Given these positive results but significant limitations in the evidence, the Work Group decided upon a Weak for recommendation for Recommendation 19. Recommendation 19 is specific to those with a history of CVD, as the REDUCE-IT population primarily consisted of secondary prevention patients (70%). Furthermore, as this CPG s systematic evidence review did not capture primary evidence investigating only or mostly patients without a history of CVD, the Work Group decided upon a separate Neither for nor against recommendation for Recommendation 18, which pertains to primary prevention patients. Although a subgroup analysis of primary prevention patients in the REDUCE-IT trial showed no difference in the primary CV endpoint, the Work Group determined such analyses have limitations and should be used for hypothesis generation rather than clinical decision making. More RCT data is needed on the effectiveness and safety of icosapent ethyl in primary and secondary prevention populations. Use of placebo without mineral oil, and trials composed of mostly primary prevention populations, are needed to more accurately and comprehensively understand the potential effects of icosapent ethyl on CV outcomes. Recommendation 20. For primary or secondary prevention, we suggest against the use of omega-3 fatty acids as a dietary supplement to reduce cardiovascular disease risk. (Weak against | Reviewed, New-added) Discussion The systematic review by Abdelhamid et al. (2018) evaluated 79 RCTs for the effect of omega-3 supplements on primary and secondary prevention of CVD.[100] The evidence showed no statistically significant effect of omega-3 supplementation on CV mortality, composite CV events, MI, stroke, or all- cause mortality. The risk of bias was low for 25 RCTs and moderate-to-high in the remaining 54 RCTs.[100] In this systematic review, omega-3 supplementation ranged from 0.5 grams/day to greater than 5 grams/day.