Fish Oil for Secondary Prevention of Atrial Fibrillation
2011; Lippincott Williams & Wilkins; Volume: 124; Issue: 10 Linguagem: Inglês
10.1161/circulationaha.111.048140
ISSN1524-4539
AutoresA. John Camm, Irina Savelieva,
Tópico(s)Vitamin K Research Studies
ResumoHomeCirculationVol. 124, No. 10Fish Oil for Secondary Prevention of Atrial Fibrillation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBFish Oil for Secondary Prevention of Atrial FibrillationShould We Still Believe in Its Antiarrhythmic Effect? A. John Camm, MD and Irina Savelieva, MD A. John CammA. John Camm From the Clinical Sciences Division, St. George's University of London, London, United Kingdom. and Irina SavelievaIrina Savelieva From the Clinical Sciences Division, St. George's University of London, London, United Kingdom. Originally published6 Sep 2011https://doi.org/10.1161/CIRCULATIONAHA.111.048140Circulation. 2011;124:1093–1096Several epidemiological and large randomized, clinical trials carried out in the general population and in patients with cardiovascular disease have reported a significantly lower incidence of sudden cardiac death (presumably arrhythmic) with high dietary fish consumption or omega-3 polyunsaturated fatty acid (PUFA) supplements.1 This has prompted interest in exploring the antiarrhythmic potential of PUFAs in patients at particularly high risk of sudden arrhythmic death (ie, patients with internal cardioverter-defibrillators for secondary prevention), but the results were unexpectedly disappointing: the meta-analysis of the controlled studies failed to show any benefit from treatment with PUFAs.2 At about the same time, a proof-of-concept open-label study demonstrated a remarkable 65% reduction in the occurrence of atrial fibrillation (AF) after coronary artery bypass grafting surgery,3 and the search for antiarrhythmic activity of PUFAs in atrial tachyarrhythmias has begun.Article see p 1100Various animal models of AF, including atrial pacing, simultaneous atrioventricular pacing, vagal stimulation, cardiac surgery and sterile pericarditis, and congestive heart failure induced by ventricular tachypacing or intracoronary infusion of doxorubicin, have been used to demonstrate the effects of PUFAs on electric and structural atrial remodeling.4 In these experiments, treatment with PUFAs prevented significant shortening of the atrial effective refractory period associated with AF, reduced inducibility of AF and duration of induced AF, and attenuated atrial fibrosis although a difference in response was noted in some models (eg, lack of effect in atrial tachypacing was reported).5Results in the clinical arena have been less consistent. Although an early open-label and a larger observational study reported a reduction in the incidence of postoperative AF,3 3 subsequent trials with a more rigorous design (double-blind, placebo-controlled) did not reproduce these results.6 Similarly, in several epidemiological analyses, high dietary-fish consumption conferred no benefit on the prevention of AF in the general population, and some even reported a strong trend toward more AF among individuals eating >5 fish meals per week.6Several secondary prevention trials of PUFAs in AF have been published fairly recently, and some are available as preliminary reports.7 Among these, 4 randomized studies (3 double-blind, placebo-controlled) that enrolled patients with either paroxysmal or cardioverted persistent AF8 and patients scheduled for electric cardioversion of AF9–11 showed no effect of therapy with PUFAs on the incidence of recurrent AF either as monotherapy or in addition to conventional antiarrhythmic drugs.In the current issue of Circulation, Nodari et al12 report the results of a double-blind, placebo-controlled study of PUFA supplements in patients with recurrent persistent AF who previously had, on average, 2 cardioversions. The study was first presented at the American College of Cardiology Sessions in Atlanta in March 2010. Of 254 screened patients, 199 were randomized to therapy with PUFA 2 g/d with an eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) ratio of 1.2, or placebo (olive oil) starting 4 weeks before electric cardioversion. In contrast to the 2 previous studies, significantly fewer patients who received PUFAs had a recurrence of AF after 1-year follow-up compared with placebo (37% versus 56%). The mean time to first recurrence was 