However, a statistically and clinically significant reduction was demonstrated in each of the component endpoints, including vascular death and other patient-important outcomes. Additionally, a similar 26% reduction in the secondary composite endpoint of CV death, non-fatal MI, and non-fatal stroke (MACE) was observed (NNT=28), further suggesting a potential benefit in patient-oriented outcomes. These beneficial results were balanced by an increased risk of hospitalization for atrial fibrillation (3.1% versus 2.1%; absolute risk increase [ARI]: 1%; NNH=100; p=0.004) and a higher rate of serious bleeding events (ARI: 0.6%; p=0.06) in the icosapent ethyl treatment arm.[99] The available evidence for icosapent ethyl has various significant limitations. First, the evidence base is limited to a single RCT without subsequent trials either corroborating or questioning the findings by Bhatt et al. (2019).[99] Further, Bhatt has numerous methodologic flaws that constrain interpretation, including the use of composite endpoints, lack of allocation concealment, conflict of interest concerns related to industry s heavy role, and the potential confounding related to the choice of placebo. In this latter limitation, the Work Group noted a 30% rise in hsCRP in the placebo group during the study period, while a 12% reduction was observed in the icosapent ethyl group. As hsCRP has been implicated in atherogenesis and plaque stability through inflammatory mechanisms, this imbalance in hsCRP could represent a loss of CV prognostic balance between groups by the study s conclusion, potentially confounding the results. One potential mechanism is the mineral oil used in the placebo, which could have reduced the adsorption of the statin therapy patients had been receiving before the trial period. 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. 