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The ?-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial--rationale and design.

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 ?-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 ?-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 ?-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 ?-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 ?-3-PUFAs influence cardiac arrhythmias; and potential regulatory standards and clinical use of this simple, inexpensive, and low-risk intervention to prevent PoAF.

SUBMITTER: Mozaffarian D

PROVIDER: S-EPMC3134828 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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The ω-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial--rationale and design.

Mozaffarian Dariush D Marchioli Roberto R Gardner Tim T Ferrazzi Paolo P O'Gara Patrick P Latini Roberto R Libby Peter P Lombardi Federico F Macchia Alejandro A Page Richard R Santini Massimo M Tavazzi Luigi L Tognoni Gianni G

American heart journal 20110612 1

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 ...[more]

PMID: 21742090

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Project description:ContextPostoperative atrial fibrillation or flutter (AF) is one of the most common complications of cardiac surgery and significantly increases morbidity and health care utilization. A few small trials have evaluated whether long-chain n-3-polyunsaturated fatty acids (PUFAs) reduce postoperative AF, with mixed results.ObjectiveTo determine whether perioperative n-3-PUFA supplementation reduces postoperative AF.Design, setting, and patientsThe Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) double-blind, placebo-controlled, randomized clinical trial. A total of 1516 patients scheduled for cardiac surgery in 28 centers in the United States, Italy, and Argentina were enrolled between August 2010 and June 2012. Inclusion criteria were broad; the main exclusions were regular use of fish oil or absence of sinus rhythm at enrollment.InterventionPatients were randomized to receive fish oil (1-g capsules containing ≥840 mg n-3-PUFAs as ethyl esters) or placebo, with preoperative loading of 10 g over 3 to 5 days (or 8 g over 2 days) followed postoperatively by 2 g/d until hospital discharge or postoperative day 10, whichever came first.Main outcome measureOccurrence of postoperative AF lasting longer than 30 seconds. Secondary end points were postoperative AF lasting longer than 1 hour, resulting in symptoms, or treated with cardioversion; postoperative AF excluding atrial flutter; time to first postoperative AF; number of AF episodes per patient; hospital utilization; and major adverse cardiovascular events, 30-day mortality, bleeding, and other adverse events.ResultsAt enrollment, mean age was 64 (SD, 13) years; 72.2% of patients were men, and 51.8% had planned valvular surgery. The primary end point occurred in 233 (30.7%) patients assigned to placebo and 227 (30.0%) assigned to n-3-PUFAs (odds ratio, 0.96 [95% CI, 0.77-1.20]; P = .74). None of the secondary end points were significantly different between the placebo and fish oil groups, including postoperative AF that was sustained, symptomatic, or treated (231 [30.5%] vs 224 [29.6%], P = .70) or number of postoperative AF episodes per patient (1 episode: 156 [20.6%] vs 157 [20.7%]; 2 episodes: 59 [7.8%] vs 49 [6.5%]; ≥3 episodes: 18 [2.4%] vs 21 [2.8%]) (P = .73). Supplementation with n-3-PUFAs was generally well tolerated, with no evidence for increased risk of bleeding or serious adverse events.ConclusionIn this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFAs, compared with placebo, did not reduce the risk of postoperative AF. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00970489.

Project description:Background:Cognitive decline has been reported following cardiac surgery, leading to great interest in interventions to minimize its occurrence. Long-chain n-3 (?-3) polyunsaturated fatty acids (PUFAs) have been associated with less cognitive decline in observational studies, yet no trials have tested the effects of n-3 PUFAs on cognitive decline after surgery. Objective:We sought to determine whether perioperative n-3 PUFA supplementation reduces postoperative cognitive decline in patients postcardiac surgery. Methods:The study comprised a randomized, double-blind, placebo-controlled, multicenter, clinical trial conducted on cardiac surgery recipients at 9 tertiary care medical centers across the United States. Patients were randomly assigned to receive fish oil (1-g capsules containing ?840 mg n-3 PUFAs as ethyl esters) or placebo, with preoperative loading of 8-10 g over 2-5 d followed postoperatively by 2 g/d until hospital discharge or postoperative day 10, whichever came first. Global cognition was assessed using in-person testing over 30 d with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (primary outcome), Mini-Mental State Exam (secondary outcome), and Trails A and B (secondary outcome) tests. All end points were prespecified. Statistical methods were employed, including descriptive statistics, logistic regression, and various sensitivity analyses. Results:A total of 320 US patients were enrolled in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Cognitive Trial (OCT), a substudy of OPERA. The median age was 62 y (IQR 53, 70 y). No differences in global cognition were observed between placebo and fish oil groups at day 30 (P = 0.32) for the primary outcome, a composite neuropsychological RBANS score. The population demonstrated resolution of initial 4-d cognitive decline back to baseline function by 30 d on the RBANS. Conclusion:Perioperative supplementation with n-3 PUFAs in cardiac surgical patients did not influence cognition ?30 d after discharge. Modern anesthetic, surgical, and postoperative care may be mitigating previously observed long-term declines in cognitive function following cardiac surgery. This trial was registered at clinicaltrials.gov as NCT00970489.

Project description:Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and post-operative atrial fibrillation (POAF) is a major healthcare burden, contributing to an increased risk of stroke, kidney failure, heart attack and death. Genetic studies have identified associations with AF, but no molecular diagnostic exists to predict POAF based on pre-operative measurements. Such a tool would be of great value for perioperative planning to improve patient care and reduce healthcare costs. In this pilot study of epigenetic precision medicine in the perioperative period, we carried out bisulfite sequencing to measure DNA methylation status in blood collected from patients prior to cardiac surgery to identify biosignatures of POAF. Methods: We enrolled 221 patients undergoing cardiac surgery in this prospective observational study. DNA methylation measurements were obtained from blood samples drawn from awake patients prior to surgery. After controlling for clinical and methylation covariates, we analyzed DNA methylation loci in the discovery cohort of 110 patients for association with POAF. We also constructed predictive models for POAF using clinical and DNA methylation data. We subsequently performed targeted analyses of a separate cohort of 101 cardiac surgical patients to measure the methylation status solely of significant methylation loci in the discovery cohort. Results: A total of 47 patients in the discovery cohort (42.7%) and 43 patients in the validation cohort (42.6%) developed POAF. We identified 12 CpGs that were statistically significant in the discovery cohort after correcting for multiple hypothesis testing. Of these sites, 6 were amenable to targeted bisulfite sequencing and chr16:24640902 was statistically significant in the validation cohort. In addition, the methylation POAF prediction model had an AUC of 0.79 in the validation cohort. Conclusions: We have identified DNA methylation biomarkers that can predict future occurrence of POAF associated with cardiac surgery. This research demonstrates the use of precision medicine to develop models combining epigenomic and clinical data to predict disease.

Dataset Information

The ?-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial--rationale and design.

Publications

The ω-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial--rationale and design.

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