168±116 days in the PUFA arm and 139±113 days in the placebo arm; there was no difference in the proportion of patients with symptomatic AF recurrence (40% versus 44%). In addition, therapy with PUFAs may have facilitated electric cardioversion as judged by the number of patients with cardioversion failure (2% versus 6%) and the number of patients cardioverted with a single shock (78% versus 33%).A recent meta-analysis of 5 studies in 1179 patients (621 events), including the preliminary data from Nodari et al, showed no effect of PUFAs on secondary prevention of AF (odds ratio 0.83, 95% confidence interval 0.48 to 1.45; P=0.51). However, there was significant heterogeneity between studies because of differences in patient populations, follow-up duration, and dosage, type, and duration of treatment with PUFAs.13There are some differences in the study populations (the Table). Nodari et al included patients with more refractory AF (ie, with recurrent AF after previous cardioversion) and more advanced underlying heart disease, who were slightly older and had a lower left ventricular ejection fraction than those in other trials, which was the likely reason for higher rate of recurrence in the placebo arm in the Nodari study. All patients were treated with amiodarone. The trial is a clear outlier with respect to the reduction of AF in the PUFA arm (the Figure). One interpretation of this result may be that PUFAs have a synergistic effect with antiarrhythmic drug therapy and specifically with amiodarone. However, this is not supported by the results of an admittedly smaller and less robustly designed trial reported by Özaydin et al11 that did not show any difference in the recurrence rates between combination therapy with amiodarone and PUFAs and amiodarone alone.Table. Randomized Clinical Trials of Polyunsaturated Fatty Acids for Secondary Prevention of Atrial Fibrillation after CardioversionStudyNodari et al.Bianconi et al.Özaydin et al.Erdogan et al.Margos et al.Kowey et al.No. of patients1992044710840121Type of PUFA supplementEPA, DHA 850–882 mgEPA, DHA 850 mgEPA, DHA 500 mgα-linolenic acid 301.5 mgNot specifiedEPA, DHA 840 mgType of placeboOlive oilOlive oilNoneNot statedNoneCorn oilDose2 g/day 4 wk before CV and for the duration of the study3 g/day for ≥1 wk before CV; 2 g/day thereafter2 g/day started after CV∼1 g/day 4 wk before CV and for the duration of the studyNot stated, started post-CVOral, 8 g/day loading dose for 7 d; maintenance dose 4 g/dayFollow-up, months126121266Primary end pointProbablility of maintenance of sinus rhythm at 1 yPercentage of patients with recurrence of AFRecurrence of AFRecurrence of AFTime to first recurrence of AFTime to first symptomatic recurrence of AF or atrial flutterAge, years70±6 (PUFA)69.2±7.961±1166.5 (PUFA)54±15 (PUFA)58.2±13.669±9 (placebo)63.5 (placebo)57±16 (control)Men, %56.77042727073Previous cardioversion, %2.27±0.62 (PUFA)21.425.5Not statedNot statedAt least 1 in all patients2.14±0.49 (placebo)Lone AF, %9.53141Not statedNot statedNot statedLA size, mm46.4±4.5 (PUFA)44.9±6.544±4Not stated, but ≤60 mm45.4±5.3 (PUFA)Not stated*45.6±4.2 (placebo)44.3±4.6 (control)LVEF, %49±11 (PUFA)57.7±11.360±8 (PUFA)Not stated55.9±5.8 (PUFA)Not stated*50±10 (placebo)61±7 (control)58.6±4.8 (placebo)RAS inhibitors, %10066.859Greater use in the PUFA armNot stated41Statins, %48.7Not stated25Not statedNot stated45Beta-blockers, %61.844.925.5Not statedNot stated66Antiarrhythmic drugs, %10063.6100Not allowed at inclusion57.5%Not allowed at inclusion; subsequent use: 17Amiodarone, %10027.8100 (started after CV)Not statedMainly amiodaroneNot statedAbbreviations: AF, atrial fibrillation; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LA, left atrium; LVEF, left ventricular ejection fraction; PUFAs, polyunsaturated fatty acids; RAS, renin-angiotensin system; CV, cardioversion.