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

Currently, the most effective therapy to prevent PAF after cardiac surgery remains
undetermined. Amiodarone administration should be considered to decrease the incidence of
new-onset postoperative atrial fibrillation (PAF) after cardiac operations. However, PAF
requiring anticoagulation therapy occurs in 40-50% of cases early after cardiac surgery
despite amiodarone prophylaxis. PAF is associated with increased morbidity and mortality
including complications resulting from long-term anticoagulation. The findings that an
exaggerated inflammatory response manifested by elevated acute oxidative stress proteins, and
the induction of apoptotic mediators in right atrial myocytes may be responsible for PAF, and
that steroidal or non-steroidal anti-inflammatory drug therapy can reduce PAF support this
mechanism as a possible etiological factor. Minocycline, a tetracycline antibiotic, has
specific atrial myocyte anti-apoptotic effect which decreases right atrial tissue
inflammation, oxidative stress activity and molecular indices of apoptosis. Apoptosis of
cardiac myocytes is thought to be one etiologic factor underlying postoperative atrial
fibrillation. These observations lead to this trial hypothesis that the addition of
minocycline to amiodarone may favorably affect suppression of PAF. This randomized controlled
trial compares the efficacy and safety of treatment effects of 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, in the prevention of PAF among adult patients undergoing coronary artery
bypass grafts, heart valve replacement/repair, 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. PAF is detected by
telemetry during hospitalization and 2 weeks following hospital discharge, by a 12-lead
electrocardiogram. The primary outcome is PAF occurrence. Secondary outcomes include
thromboembolic stroke, need for pharmacologic or electric cardioversion, mediastinal
exploration for anticoagulation-related bleeding, serious drug side effects, Clostridium
difficile superinfection, length of hospital stay and 30-day mortality from cardiovascular
causes. Based on a projected PAF incidence of 26% and assuming 5% dropout rate and a
two-sided alpha of 0.05, this design requires 400 subjects to detect a reduction of 50% in
the primary outcome with 90% power. This is a valuable trial that would affect the method in
which the investigators practice.

Inclusion Criteria:

-Eligibility criteria includes all non-congenital cardiac operations are included:

- coronary artery bypass graft (CABG),

- valve repair/replacement, or

- combination of CABG and heart valve operations.

Exclusion Criteria:

- prior (within 6 months) or current PAF or flutter,

- 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),

- thyrotoxicosis,

- pregnancy,

- severe COPD (FEV1/FVC <70%),

- recent history of drug or alcohol abuse, and

- intolerance to tetracycline or amiodarone.

Finally, because a core scientific basis of the trial concerned the role of underlying
atrial tissue inflammatory 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 oral corticosteroids, or estrogen
replacement; and a newly diagnosed cancer (<5 years).