Minocycline Plus Amiodarone Versus Amiodarone Alone for the Prevention of Atrial Fibrillation After Cardiac Surgery (MINA)

Minocycline Plus Amiodarone Versus Amiodarone Alone for the Prevention of Atrial Fibrillation After Cardiac Surgery (MINA)

. New- onset postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and its occurrence increases with age. POAF can result in clinically significant morbidity and mortality. The national trend in the US is that the population older than 65 years is increasing, making healthcare expenditure related to POAF to be a major burden on health care system. Effective treatment of POAF is imperative in ensuring quality of care and reduction of costs.

In 2021 there is a projected total of 377,763 cardiovascular surgeries in the US alone with approximately half of which will have POAF with longer postoperative length of stay (+3.9 days) and higher discharge costs (+$13,993) than no-POAF patients (Reference: Ann Thorac Surg. 2015 Jan;99(1):109-14). Amiodarone, the currently used therapy, is often insufficient to prevent POAF and has multiple side-effects. In this study, we expect to improve the incidence of POAF by using a common acne drug (Minocycline) that is safe and that could be incorporated in clinical care of this disease.

Study Overview

• Status: Not yet recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Amiodarone; Drug: Minocycline

Detailed Description

New-onset postoperative atrial fibrillation after cardiac surgery (POAF) is commonly observed and it increases morbidity, mortality, and health care expenditure. Amiodarone administration is proposed initial agent for prevention and treatment of POAF, but while useful, this drug has a number of adverse side-effects and relapse requiring anticoagulation therapy at hospital discharge is prevalent. Effective medications are needed with respect to management. Minocycline, an old tetracycline antibiotic, has additional effects including inhibition of atrial myocyte apoptosis.The finding that apoptosis of right atrial myocytes is thought to be one etiologic factor underlying POAF supports examining the hypothesis in this project that adding minocycline to amiodarone could favorably reduce POAF frequency rate. Minocycline has been used for over four decades and has a good safety profile, therefore this investigation is not a phase I trial. With a limited sample size, while the data of our MINAA Exploratory trial (the Minocycline Plus Amiodarone Versus Amiodarone Alone for the Prevention of Atrial Fibrillation After Cardiac Surgery) were not sufficient to draw definite conclusions, rather they suggested feasibility of such therapy in this cohort. In the current pilot study, we assess the clinical effectiveness and safety of minocycline plus amiodarone in preventing POAF with a larger cohort of two parallel groups (n=40, each) randomly assigned in a 1:1 ratio.In this trial we compare intravenous minocycline 100 mg daily x 5 days starting intra-operatively combined with oral amiodarone (400 mg twice daily for 7 days, then 200 mg twice daily for the next 7 days), versus the same dose oral amiodarone alone, for prevention of POAF among adult patients undergoing coronary artery bypass grafts, heart valve repair or replacement, or combined procedures. All patients receive 150 mg intravenous amiodarone intraoperatively and a 2nd similar dose of amiodarone bolus is permitted for tachyarrhythmia any time within 24 hours after surgery.The primary outcome is a newly detected POAF by telemetry, Holter monitoring, or by daily wireless ECG sensors within 6 weeks from the time of randomization. Composite secondary outcomes include death at 30 days, length of hospital stay, and other adverse events.To elucidate how minocycline causally elicits its pharmacologic effects, sera sampling of biomarkers such as NF-Kappa B, cleaved caspase-3, and NT-pro-BNP are measured pre-procedure, then on the 3rd and 5th postoperative days. If the proposed intervention is successful, it underscores what can ensue when the target evolves to the common population level requiring a nuanced approach pursued by Phase III-IV proposals

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Abdallah Alameddine, MD; Phone Number: 17815212074; Email: akalameddine@gmail.com
• Study Contact Backup: Name: Abdallah k Alameddine, md; Phone Number: 5303 413 794-0000; Email: akalameddine@gmail.com

Study Locations

• United States
  • Massachusetts
    • Melrose, Massachusetts, United States, 02176
      • Abdallah Alameddine
      • Contact: Abdallah Alameddine, MD; Phone Number: 781-521-2074; Email: akalameddine@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria are adults, including women and minorities > 18 years of age, who are also willing to participate for the duration of the trial (6 weeks). All non-congenital cardiac operations are included: Coronary Artery Bypass Graft, valve repair/replacement, or combination of CABG and heart valve operations. Patients should be able to access iPhones and download ECGs using their electronic Devices. Exclusion criteria Patients with prior (within 6 months) or current atrial fibrillation (AF) or flutter, patients undergoing concomitant surgical AF ablation or a history of AF, transcatheter aortic valve replacement or other minimally invasive procedures, prior cerebrovascular event, cardiogenic shock or resuscitation, evidence of hepatic or renal dysfunctions (i.e., an alanine aminotransferase level that is ≥ twice the upper limit of the normal range, or either a serum creatinine level that is ≥ 2.0 mg/dL or need for preoperative dialysis) are excluded. Other exclusion criteria are the following: thyrotoxicosis, pregnancy, severe chronic obstructive pulmonary disease (COPD, with FEV1/FVC <70%), recent history of drug or alcohol abuse, and intolerance to tetracycline or amiodarone. Because a core scientific basis of this trial concerning the role of underlying atrial tissue inflammatory/apoptotic activity, patients with inflammatory conditions such as lupus, severe arthritis, thyroiditis or inflammatory bowel disease are excluded; as are patients taking preoperative immunosuppressant agents, long-term (>10 days) oral corticosteroids (prednisolone > 10mg or other), or estrogen replacement; and finally patients with newly diagnosed cancer (<5 years) are also excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Amiodarone; oral amiodarone	Drug: Amiodarone; oral amiodarone (400 mg twice daily for 7 days, then 200 mg twice daily for the next 7 days
Experimental: minocycline; intravenous minocycline 100 mg daily x 5 days starting intra-operatively combined with oral amiodarone (400 mg twice daily for 7 days, then 200 mg twice daily for the next 7 days	Drug: Amiodarone; oral amiodarone (400 mg twice daily for 7 days, then 200 mg twice daily for the next 7 days; Drug: Minocycline; intravenous minocycline 100 mg daily x 5 days starting intra-operatively combined with oral amiodarone (400 mg twice daily for 7 days, then 200 mg twice daily for the next 7 days; Other Names: Minocin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-op Atrial Fibrillation	frequency of a newly detected episode of POAF occuring after the initial surgery, or within 6 weeks after hospital discharge	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thromboembolism	cerebral or pulmonary	6 weeks
Heart failure	Symptoms include dyspnea, leg edema, low Ejection Fraction, high Central Venous Pressure, high level of natriuretic hormone	6 weeks
30-day hospital death	cardiac or overall	30-days

Collaborators and Investigators

• Sponsor: Baystate Medical Center
• Investigators: Principal Investigator: Abdallah k Alameddine, MD, Baystate Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2024
• Primary Completion (Estimated): January 24, 2027
• Study Completion (Estimated): January 24, 2028

Study Registration Dates

• First Submitted: August 17, 2011
• First Submitted That Met QC Criteria: August 22, 2011
• First Posted (Estimated): August 23, 2011

Study Record Updates

• Last Update Posted (Actual): July 27, 2023
• Last Update Submitted That Met QC Criteria: July 26, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: cardiac surgery; atrial fibrillation; minocycline; amiodarone
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Amiodarone; Minocycline
• Other Study ID Numbers: BH-09-176

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: yes
• IPD Sharing Time Frame: Three years
• IPD Sharing Access Criteria: de-identified computerized dataset
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No