Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial

Abstract

Background: Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown.

Methods: In a multicenter, double-blind, placebo-controlled trial, participants presenting with an acute myocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size.

Results: By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left ventricular systolic volume index (-5.8%, P=0.017), and noninfarct myocardial fibrosis (-5.6%, P=0.026) in comparison with placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparison with the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with high-dose omega-3 fatty acid therapy.

Conclusions: Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guideline-based standard of care.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00729430.

Keywords: endomyocardial fibrosis; fatty acids, omega-3; infarction; magnetic resonance imaging; ventricular remodeling.

Figure 1. Enrollment and Randomization

The treatment duration was 6 months for both randomized arms (between study visit 1 and 2). CMR denotes cardiac magnetic resonance imaging, ICD implantable cardioverter-defibrillator, O-3FA omega-3 fatty acids from fish oil.

Figure 2. Percent Change of Fatty Acid Levels from Baseline to Post Treatment

Percent changes from baseline to post treatment levels of red blood cell omega-3 fatty acid are shown for the omega-3 fatty acid treated group (red bars) and placebo arm (blue bars). P values are for comparisons of percent change in red blood cell fatty acid levels between the randomized treatment arms. ALA denoted α-Linolenic acid, DHA docosahexanoic acid, DPA docosapentaenoic acid, EPA eicosapentanoic acid, and O-3FA omega-3 fatty acids from fish oil.

Figure 3. Percent Change of Primary and Secondary Endpoints Post Treatment

Percent changes from baseline to post treatment of the primary and secondary endpoints are shown for the omega-3 fatty acid treated group (red bars) and placebo arm (blue bars). LVESVI denotes left ventricular end-systolic volume index, and LVEF left ventricular ejection fraction.

Figure 4. Comparison of Percent Change in Study Endpoints with Quartiles of Change in Omega-3-Index Post Treatment for Patients that Completed Both Study Visits

Percent changes from pre-treatment to post-treatment of LVESVI, non-infarct myocardial fibrosis, and LVEF versus quartile changes of the red blood cell omega-3 index levels for all patients who completed both study visits (n=227). The quartiles for change in the red blood cell omega-3 index were −0.6% to 0.5%, 0.5 to 2.6%, 2.6 to 5.8%, and > 5.8%. The 5^th and 95^th percentiles for change in the omega-3 index were −1.0% and 6.8%, respectively. * indicate p-value < 0.05 compared to first quartile (reference), linear trend p-values are also reported.

Figure 5. Comparison of Percent Change in Systemic Biomarkers with Quartiles of Change in Omega-3-Index Post Treatment for Patients that Completed Both Study Visits

Percent changes from pre-treatment to post-treatment of systemic biomarkers versus quartile changes of the red blood cell omega-3 index levels for all patients who completed both study visits (n=227). The quartiles for change in the red blood cell omega-3 index were −0.6% to 0.5%, 0.5 to 2.6%, 2.6 to 5.8%, and > 5.8%. The 5th and 95th percentiles for change in the omega-3 index were −1.0% and 6.8%, respectively. * indicate p-value < 0.05 compared to first quartile (reference), linear trend p-values are also reported. CRP denotes high sensitivity C-reactive protein, Lp-PLA2 lipoprotein-associated phospholipase A2, and NT-proBNP N-terminal of the prohormone brain natriuretic peptide.

Figure 6. Scatter Plot of Percent Change in Serum Biomarker ST2 versus Percent Change of Non-Infarct Myocardial Fibrosis Post Treatment

Percent change from baseline to post treatment of the serum biomarker ST2 correlated against percent change in non-infarct myocardial fibrosis following 6 months of treatment with high dose omega-3 fatty acids from fish oil. P-value is for Pearson correlation coefficient.