The ICER response to MRC........
edical Research Collaborative
1.
MRC:
In its draft report, ICER has taken the view that, “Although we are uncertain whether the use of mineral oil may have caused some harm to the placebo group, we do not believe that this theory can account for the entire benefit observed in the REDUCE-IT trial.” However, ICER gives no additional input, and chooses to then use the entire recorded benefit from the trial in their modeling, despite Dr. Bhatt’s statement that the actual primary MACE composite RRR could be closer to 20% (and thus, all other endpoints also less impactful). Our analysis suggests that accepting the premise that the stated percentage reductions from the trial results are the most reliable datapoints to base modeling on will result in misleading cost-effectiveness analyses.
ICER:
We are unaware of the source of the statement attributed to Dr. Bhatt regarding an actual relative risk reduction of 20%. We also note that, over wide ranges of relative risk for MI, stroke, and CV death, the cost-effectiveness of icosapent ethyl ranged between $12,000 and $27,000 per QALY gained (see Figure 4.3 in the report).
2.
MRC:
The increase in LDL-C in the placebo group in REDUCE-IT, concurrent with highly significant increases in all other atherogenic markers (representative of statin malabsorption), could infer a multi-fold reduction in the effect of the administered statin dose.
ICER:
While this is an interesting supposition, the conclusion is highly speculative and not informed by any data available from REDUCE-IT.
3.
MRC:
These observations increase the likelihood that the 13.9% significant reduction in hs-CRP levels from baseline in IPE arm observed in REDUCE-IT was largely the result of a regression to the mean rather than a treatment effect of EPA, and the make the sharp increase in placebo group that occurred despite this tendency, noteworthy.
ICER:
See comment above [from #2].
4.
MRC:
A line in the supplement to the NEJM paper on REDUCE-IT cites the result of an analysis of log-transformed hs-CRP data, showing a highly significant 21.8% reduction in IPE group, and no change from baseline in the placebo group. The sponsor's website provides an explanation for the analysis, stating that "individual outlier results can affect a mean or median population measurement in a way that can convey a misleadingly skewed result for the population studied. However, with a trial as large as REDUCE-IT, and with nine separate fasting lipid panels performed on average per subject to ascertain levels, log-transforming these biomarker data is unnecessary...
ICER:
While log-transforming hs-CRP data may have been unnecessary, we note that the results are consistent in both the untransformed and log- transformed analyses (i.e., statistically-significant reductions from baseline to year two in the icosapent ethyl group).
5.
MRC:
If MO (mineral oil) quite possibly inhibited statin absorption in placebo group (observable by highly significant increases in LDL-C, apoB, non-HDL-C and CRP from baseline), does that not increase the likelihood of malabsorption of other cardiac medications, such as antithrombotics and antihypertensives?
ICER:
Please see our response to your second comment
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