The relatively stable level of LDL-C seen in the icosapent ethyl group and unexplained 10% rise in the placebo group might indicate a reduction in statin effect in the control arm. Although this relatively small proportional change in LDL might not reasonably explain the large differences in CV outcomes observed between treatment groups, loss of statin class effects independent of changes in LDL remain a possible explanation. Furthermore, subgroup analyses demonstrated similar effects on CV outcomes regardless of baseline TG level (including normal levels, defined as <150 mg/dL, for the secondary efficacy endpoint only) and whether TG levels were normalized to <150 mg/dL or not after treatment. This could suggest icosapent ethyl carries metabolic mechanisms other than TG lowering; however, a placebo-related elevation in the CV risk of the control arm unrelated to baseline or post-study TG levels remains a viable explanation. In addition to the evidence regarding potential beneficial effects and safety concerns with icosapent ethyl, the Work Group considered the drug s high cost and pill burden (i.e., two large pills twice daily) when crafting this recommendation. Both of these factors may be unacceptable for some patients. As these are Reviewed, New-added recommendations, the Work Group systematically reviewed evidence related to these recommendations.[99] The Work Group s confidence in the quality of the evidence was moderate. Limitations included a small evidence base (i.e., one clinical trial), unclear allocation concealment, and the potential for confounding related to the choice of placebo. Nonetheless, the study was a large RCT with results that demonstrated a favorable risk-benefit effect on patient outcomes. Given these positive results but significant limitations in the evidence, the Work Group decided upon a Weak for recommendation for Recommendation 19. 