Can anyone link specific responses to his concerns 1) Increase in A Fib ...from what I remember there was no increase in strokes 2) Mineral oil ....does anyone remember the specific Dr Bhatt or AMRN response to that . 3) FDA wanting more than 1 trial
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Adverse events (AE) occurring in ≥5% of VASCEPA patients and statistically more frequently with VASCEPA than placebo: Peripheral edema (6.5% VASCEPA patients versus 5.0% placebo patients) There was no significant difference in the prespecified adjudicated tertiary endpoints of new congestive heart failure which occurred in 4.1% of VASCEPA patients versus 4.3% of placebo patients, or in new heart failure requiring hospitalization, which occurred in 3.4% of VASCEPA and 3.5% of placebo patients. Constipation (5.4% VASCEPA patients versus 3.6% placebo patients) Atrial fibrillation (5.3% VASCEPA patients versus 3.9% placebo patients) This adverse event (AE) finding is consistent with an increase in the prespecified adjudicated tertiary endpoint of atrial fibrillation or flutter requiring hospitalization, which occurred in 3.1% of VASCEPA patients versus 2.1% of placebo patients (p=0.004). A limitation of the REDUCE-IT cardiovascular outcomes trial is that it was not designed to evaluate whether VASCEPA contributed to an increase in atrial fibrillation or flutter, or whether VASCEPA prevented patients who would have otherwise have had atrial fibrillation or flutter from having another major adverse cardiovascular event such as cardiac arrest or sudden cardiac death. Importantly, there was no increase in stroke, the most serious atrial fibrillation-related complication, but rather a statistically significant 28% reduction with VASCEPA versus placebo (p=0.01). Significant and substantial reductions were also observed in the secondary and tertiary endpoints of myocardial infarction (31%), cardiac arrest (48%), and sudden cardiac death (31%) with VASCEPA versus placebo. Among patients with atrial fibrillation/flutter hospitalization endpoints while in REDUCE-IT, rates were similar for stroke (3.1% with VASCEPA versus 7.1% with placebo; p=0.20), new anticoagulant therapy (64.6% with VASCEPA versus 63.1% with placebo; p=0.88), and serious bleeding (8.7% with VASCEPA versus 6.0% with placebo; p=0.60). In 751 patients with a baseline history of atrial fibrillation/flutter, atrial fibrillation/flutter hospitalization rates were 12.5% (46/368) with VASCEPA versus 6.3% (24/383) with placebo (p=0.007). In 7,428 patients without baseline history of atrial fibrillation/flutter, atrial fibrillation/flutter hospitalization rates were 2.2% with VASCEPA versus 1.6% with placebo (p=0.09). Other adverse events (AE) of interest: The rate of treatment-emergent serious adverse events for bleeding was 2.7% in the VASCEPA group versus 2.1% in the placebo group, with a nonsignificant, but trending p-value of 0.06. There was: No significant increase in adjudicated hemorrhagic stroke (0.3% in VASCEPA patients versus 0.2% in placebo patients; p=0.55), No significant increase in serious central nervous system bleeding (0.3% in VASCEPA patients versus 0.2% in placebo patients; p=0.42), and No significant increase in gastrointestinal bleeding (1.5% in VASCEPA patients versus 1.1% in placebo patients; p=0.15). A significantly higher incidence of any bleeding occurred with VASCEPA (11.8% versus 9.9%; p=0.006), but as noted above between group differences were not statistically significant for serious bleeding, serious central nervous system bleeding, serious gastrointestinal bleeding, or adjudicated hemorrhagic stroke, and there were no bleeding-associated deaths assessed by investigators as related to VASCEPA.
Mineral oil placebo consideration and analysis
In REDUCE-IT, a placebo containing mineral oil was used to mimic the color and consistency of the drug studied. No strong evidence for biological activity of the same mineral oil was identified in connection with FDA approval of VASCEPA in July 2012 based on the MARINE phase 3 clinical trial, in connection with FDA review of the ANCHOR phase 3 clinical trial, or after several years of quarterly review by the Data Monitoring Committee (DMC) for REDUCE-IT after FDA requested that the DMC periodically assess unblinded lipid data to monitor for signals that the placebo might not be inert. While the DMC noted variation in LDL-C measurements in both arms and that a small physiological effect of mineral oil might be possible, the DMC concluded that it was not possible to determine if the LDL-C increase in the placebo arm was a natural increase over time or due to the mineral oil, and they found no apparent effect on outcomes and considered this small change as unlikely to explain the observed benefit of VASCEPA over placebo.
Each of the three VASCEPA clinical trials, MARINE, ANCHOR and REDUCE-IT, was conducted under a special protocol, or SPA, agreement with FDA in which mineral oil was agreed with FDA as an acceptable placebo.
REDUCE-IT patients represent a population at significant risk for CV events as reflected in the study design that assumed an annual placebo group primary endpoint event rate of 5.9% based on historical data, and as suggested by the observed annualized placebo event rate (5.74%), which remains consistent with historical data for similar at-risk statin-treated patient populations.
As published within the main New England Journal of Medicine presentation of the REDUCE-IT results, at baseline, the median LDL-C was 75.0 mg/dL. The median change in LDL-C was 3.1% (+2.0 mg/dL) for VASCEPA and 10.2% (+7.0 mg/dL) for the mineral oil placebo arm; placebo-corrected median change from baseline of -6.6% (-5.0 mg/dL; p < 0.001). If mineral oil in the placebo might have affected outcomes in some patients, this might have contributed to differences in outcomes between the groups. However, the relatively small differences in LDL-C levels between groups would not likely explain the 25% risk reduction observed with VASCEPA, and a post hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDL-C level among the patients in the placebo group or regardless of the experience of diarrhea while on study. In addition, although open label, Japan EPA Lipid Intervention Study (JELIS) previously demonstrated a 19% risk reduction without a mineral oil placebo.
