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Relation
Dominguez-Rodriguez A, Abreu-Gonzalez P, de la Torre-Hernandez JM, et al. Utility of early treatment with melatonin to reduce infarct size in patients with ST-segment elevation myocardial infarction receiving percutaneous coronary intervention (from melatonin supplementation in the Acute Myocardial Infarction Treated With Angioplasty trial).Am J Cardiol. 2017;120(4):522-526.
Study objective
To evaluate whether the treatment effect of high-dose melatonin therapy in patients with ST-segment elevation myocardial infarction (STEMI) is influenced by the time to administration in relation to the cardiac event.
Draft
The authors conducted a post hoc analysis of melatonin supplementation in the Acute Myocardial Infarction Treated With Angioplasty (MARIA) trial (NCT00640094), in which STEMI patients were randomly assigned to melatonin (intravenous and intracoronary bolus) or placebo during primary percutaneous coronary intervention (PCI).
Participant
The MARIA study included 146 patients who presented with STEMI within 6 hours of chest pain onset. Participants were randomized to receive intravenous and intracoronary melatonin (n=73) or placebo (n=73) during primary PCI.
Study medication and dosage
Participants in the MARIA study received 12 mg of melatonin intravenously as a continuous infusion for 60 minutes. This dose increases melatonin blood levels approximately 12,000 times higher than peak nighttime levels. Additionally, patients received a bolus of 2 mg intracoronary melatonin administered through the PCI guiding catheter after blood flow to the infarct-associated artery was restored.
Target parameters
The primary efficacy endpoint of the original MARIA study was to determine whether melatonin treatment reduced infarct size, as determined by cumulative release of alpha-hydroxybutyrate dehydrogenase (area under the curve: 0 to 72 h). Secondary endpoints were clinical events occurring within the first 90 days: death, sustained ventricular arrhythmias, resuscitation after cardiac arrest, cardiogenic shock, heart failure, major bleeding, stroke, need for revascularization, recurrent ischemia, reinfarction, and rehospitalization.1
Over the past year, there has been strong evidence that melatonin has been useful.
The study reviewed here is a secondary post hoc analysis of data from the MARIA study. The authors divided patients treated in the MARIA trial into 3 groups (tertiles) based on the time between symptom onset and “balloon time” (when the balloon is inflated to restore flow during PCI):
- Erstes Tertil: 136 ± 23 Minuten
- Zweites Tertil: 196 ± 19 Minuten
- Drittes Tertil: 249 ± 41 Minuten
They used statistical analyzes to assess the relationships between treatment effect and time.
Key insights
This is the second of 2 major publications from the MARIA study on melatonin and heart attacks this year. This study examined whether the treatment effect of melatonin therapy in patients with STEMI is influenced by time to administration.
The original MARIA study began in 2007 and was a single-center, prospective, randomized, double-blind, placebo-controlled phase 2 study of intravenous administration of melatonin. The results of this study were published in January 2017.2
The present analysis was published in August 2017 and examined the effect of time to melatonin administration in MIs. The information from these two studies is relevant.
The first publication of MARIA results in January showed little benefit from melatonin administration. Baseline characteristics between groups were similar. Myocardial infarction size, as assessed by MRI within 1 week of the procedure, did not differ between the melatonin and placebo groups (P=0.63). Infarct size 130 days after primary PCI performed in 91 patients (72.8%) showed no statistically significant differences between groups (P=0.27). Recovery of left ventricular volume and ejection fraction (LVEF) from 6 to 130 days postprocedure was not significantly different, although the placebo group trended toward higher volumes (60.0 ± 10.4% vs. 53.1 ± 12.5%;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). Therefore, in an unrestricted STEMI population, intravenous and intracoronary melatonin was not associated with a reduction in infarct size and has an adverse effect on ventricular volumes and LVEF development.2
Among patients in the first tertile who underwent the procedure sooner after symptom onset, infarct size was significantly smaller in subjects treated with melatonin compared to placebo (14.6 ± 14.2 vs. 24.9 ± 9.0%;P=0.003).
On the other hand, melatonin treatment was associated with larger infarct size in patients included in the third tertile (20.5 ± 8.7% vs. 11.2 ± 5.2%;P=0.001).
Practice implications
Everyone would like to have a simple intervention that can be given to a patient during and after a heart attack that reduces long-term damage and speeds recovery.
In these reviews we generally report good news; The MARIA study is something of an exception to this rule. The intervention did not provide any benefit to these patients, but frankly it is not an intervention that a naturopath would consider - it is outside our scope and certainly outside our philosophy.
Over the past year, there has been strong evidence that melatonin has been useful. A June 2017 study reported that melatonin alleviated myocardial ischemia/reperfusion injury in rats.3It also suppresses platelet activation triggered by cardiac ischemia/reperfusion injury.4
Maybe the MARIA melatonin dose was just too high or too intense. Perhaps it reached the heart too late to be of any use.
A year ago, Javanamard et al reported that they had conducted a double-blind, randomized, controlled trial of 39 patients (32 men and 7 women) with 3-vessel coronary artery disease who had undergone coronary artery bypass graft surgery. Of these patients, 20 received 10 mg of melatonin orally at bedtime for 1 month. The 19-member control group received placebo. Mean levels of 3 markers of endothelial cell function, including intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and C-reactive protein (CRP), showed statistically significant reductions in the melatonin group. There was a statistically significant decrease in serum nitric oxide (NO) in the control group but no change in the melatonin group.5
This is confusing. We had hoped that the MARIA study would provide a clear justification for aggressively targeting melatonin for use in patients with heart attacks or balloon procedures to limit tissue damage and speed recovery. In this case, timing makes a big difference; Early administration could still prove beneficial, but treating later could backfire.
Harvard researcher Eva Schernhammer reported in May 2017 that there is a significant inverse association between melatonin secretion and MI risk, with lower melatonin secretion being significantly associated with a higher risk of MI. The odds ratio (OR) for each unit lower log-transformed sulfatoxymelatonin/creatinine ratio was 1.51 (95% confidence interval [CI]: 1.16-1.96). Women in the highest category had an estimated absolute risk of MI of 84 cases per 100,000 person-years compared to 197 cases per 100,000 person-years in the lowest category. The association was strongly modified by BMI (P value for interaction = 0.02).6
In a 2014 study of lower body ischemia and reperfusion during abdominal aortic repair, a 50 mg dose of melatonin plus a postoperative dose of 30 mg reduced oxidative stress and myocardial damage.7
It's clear that melatonin can be helpful, we probably just need the right dose at the right time. We're not there yet.