*Clinically significant abnormality on an echocardiogram reported in 7%.Download figureDownload PowerPointFigure. Incidence of recurrent AF after cardioversion in prospective randomized controlled studies of n-3 PUFAs. PUFAs indicates polyunsaturated fatty acids.Another contributing factor may be the duration of pretreatment with PUFAs and antiarrhythmic therapy before cardioversion. An interesting finding in the study by Nodari et al was the absence of a high recurrence rate in the first weeks after cardioversion, which is usually observed in such studies. In contrast, this typical drop in the proportion of patients remaining free from the arrhythmia was seen in the study by Bianconi et al.9 Also, in the study by Kowey et al8 nearly half the recurrences of AF occurred within the first 2 weeks despite a high loading dose. This suggests that the antiarrhythmic effect of PUFAs may take a longer time to develop than would direct blockade of ion channels. There is evidence that incorporation of PUFAs into human atrial cell membrane phospholipids continues after stable plasma concentrations are achieved, supporting the possibility of a delayed antiarrhythmic effect of PUFAs.14 The maximum PUFA content in the cell membrane was observed at approximately 1 month of treatment with relatively high doses (6 g/d). This progressive accumulation of PUFAs may explain early lack of efficacy in secondary prevention trials. Indeed, in both negative studies, the majority of AF recurrences occurred within the first 30 to 40 days of treatment.The ability of PUFAs to increase parasympathetic tone may theoretically be proarrhythmic in younger individuals with normal hearts in whom a vagal component may play a role in promoting AF. The proportion of such patients with lone AF or mild cardiovascular disease was higher in the studies that failed to demonstrate a benefit from PUFA therapy.Several other issues warrant discussion. Unlike other trials, which used regular transtelephonic monitoring,8,9 Nodari et al relied on scheduled clinic visits, self-reporting, and notification from other health professionals after incidental detection of AF (eg, anticoagulation clinics). In addition, unlike previous trials, there was no monitoring of adherence with therapy and no evidence of correlation with plasma membrane EPA/DHA content because no such measurements were reported. The confounding effect of dietary fish intake must also be considered given that none of the reported studies appears to have adequately controlled for this. These limitations of the study raise the question of whether the positive result in this relatively small and suboptimally controlled (limited monitoring of AF recurrence and of adherence to therapy) may reflect a random effect rather than any conclusive antiarrhythmic consequence.The mechanism of potential antiarrhythmic action of PUFAs is complex and, similarly to that of statins, is probably the result of their many pleiotropic effects on atrial electrophysiology and structure. These effects range from modulation of membrane fluidity and the consequent activity of multiple membrane proteins, counteraction of the arrhythmogenic effects of atrial stretch, antiinflammatory and antioxidant actions, decrease of endothelial dysfunction, regulation of profibrotic activity of mitogen activated protein kinases and matrix metalloproteinases and reduction of the expression of proinflammatory and profibrotic genes.4 Unlike other upstream therapies, PUFAs also have direct electrophysiological effects on several ion channels which are relevant in AF, such as INa, IKur, IKAch, Ito, and ICa,L currents and the Na+/Ca2+ exchanger.15,16 Animal studies have reported the protective effect of PUFAs in relatively unremodeled atria, but there has been no study demonstrating reverse remodeling.The content of individual PUFAs, mainly EPA and DHA, may be more important than the total PUFA concentration because the electrophysiological effects produced by different PUFA components are not the same. DHA exerts a stronger sodium current block whereas EPA (and -linolenic acid found in vegetable oils) have a greater potential to block potassium currents.16 In the population-based Kuopio Ischemic Heart Disease Risk Factor Study high serum DHA content was associated with a 38% reduction in relative risk of incident AF, but no such association was found for EPA.17 In the secondary prevention studies, DHA levels increased to a lesser extent than that of EPA. Kowey et al reported a greater increment in EPA content (about 250–300% from baseline) compared with DHA concentration (a 100% increase). Also in the study by Bianconi et al, EPA levels more than doubled, whereas DHA levels only increased by 25%.In conclusion, although the theoretical background and experimental evidence suggest an antiarrhythmic effect of PUFAs in AF, this has not been demonstrated in randomized clinical trials. The dose of PUFAs that may produce the