Abstract
Postoperative atrial fibrillation/flutter (PoAF) commonly complicates cardiac surgery, occurring in 25% to 60% of patients. Postoperative atrial fibrillation/flutter is associated with significant morbidity, higher long-term mortality, and increased health care costs. Novel preventive therapies are clearly needed. In experiments and short-term trials, seafood-derived long-chain ω-3 polyunsaturated fatty acids (PUFAs) influence several risk factors that might reduce risk of PoAF. A few small and generally underpowered trials have evaluated effects of ω-3-PUFAs supplementation on PoAF with mixed results. The OPERA trial is an appropriately powered, investigator-initiated, randomized, double-blind, placebo-controlled, multinational trial to determine whether perioperative oral ω-3-PUFAs reduces occurrence of PoAF in patients undergoing cardiac surgery. Additional aims include evaluation of resource use, biologic pathways and mechanisms, postoperative cognitive decline, and safety. Broad inclusion criteria encompass a "real-world" population of outpatients and inpatients scheduled for cardiac surgery. Treatment comprises a total preoperative loading dose of 8 to 10 g of ω-3-PUFAs or placebo divided over 2 to 5 days, followed by 2 g/d until hospital discharge or postoperative day 10, whichever comes first. Based on anticipated 30% event rate in controls, total enrollment of 1,516 patients (758 per treatment arm) will provide 90% power to detect 25% reduction in PoAF. The OPERA trial will provide invaluable evidence to inform biologic pathways; proof of concept that ω-3-PUFAs influence cardiac arrhythmias; and potential regulatory standards and clinical use of this simple, inexpensive, and low-risk intervention to prevent PoAF.
Highlights
Post-operative atrial fibrillation or flutter (PoAF) commonly complicates cardiac surgery, occurring in 25–60% of all patients, depending on underlying patient characteristics and methods of arrhythmia ascertainment.[1,2,3,4,5,6] PoAF can produce hemodynamic instability or symptoms requiring cardioversion or pressor support, and is associated with greater infectious, renal, and neurological complications.[3]
In an openlabel single-center trial (n=160), omega-3-polyunsaturated fatty acids (PUFA) (2 g/d initiated at least 5 days pre-operatively, continued until hospital discharge) reduced PoAF (15.2% vs. 33.3%, p=0.009) and hospital length-of-stay.[11]
Our primary aim is to determine in a randomized, double-blind, placebo-controlled clinical trial whether peri-operative oral omega-3-PUFA reduces occurrence of PoAF following cardiac surgery
Summary
Post-operative atrial fibrillation or flutter (PoAF) commonly complicates cardiac surgery, occurring in 25–60% of all patients, depending on underlying patient characteristics and methods of arrhythmia ascertainment.[1,2,3,4,5,6] PoAF can produce hemodynamic instability or symptoms requiring cardioversion or pressor support, and is associated with greater infectious, renal, and neurological complications.[3]. Observational studies and randomized trials suggest that omega-3-PUFA prevent ventricular arrhythmias at low doses, e.g., 250–500 mg/d EPA+DHA.[10] Similar low dietary doses were associated with lower incidence of AF among ambulatory adults.[15] Supplementation alters circulating and tissue levels of EPA and DHA within days;[19] and in one small trial, a 10 g loading dose over 5 days pre-operatively followed by 2 g/d postoperatively reduced PoAF.[11] Because omega-3-PUFA persist in tissues for several days, a loading dose provides some buffer in patients who might not tolerate oral medications for several days post-surgery. Higher doses (e.g., 5+ g/d) could increase patient dyspepsia and potential concern among treating physicians for bleeding risk ( bleeding concerns are not supported by studies todate; see below)
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