Supplementation of n-3 polyunsaturated fatty acids to prevent postoperative atrial fibrillation in patients subjected to heart surgery

Abstract

The debate on the effectiveness of n-3 polyunsaturated fatty acids (PUFAs) in cardiovascular disease has recently been fueled by the publication of 3 meta-analyses.1Kwak S.M. Myung S.K. Lee Y.J. Seo H.G. Korean Meta-analysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials.Arch Intern Med. 2012; 172: 686-694Crossref PubMed Scopus (2) Google Scholar, 2Mariani J. Doval H.C. Nul D. Varini S. Grancelli H. Ferrante D. et al.N-3 polyunsaturated fatty acids to prevent atrial fibrillation: updated systematic review and meta-analysis of randomized controlled trials.J Am Heart Assoc. 2013; 2: e005033Crossref Scopus (80) Google Scholar, 3Costanzo S, di Niro V, Di Castelnuovo A, Gianfagna F, Donati MB, de Gaetano G, et al. Prevention of postoperative atrial fibrillation in open heart surgery patients by preoperative supplementation of n-3 polyunsaturated fatty acids: an updated meta-analysis. J Thorac Cardiovasc Surg. April 12, 2013 [Epub ahead of print].Google Scholar Furthermore, attempts to apply trial sequential analysis (TSA) to these issues have also contributed to the debate.4Messori A, Fadda V, Maratea D, Trippoli S. ω-3 fatty acid supplements for secondary prevention of cardiovascular disease: from “no proof of effectiveness” to “proof of no effectiveness.” JAMA Int Med. June 17, 2013 [Epub ahead of print].Google Scholar, 5Messori A, Fadda V, Maratea D, Trippoli S. Omega-3 polyunsaturated fatty acids for patients at risk of sudden cardiac death and ventricular arrhythmias: trial sequential analysis. Heart Lung. July 11, 2013 [Epub ahead of print].Google Scholar With regard to secondary prevention of cardiovascular disease, the meta-analysis by Kwak and colleagues1Kwak S.M. Myung S.K. Lee Y.J. Seo H.G. Korean Meta-analysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials.Arch Intern Med. 2012; 172: 686-694Crossref PubMed Scopus (2) Google Scholar found no proof of effectiveness for PUFAs. Later, a TSA that was based on the same data provided a stronger negative conclusion in terms of proof of no effectiveness (futility).4Messori A, Fadda V, Maratea D, Trippoli S. ω-3 fatty acid supplements for secondary prevention of cardiovascular disease: from “no proof of effectiveness” to “proof of no effectiveness.” JAMA Int Med. June 17, 2013 [Epub ahead of print].Google Scholar Likewise, with regard to the role of PUFAs to prevent atrial fibrillation, a meta-analysis showing no effectiveness was published,2Mariani J. Doval H.C. Nul D. Varini S. Grancelli H. Ferrante D. et al.N-3 polyunsaturated fatty acids to prevent atrial fibrillation: updated systematic review and meta-analysis of randomized controlled trials.J Am Heart Assoc. 2013; 2: e005033Crossref Scopus (80) Google Scholar followed by a TSA indicating futility.5Messori A, Fadda V, Maratea D, Trippoli S. Omega-3 polyunsaturated fatty acids for patients at risk of sudden cardiac death and ventricular arrhythmias: trial sequential analysis. Heart Lung. July 11, 2013 [Epub ahead of print].Google Scholar In this framework, the meta-analysis by Costanzo and associates3Costanzo S, di Niro V, Di Castelnuovo A, Gianfagna F, Donati MB, de Gaetano G, et al. Prevention of postoperative atrial fibrillation in open heart surgery patients by preoperative supplementation of n-3 polyunsaturated fatty acids: an updated meta-analysis. J Thorac Cardiovasc Surg. April 12, 2013 [Epub ahead of print].Google Scholar recently published in the Journal has been focused on the preoperative supplementation of PUFAs to prevent postoperative atrial fibrillation in heart surgery. The results of this meta-analysis were borderline, because most effectiveness indices were at the limits of statistical significance. In an attempt to clarify the uncertainty surrounding the effectiveness of PUFAs for this indication, we undertook a TSA aimed at reexamining the same 8 trials evaluated by Costanzo and associates.3Costanzo S, di Niro V, Di Castelnuovo A, Gianfagna F, Donati MB, de Gaetano G, et al. Prevention of postoperative