Lilly, Xigris, the XPRESS trial and non-inferiority shenanigans

The problem with non-inferiority trials (in addition to the apparent fact that the pharmaceutical industry uses them to manufacture false realities) is that people don't generally understand them (which is what allows false realities to be manufactured and consumed.) One only need look at the Windish article described below to see that the majority of folks struggle with biomedical statistics.

The XPRESS trial, published in AJRCCM Sept. 1st, (http://ajrccm.atsjournals.org/cgi/content/abstract/176/5/483) was mandated by the FDA as a condition of the approval of drotrecogin-alfa for severe sepsis. According to the authors of this study, the basic jist is to see if heparin interferes with the efficacy of Xigris (drotrecogin-alfa) in severe sepsis. The trial is finally published in a peer-reviewed journal, although Lilly has been touting the findings as supportive of Xigris for quite a while already.


The stated hypothesis was that Xigris+placebo is equivalent to Xigris+heparin (LMWH or UFH). [Confirmation of this hypothesis has obvious utility for Lilly and users of this drug because it would allay concerns of coadministration of Xigris and heparinoids, the use of the latter which is staunchly entrenched in ICU practice).

The hypothesis was NOT that Xigris+heparin is superior to Xigris alone. If Lilly had thought this, they would have conducted a superiority trial. They did not. Therefore, they must have thought that the prior probability of superiority was low. If the prior probability of a finding (e.g., superiority) is low, we need a strong study result to raise the posterior probability into a reasonable range - that is, a powerful study which produces a very small p-value (e.g., <0.001)>

This study used 90% confidence intervals. Not appropriate. This is like using a p-value of 0.10 for significance. I have calculated the more appropriate 95% CIs for the risk difference observed and they are: -0.077 to +0.004.

The analysis used was intention to treat. The more conservative method for an equivalence trial is to present the results as "as treated". This could be done at least in addition to the ITT analysis to see if the results are consistent.

Here we are doing an equivalence trial with mortality as an outcome. This requires us to choose a "delta" or mortality difference between active treatment and control which is considered to be clinically negligible. Is an increased risk of death of 6.2% negligible? I think not. It is simply not reasonable to conduct a non-inferiority or equivalence trial with mortality as the outcome. Mortality differences would have to be, I would say, less than 1% to convince me that they might be negligible.

Because an equivalence design was chosen, the 95% CIs (90% if you're willing to accept that -and I'm not) for the treatment difference would have to fall entirely outside of delta (6.2%) in order for treatment to be declared superior to placebo. Clearly it does not. So any suggestion that Xigris+heparin is superior to Xigris alone based on this study is bunkum. Hogwash. Tripe. Based upon the chosen design, superiority is not even approached. The touted p-value of 0.08 conceals this fact. If they had chosen an superiority design, yes, they would have been close. But they did not.

Equivalence was not demonstrated in this trial either, as the 95% (and the 90%) CIs crossed the pre-specified delta. So sorry.

The design of this study and its very conception as an equivalence trial with a mortality endpoint is totally flawed. Equivalence was not demonstrated even with a design that would seem to favor its demonstration. (Interestingly, if a non-inferiority design had been chosen, superiority of Xigris+heparin would in fact have been demonstrated! [with 90, but NOT with 95% CIs] ).

The biggest problem I'm going to have is when the Kaplan-Meier curve presented in Figure 3A with its prominently featured "near miss" p-value of 0.09 is used as ammunition for the argument that Xigris+heparin trended toward superior in this study. If it had been a superiority trial, I would be more receptive of that trend. But you can't have your cake and eat it too. You either do a superiority trial, or you do an equivalence trial. In this case, the equivalence trial appeared to backfire.

Having said all that, I think we can be reassured that Xigris+heparin is not worse than Xigris+placebo and the concern that heparin abrogates the efficacy of Xigris should be mostly dispelled. And because almost all critically ill patients are at high frisk of DVT/PE, they should all be treated with heparinoids, and the administration of Xigris should not change that practice.

I just think we should stop letting folks get away with these non-inferiority/equivalence shenanigans. In this case, there is little ultimate difference. But in many cases a non-inferiority or equivalence trial such as this will allow the manufacture of a false reality. So I'll call this a case of "attempted manufacture of a false reality".