antiarrhythmic effect and the duration of treatment have not been established, and the patient populations that may best benefit from this therapy have not been identified. The 2010 European Society of Cardiology Guidelines have made no recommendations on the use of PUFAs for prevention of AF because of the absence of robust evidence.18 The contribution from Nodari is consistent with basic science data but curiously at odds with similar clinical studies. We must await the results from on-going secondary prevention trials, including the large FORωARD (Fish Oil Research with ω-3 for Atrial Fibrillation Recurrence Delay) study, which is expected to enroll 1400 patients with paroxysmal or persistent AF, A Randomized Double-Blind Placebo-Controlled Study to Evaluate the Effect of PUFAs on Arrhythmia Recurrence in Atrial Fibrillation (AFFORD) (NCT02135130, n=332), and NCT00552084, which will also explore the effects on inflammatory markers and cytokines, and 2 smaller trials in patients undergoing left atrial ablation for AF (NCT00791089 and NCT00841451).7DisclosuresDr Camm is an advisor/speaker/investigator for Servier, Novartis, Sanofi, Astra Zeneca, Xention, Bristol-Myers Squibb, Menarini, Daiichi, Merck, Boehringer Ingelheim, Medtronic, St. Jude Medical, Biotronic, and Boston Scientific. Dr Camm is also a British Heart Foundation professor. Dr Savelieva is an advisor/speaker/investigator for Sanofi, Bristol-Myers Squibb, Takeda, Daiichi, Boehringer Ingelheim, Servier, Astra Zeneca, Astellas, Mitsubishi Pharma, and Merck.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Dr I. Savelieva, Clinical Sciences Division, St. George's University of London, Cranmer Terrace, London SW17 0RE, United Kingdom. E-mail [email protected]ac.ukReferences1. Lavie CJ, Milani RV, Mehra MR, Ventura HO. Omega-3 polyunsaturated fatty acids and cardiovascular diseases. J Am Coll Cardiol. 2009; 54:585–594.CrossrefMedlineGoogle Scholar2. Brouwer IA, Raitt MH, Dullemeijer C, Kraemer DF, Zock PL, Morris C, Katan MB, Connor WE, Camm JA, Schouten EG, McAnulty J. Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators. Eur Heart J. 2009; 30:820–826.CrossrefMedlineGoogle Scholar3. Calò L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de Ruvo E, Meo A, Pandozi C, Staibano M, Santini M. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol. 2005; 45:1723–1728.CrossrefMedlineGoogle Scholar4. Savelieva I, Kourliouros A, Camm J. Primary and secondary prevention of atrial fibrillation with statins and polyunsaturated fatty acids: review of evidence and clinical relevance. Naunyn Schmiedebergs Arch Pharmacol. 2010; 381:1–13.MedlineGoogle Scholar5. Sakabe M, Shiroshita-Takeshita A, Maguy A, Dumesnil C, Nigam A, Leung TK, Nattel S. Omega-3 polyunsaturated fatty acids prevent atrial fibrillation associated with heart failure but not atrial tachycardia remodeling. Circulation. 2007; 116:2101–2109.LinkGoogle Scholar6. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention. Europace. 2011; 13:308–328.CrossrefMedlineGoogle Scholar7. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part II: secondary prevention. Europace. 2011; 13:610–625.CrossrefMedlineGoogle Scholar8. Kowey PR, Reiffel JA, Ellenbogen KA, Naccarelli GV, Pratt CM. Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. 2010; 304:2363–2372.CrossrefMedlineGoogle Scholar9. Bianconi L, Calò L, Mennuni S, Santini L, Morosetti P, Azzolini P, Barbato G, Biscione F, Romano P, Santini M. n-3 Polyunsatyrated fatty acids for the prevention of atrial fibrillation recurrence after electrical cardioversion of chronic persistent atrial fibrillation: a randomized, double-blind, multicentre study. Europace. 2011; 13:174–181.CrossrefMedlineGoogle Scholar10. Erdogan A, Bayer M, Kollath D, Greiss H, Voss R, Neumann T, Franzen W, Most A, Mayer K, Tillmanns H. Omega AF study: polyunsaturated fatty acids (PUFA) for prevention of atrial fibrillation relapse after successful external cardioversion. Heart Rhythm. 2007; 4:S185–S186. Abstract.Google Scholar11. Ozaydın M, Erdoğan D, Tayyar S, Uysal BA, Doğan A, Iĉli A, Ozkan E, Varol E, Türker Y, Arslan A. N-3 polyunsaturated fatty acids administration does not reduce the recurrence rates of atrial fibrillation and inflammation after electrical cardioversion: a prospective randomized study. Anadolu Kardiyol Derg. 2011; 11:305–309.MedlineGoogle Scholar12. Nodari S, Triggiani M, Campia U, Manerba A, Milesi G, Cesana BM, Gheorghiade M, Dei Cas L. N-3 polyunsaturated fatty acids in the prevention of atrial fibrillation recurrences after electrical cardioversion: a prospective randomized study. Circulation.2011; 124:1100–1106.LinkGoogle Scholar13. Liu T, Korantzopoulos P, Shehata M, Li G, Wang X, Kaul S. Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials. Heart. 2011; 97:1034–1040.CrossrefMedlineGoogle Scholar14. Metcalf RG, James MJ, Gibson RA, Edwards JR, Stubberfield J, Stuklis R, Roberts-Thomson K, Young GD, Cleland LG. Effects of fish-oil supplementation on myocardial fatty acids in humans. Am J Clin Nutr. 2007; 85:1222–1228.CrossrefMedlineGoogle Scholar15. Li GR, Sun HY, Zhang XH, Cheng LC, Chiu SW, Tse HF, Lau CP. Omega-3 polyunsaturated fatty acids inhibit transient outward and ultra-rapid delayed rectifier K+currents and Na+current in human atrial myocytes. Cardiovasc Res. 2009; 81:286–293.CrossrefMedlineGoogle Scholar16. Dhein S, Michaelis B, Mohr FW. Antiarrhythmic and electrophysiological effects of long-chain omega-3 polyunsaturated fatty acids. Naunyn Schmiedebergs Arch Pharmacol. 2005; 371:202–211.CrossrefMedlineGoogle Scholar17. Virtanen JK, Mursu J, Voutilainen S, Tuomainen TP. Serum long-chain n-3 polyunsaturated fatty acids and risk of hospital diagnosis of atrial fibrillation in men. Circulation. 2009; 120:2315–2321.LinkGoogle Scholar18. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY. Guidelines for the management of atrial fibrillation. the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace. 2010; 12:1360–1420. CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Saravanan P, West A, Bridgewater B, Davidson N, Calder P, Dobrzynsky H, Trafford A and O'Neill S (2016) Omega-3 fatty acids do not alter P-wave parameters in electrocardiogram or expression of atrial connexins in patients undergoing coronary artery bypass surgery, Europace, 10.1093/europace/euv398, 18:10, (1521-1527), Online publication date: 1-Oct-2016. Nestel P, Clifton P, Colquhoun D, Noakes M, Mori T, Sullivan D and Thomas B (2015) Indications for Omega-3 Long Chain Polyunsaturated Fatty Acid in the Prevention and Treatment of Cardiovascular Disease, Heart, Lung and Circulation, 10.1016/j.hlc.2015.03.020, 24:8, (769-779), Online publication date: 1-Aug-2015. Darghosian L, Free M, Li J, Gebretsadik T, Bian A, Shintani A, McBride B, Solus J, Milne G, Crossley G, Thompson D, Vidaillet H, Okafor H, Darbar D, Murray K and Stein C (2015) Effect of Omega-Three Polyunsaturated Fatty Acids on Inflammation, Oxidative Stress, and Recurrence of Atrial Fibrillation, The American Journal of Cardiology, 10.1016/j.amjcard.2014.10.022, 115:2, (196-201), Online publication date: 1-Jan-2015. Bjorgvinsdottir L, Arnar D, Indridason O, Heidarsdottir R, Skogstrand K, Torfason B, Hougaard D, Palsson R and Skuladottir G (2013) Do High Levels of n-3 Polyunsaturated Fatty Acids in Cell Membranes Increase the Risk of Postoperative Atrial Fibrillation?, Cardiology, 10.1159/000351432, 126:2, (107-114), . Ramadeen A, Connelly K, Leong-Poi H, Hu X, Fujii H, Van Krieken R, Laurent G, Holub B, Bazinet R and Dorian P (2012) N-3 polyunsaturated fatty acid supplementation does not reduce vulnerability to atrial fibrillation in remodeling atria, Heart Rhythm, 10.1016/j.hrthm.2012.02.013, 9:7, (1115-1122.e4), Online publication date: 1-Jul-2012. Kazemian P, Kazemi-Bajestani S, Alherbish A, Steed J and Oudit G (2012) The Use of ω-3 Poly-Unsaturated Fatty Acids in Heart Failure: A Preferential Role in Patients with Diabetes, Cardiovascular Drugs and Therapy, 10.1007/s10557-012-6397-x, 26:4, (311-320), Online publication date: 1-Aug-2012. Shenasa M, Soleimanieh M and Shenasa F (2012) Individualized therapy in patients with atrial fibrillation: new look at atrial fibrillation, Europace, 10.1093/europace/eus280, 14:suppl 5, (v121-v124), Online publication date: 1-Nov-2012. Li A and Behr E (2012) Advances in the management of atrial fibrillation, Clinical Medicine, 10.7861/clinmedicine.12-6-544, 12:6, (544-552), Online publication date: 1-Dec-2012. September 6, 2011Vol 124, Issue 10 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.111.048140PMID: 21900094 Originally publishedSeptember 6, 2011 Keywordsatrial fibrillationcardioversionpolyunsaturated fatty acidsEditorialsremodelingfish oilsecondary preventionPDF download Advertisement SubjectsArrhythmiasPharmacology
Referência(s)