Cardiac Surgery and the Risk of Atrial Fibrillation: an Intervention Trial Evaluating Melatonin

Phase 2

Withdrawn

• Conditions: Atrial Fibrillation
• Interventions: Drug: Placebo (for Melatonin); Drug: Melatonin

• Registration Number: NCT02099331
• Lead Sponsor: Johns Hopkins University

Brief Summary

Atrial fibrillation is a common heart rhythm condition that can occur after cardiac surgery and has been associated with an increase in hospital length of stay, overall hospital costs, worsening clinical condition and higher rates of death. Newer research indicates that inflammation is a key contributor to atrial fibrillation in this setting.

Melatonin is a naturally made hormone that is regarded as an extremely effective anti-inflammatory substance, with a very favorable safety profile. This clinical trial is being done to test the ability of melatonin to reduce the risk of developing atrial fibrillation after cardiac surgery.

This is a research study where patients will be given either oral melatonin at 40 mg or placebo nightly prior to sleep. The study product will start approximately 2 days prior to the scheduled surgery date and will continue until the 3rd day after the operation. The remainder of the clinical care will remain the same.

The investigators project that patients who receive melatonin will have a significant decrease in the occurrence of atrial fibrillation after surgery.

Detailed Description

Atrial fibrillation is the most common arrhythmia to occur after coronary artery bypass graft (CABG) surgery. This arrhythmia occurs in approximately 1 in every 3 patients in this setting and the rate is even higher after valve or combined valve and CABG procedures. The majority of episodes of atrial fibrillation occur within the first 3 days after cardiac surgery and for those who have an initial episode of atrial fibrillation, the majority will go on to have another recurrence within 2 days of the first episode. Postoperative atrial fibrillation has been associated with an increase in neurological, renal and infectious complications as well as prolonged hospitalization and a significant increase in overall healthcare costs.

There is a considerable amount of emerging data indicating that inflammation and oxidative stress, by way of reactive oxygen species (ROS), associated with cardiac surgery and cardiopulmonary bypass (CPB) may play an important role in the in the development of postoperative atrial fibrillation. Prior animal studies have demonstrated that ROS may lead to electroanatomical remodeling and increase the vulnerability to atrial fibrillation by promoting progressive fibrosis and subsequent alteration of the extracellular matrix. A few randomized controlled trials have demonstrated the beneficial effects of pre-treatment with anti-inflammatory medications such as statins for the prevention of post-operative atrial fibrillation. With this in mind, other anti-inflammatory therapies may also be effective in preventing postoperative atrial fibrillation.

Melatonin (N - acetyl - 5 - methoxytryptamine) is the main product secreted from the pineal gland and has been shown to be a powerful scavenger of ROS and is regarded as the most potent endogenous antioxidant. In fact, melatonin is more effective than other antioxidants in removing free radicals and it has both lipophilic and hydrophilic properties contributing to its more consistent penetration through cellular membranes. In addition to being a naturally synthesized hormone, melatonin has been shown to have a very favorable safety profile when administered in the clinical setting.

For these reasons, investigators have designed a randomized, double-blind, placebo-controlled trial where patients who are to undergo cardiac surgery and CPB, will be randomized to melatonin or placebo and the investigators will determine the incidence of post operative atrial fibrillation in both groups. Additionally, the investigators will measure ROS from serum as well as right atrial appendage samples of subjects and assess the effects of melatonin on ROS levels as compared to placebo.

Study Timeline

• Study First Submitted: 2014-03-22
• Study First Submitted QC: 2014-03-25
• Study First Posted: 2014-03-28
• Study Start: 2014-09
• Primary Completion: 2015-07-06
• Study Completion: 2015-07-06
• Status Verified: 2021-08
• Last Update Submitted: 2021-08-05
• Last Update Posted: 2021-08-12

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Age over the age of 18.
2. Scheduled for elective cardiac surgery (coronary artery bypass grafting, valvular surgery or combined procedures)
3. Enroll at least 48 hours before surgery is scheduled
4. Presence of normal sinus rhythm on screening electrocardiogram.
5. Be willing to provide informed consent (which may be provided by a legally authorized representative if the patient is not able to do so).

Exclusion Criteria

1. History of prior atrial fibrillation
2. Inability to give informed consent.
3. Use of anti-arrhythmic drugs other than beta-blockers
4. Chronic NSAID or antioxidant use
5. History of severe autoimmune disorders with the need for autoimmune medications.
6. History of epilepsy.
7. Compromised hepatic function (aminotransferase levels > 1.5 times the upper limit of normal)
8. Current pregnancy (determined by either serum or urine pregnancy test, as ordered by the primary team)
9. Non-English Speakers
10. Current use of warfarin, nifedipine, fluvoxamine.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo (for Melatonin)	The investigators will administer matching Placebo by mouth (two tablets to match Melatonin), nightly prior to sleep. The administration will start 2 days prior to the scheduled surgery date and will continue until post-operative day 3.
Melatonin	Melatonin	The investigators will administer melatonin at 40mg by mouth (two 20 mg tablets), nightly prior to sleep. The administration will start 2 days prior to the scheduled surgery date and will continue until post-operative day 3.

Primary Outcome Measures

Name	Time	Method
Incidence of atrial fibrillation	2 years	At the end of the study, the primary outcome of incident atrial fibrillation will be assessed in each study arm.

Secondary Outcome Measures

Name	Time	Method
Levels of Reactive Oxygen Species (ROS)	2 years	The investigators will measure levels of ROS from the right atrial appendage and serum samples at the time of surgery as well as on a daily basis from the serum for three days after surgery. Specifically, the investigators will measure NADPH oxidase, peroxide anion, peroxynitrite and thiobarbituric acid reactive substances. At the end of the study, the investigators will compare these levels in both arms.

Trial Locations

Locations (1)

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States