atrial fibrillation in open heart surgery patients by preoperative supplementation of n-3 polyunsaturated fatty acids: an updated meta-analysis. J Thorac Cardiovasc Surg. April 12, 2013 [Epub ahead of print].Google Scholar Our analysis considered the end point of postoperative atrial fibrillation. Main assumptions included 2-sided testing, risk of type 1 error of 5%, and power of 80%. The intervention effect was set at an anticipated 15% or 20% relative risk reduction, with the event rate in the control group assumed to be 30% (equal to the overall rate in the 8 control groups). As usual, the main result of TSA was expressed through the graph of cumulative z curve. With reference to this graph, the boundaries for concluding superiority or inferiority or futility were calculated according to the O’Brien-Fleming α-spending function. Our analysis was done with a specific statistical software package (TSA Viewer; Copenhagen Trial Unit, Copenhagen, Denmark). Application of TSA to these 8 randomized trials generated an inconclusive result (Figure 1). In particular, our analysis estimated that the optimal information size would be 8614 or 4763 patients (according to the assumptions of relative risk reduction of 15% or 20%, respectively). At the cumulative number of 2687 patients (those included in the 8 trials published thus far), the z curve remained, in both graphs, quite far from intercepting the boundary of superiority but at the same time did not reach the futility area. In the light of the current evidence, the conclusion that PUFAs are effective for this clinical indication is not justified; on the other hand, neither can the conclusion of a proven ineffectiveness of PUFAs be made. Unless further positive trial results are made available, uncertainty remains regarding the effectiveness of PUFAs for this indication. Overall, if one considers that a clear proof of ineffectiveness has been obtained for two other important indications of PUFAs,4Messori A, Fadda V, Maratea D, Trippoli S. ω-3 fatty acid supplements for secondary prevention of cardiovascular disease: from “no proof of effectiveness” to “proof of no effectiveness.” JAMA Int Med. June 17, 2013 [Epub ahead of print].Google Scholar, 5Messori A, Fadda V, Maratea D, Trippoli S. Omega-3 polyunsaturated fatty acids for patients at risk of sudden cardiac death and ventricular arrhythmias: trial sequential analysis. Heart Lung. July 11, 2013 [Epub ahead of print].Google Scholar the overall picture of the therapeutic role of these agents seems to be extremely weak. Prevention of postoperative atrial fibrillation in open heart surgery patients by preoperative supplementation of n-3 polyunsaturated fatty acids: An updated meta-analysisThe Journal of Thoracic and Cardiovascular SurgeryVol. 146Issue 4PreviewSeveral randomized clinical trials evaluated whether preoperative supplementation of omega-3 (n-3) polyunsaturated fatty acids protects against postoperative atrial fibrillation after cardiac surgery, a condition associated with increased cardiac and cerebral mortality. However, their efficacy remains still controversial. An updated meta-analysis was performed to clarify if preoperative n-3 polyunsaturated fatty acid supplementation prevents postoperative atrial fibrillation in patients undergoing cardiac surgery. Full-Text PDF Reply to the EditorThe Journal of Thoracic and Cardiovascular SurgeryVol. 146Issue 4PreviewIn their letter, Messori and colleagues described their performance of a trial sequential analysis (TSA) to interpret better the results of a meta-analysis we recently published in the Journal, “Prevention of postoperative atrial fibrillation in open heart surgery patients by preoperative supplementation of n-3 polyunsaturated fatty acids: An updated meta-analysis.”1 After application of TSA to the same 8 trials included in our study1 and another meta-analysis on the same topic,2 they state that the results are inconclusive but tend more toward proof of no effectiveness of n-3 polyunsaturated fatty acid (PUFA) supplementation for preventing postoperative atrial fibrillation (POAF) after heart surgery. Full-Text PDF