CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Carl J. Lavie, MD*,
Richard V. Milani, MD,
Mandeep R. Mehra, MD and
Hector O. Ventura, MD
* Ochsner Medical Center, Cardiovascular Diseases, 1514 Jefferson Highway, New Orleans, Louisiana 70121 (Email: clavie{at}ochsner.org).
We thank Drs. Saravanan and Davidson for their insightful comments regarding details of our omega-3 polyunsaturated fatty acid ( -3 PUFA) review and appreciate the opportunity to clarify issues that might have been prone to misinterpretation (1). We did not imply that the DART (Diet and Reinfarction) study (2), GISSI Prevenzione (Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico–Prevenzione) study (3) and JELIS study (Japan EPA Lipid Intervention Study) (4) were trials with a uniform population but in fact stated that they represent an aggregate of evidence toward both secondary and primary prevention. They correctly point out that the DART study (2) and the GISSI-Prevenzione study (3) are secondary prevention studies with a significant -3 PUFA benefit in over 13,000 post-myocardial infarction patients. However, even in secondary prevention, not all studies have demonstrated benefit (1). The JELIS trial (4), in contrast, tested the effects of eicosapentaenoic acid (EPA) in mostly a primary prevention cohort (n = 14,981 with hypercholesterolemia treated with statins). Here, the effect size was essentially identical (18% vs. 19%) to that seen in the secondary prevention group (n = 3,664), but the 5-year event rate was nearly 6-fold higher in the secondary prevention group (12% vs. < 2%). As Drs. Saravanan and Davidson correctly point out, in the entire primary prevention group, the benefits of EPA were not quite statistically significant (hazard ratio: 0.82; 95% confidence interval: 0.63 to 1.06; p = 0.13). In a subgroup of JELIS primary prevention patients (5), those with triglycerides  150 mg/dl and high-density lipoprotein cholesterol <40 mg/dl had event rates that were nearly 2-fold higher than those without this lipid pattern. In patients with this high-risk lipid combination, EPA reduced major cardiac event rates by 53% (p = 0.043). Along with the notable epidemiological data, we believe that the overall evidence suggests benefits of -3 PUFA at least in high-risk risk primary prevention patients as well as in those needing secondary prevention of coronary heart disease.
We agree with Drs. Saravanan and Davidson that our single, brief paragraph on the impact of -3 PUFA in atrial fibrillation (AF) was oversimplified (in an effort to make a lengthy review more concise). Although the observational study by Mozaffarian et al. (6) suggested that high fish intake was associated with a 30% reduction in AF over 12 years, the Rotterdam Study (7) found no such effect. Only 1 small randomized controlled study of 160 post-bypass patients was performed to assess the benefits of -3 PUFA on the development of postoperative AF (8). The results of this small study were remarkable in support of -3 PUFA, including 18.1% absolute risk reduction and 54.4% relative risk reduction (or only 5.5 patients needed to be treated to prevent 1 episode of AF). As this study points out and as we have discussed elsewhere in more detail (9), these results compare favorably to the results of another large meta-analysis (58 studies including 8,565 participants) (10), which examined the effects of amiodarone, sotalol, and beta blockers on post-bypass AF. In comparison, the results with -3 PUFA post-bypass seem to be similar or even superior to these other treatments to prevent AF. Clearly, larger studies are needed and some are underway (11) to assess the impact of -3 PUFA in primary and secondary prevention of AF. Additionally, higher doses of -3 PUFA (e.g., 2 to 5 g/day) need to be studied in various cardiovascular diseases (CVD), including AF, and studies are needed to determine the relative benefits of EPA and docosahexaenoic acid (DHA) in CVD. It also is not known what impact DHA or EPA alone has in disease modification, these areas being the subject of intense ongoing investigation.
Finally, we agree with Drs. Saravanan and Davidson that one could debate the details of the strengths and weaknesses of each study. However, we believe the totality of the evidence suggests an overall beneficial effect of -3 PUFA for CVD protection, a view that we are not alone in professing (12–14).
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1. Lavie CJ, Milani RV, Mehra MR, Ventura HO. Omega-3 fatty acids polyunsaturated fatty acids and cardiovascular diseases J Am Coll Cardiol 2009;54:585-594.[Abstract/Free Full Text]2. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet And Reinfarction Trial (DART) Lancet 1989;2:757-761.[Web of Science][Medline] 3. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico(errata in Lancet 2001;357:642 and Lancet 2007;369:106) Lancet 1999;354:447-455.[CrossRef][Web of Science][Medline] 4. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis(correction in Lancet 2007;370:220) Lancet 2007;369:1090-1098.[CrossRef][Web of Science][Medline] 5. Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS) Atherosclerosis 2008;200:135-140.[CrossRef][Web of Science][Medline] 6. Mozaffarian D, Psaty BM, Rimm EB, et al. Fish intake and risk of incident atrial fibrillation Circulation 2004;110:368-373.[Abstract/Free Full Text] 7. Brouwer IA, Heeringa J, Geleijnse JM, Zock PL, Witteman JC. Intake of very long-chain n-3 fatty acids from fish and incidence of atrial fibrillation. The Rotterdam Study. Am Heart J 2006;151:857-862.[CrossRef][Web of Science][Medline] 8. Calo L, Bianconi L, Colicicchi F, et al. 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.[Abstract/Free Full Text] 9. Anand RG, Alkadri M, Lavie CJ, Milani RV. The role of fish oil in arrhythmia prevention J Cardiopulm Rehabil 2008;28:92-98.[Web of Science] 10. Crystal E, Garfinkle MS, Conolly SS, Ginger TT, Sleik K, Yusuf SS. Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery Cochrane Database Syst Rev 2004CD003611. 11. Pratt CM, Reiffel JA, Ellenbogen KA, Naccarelli GV, Kowey PR. Efficacy and safety of prescription omega-3-acid ethyl esters for the prevention of recurrent symptomatic atrial fibrillation: a prospective study Am Heart J 2009;158:163-169.[CrossRef][Web of Science][Medline] 12. Harris WS, Mozaffarin D, Lefevre M, et al. Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids J Nutr 2009;139:804S-819S.[Abstract/Free Full Text] 13. Mosaffarin D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits JAMA 2006;296:1885-1899.[Abstract/Free Full Text] 14. Harris WS. International recommendations for consumption of long-chain omega-3 fatty acids J Cardiovasc Med 2007;8(Suppl 1):S50-S52.[Web of Science]
Related Article
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The Role of Omega-3 Fatty Acids in Primary Prevention of Coronary Artery Disease and in Atrial Fibrillation Is Controversial
- Palaniappan Saravanan and Neil C. Davidson
J. Am. Coll. Cardiol. 2010 55: 410-411.
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