance imaging

FIGURE 2. Change () in cardiac magnetic resonance imaging findings in the

ventricular volumes from 6 2 days (baseline) to 130 10 days (chronic) post-

percutaneous coronary intervention. LVEDV, left ventricular end-diastolic volume;

LVESV, left ventricular end-systolic volume.

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TABLES

Table 1. Baseline characteristics of 125 patients with STEMI, randomized to either


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melatonin or placebo.

Characteristic Melatonin Placebo P-value

(N=63) (N=62)

Age (years) 57.3 10 58.4 9.4 0.632

Male sex 50 (79.4) 51 (82.3) 0.681

Body mass index, kg/m2 28.0 4.6 29.6 6.7 0.111

Hypertension 29 (46.8) 34 (54.8) 0.369

Acive smoking 31 (49.2) 35 (56.5) 0.417

Dyslipidemia 40 (64.5) 31 (50.0) 0.102

Diabetes mellitus 10 (16.1) 7 (11.3) 0.433

Symptoms onset to balloon time (min) 0.264

Mean SD 215.1 81.5 228.0 70.4

Median (25th,75th) 200 (150,280) 220 (167,282)

Culprit vessel LAD 27 (42.9) 26 (41.9) 0.917

Culprit vessel RCA 35 (55.6) 32 (51.6) 0.659

Culprit vessel LCx 1 (1.6) 4 (7.5) 0.165

PCI with stent 59 (93.7) 55 (90.2) 0.526

CAD multivessel (2 o 3 vessel) 22 (34.9) 15 (24.6) 0.209

LV ejection fraction (%) measured by 56.1 10.9 57.8 10.8 0.346


echocardiography at 4 1 days, post-PCI

Peak troponin I at 24 h, ng/mL 41 (18,78) 29 (15,54) 0.184

Creatinine, mg/dL 0.84 0.18 0.84 0.17 0.653

Discharge medication

Aspirin 63 (100) 62 (100) -

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Beta Blocker 53 (84) 50 (80.6) 0.591

Statins 63 (100) 62 (100) -


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ACE inhibitors 47 (74.6) 54 (87.1) 0.138

Prasugrel 19 (30.5) 26 (41.9) 0.282

Ticagrelor 13 (20.5) 8 (12.9) 0.339

Clopidogrel 31(49) 28 (45.2) 0.745

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

coronary artery; SD, standard deviation.

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Table 2. ST-segment resolution immediately and 24 h post-PCI.
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Melatonin Placebo P-value

(N=63) (N=62)

ST-segment resolution immediately post-PCI

Absent (<30%) 5 (7.9) 7 (11.3) 0.525

Partial (30 to <70%) 13 (20.6) 12 (19.4) 0.858

Complete (70%) 45 (71.4) 43 (69.4) 0.800

ST-segment resolution 24 h post-PCI

Absent (<30%) 0 2 (3.2) 0.244

Partial (30 to <70%) 15 (23.8) 7 (11.3) 0.060

Complete (70%) 48 (76.2) 53 (85.5) 0.187

Values are counts (%).

PCI, percutaneous coronary intervention.

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Table 3. Cardiac magnetic resonance imaging at 6 2 days post-PCI.
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Cardiac MRI parameters Melatonin Placebo P-value

LV end-diastolic volume (mL) 164.1 46.1 157.6 39.4 0.06

(N = 55) (N = 53)

LV end-systole volume (mL) 81.5 38.2 70.9 27.9 0.98

(N = 55) (N = 53)

Total LV mass (g) 133.2 29.4 135.2 36.6 0.61

(N = 44) (N = 43)

LV ejection fraction (%) 52.5 10.3 55.5 10.4 0.15

(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)

Infarct size (g) 16.5 (6.7-33.5) 17.8 (6.9-25.7) 0.70

(N = 54) (N = 52)

Values are means standard deviation or median (interquartile range).

LV, left ventricular; MRI, magnetic resonance imaging.

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Table 4. Cardiac magnetic resonance imaging at 130 10 days post-PCI.
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Cardiac MRI parameters Melatonin Placebo P-value

LV end-diastolic volume (mL) 190.8 60.8 166.8 42.9 0.030

(N = 44) (N = 47)

LV end-systole volume (mL) 89.1 53 68.2 32.2 0.010

(N = 44) (N = 47)

Total LV mass (g) 130.4 36.2 129.1 36.4 0.770

(N = 40) (N = 44)

LV ejection fraction (%) 53.1 12.5 60 10.4 0.008

(N = 44) (N = 47)

Infarct size (proportion of LV mass) (%) 11.3 (4.5-16.7) 9 (5.3-12.6) 0.270

(N = 44) (N = 45)

Infarct size (g) 14.1 (5.1-25.5) 10.7 (5.9-16.2) 0.337

(N = 44) (N = 45)

Values are means standard deviation or median (interquartile range).

LV, left ventricular; MRI, magnetic resonance imaging.

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Table 5. Clinical composite endpoint through 30 7 days and through 12 1.5
months
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Clinical composite endpoint Melatonin Placebo P-value

(N=63) (N=62)

All-cause death, new onset

CHF re-hospitalization 2 (3.3) 0 0.496

Reinfarction

Angina re-hospitalization

30 7 days

All-cause death, new onset

CHF re-hospitalization 10 (15.4) 3 (4.9) 0.150

Reinfarction

Angina re-hospitalization

12 1.5 months

Values are counts (%).

CHF, congestive heart failure.

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Accepted Article

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Accepted Article

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