Saturday, September 25, 2010

In the same vein: Intercessory Prayer for Heart Surgery and Neuromuscular Blockers for ARDS

Several years back, in the American Heart Journal, was published a now-widely referenced study of intercessory prayer to aid recovery of patients who had had open heart surgery (see: Am Heart J. 2006 Apr;151(4):934-42). This study was amusing for several reasons, not least of which because, in spite of being funded by a religious organization, the results were "negative" meaning that there was no apparent positive effect of prayer. Of course, the "true believers" called foul, claiming that the design was flawed, etc. (Another ironic twist of the study: patients who knew they were being prayed for actually fared worse than those who had received no prayers.)

The most remarkable thing about this study for me is that it was scientifically irresponsible to conduct it. Science (and biomedical research) must be guided by testing a defensible hypothesis, based on logic, historical and preliminary data, and, in the case of biomedical research, an understanding of the underlying pathophysiology of the disease process under study. Where there is no scientifically valid reason to believe that a therapy might work, no preliminary data - nothing - a hypothesis based on hope or faith has no defensible justification in biomedical research, and its study is arguably unethical.

Moreover, a clinical trial is in essence a diagnostic test of a hypothesis, and the posterior probability of a hypothesis (null or alternative) depends not only on the frequentist data produced by the trial, but also on a Bayesian analysis incorporating the prior probability that the alternative (or null) hypothesis is true (or false). That is, if I conducted a trial of orange juice (OJ) for the treatment of sepsis (another unethical design) and OJ appeared to reduce sepsis mortality by, say, 10% with P=0.03, you should be suspicious. With no biologically plausible reason to believe that OJ might be efficacious, the prior probability of Ha (that OJ is effective) is very low, and a P-value of 0.03 (or even 0.001) is unconvincing. That is, the less compelling the general idea supporting the hypothesis is, the more robust a P-value you should require to be convinced by the data from the trial.

Thus, a trial wherein the alternative hypothesis tested has a negligible probability of being true is uninformative and therefore unethical to conduct. In a trial such as the intercessory prayer trial, there is NO resultant P-value which is sufficient to convince us that the therapy is effective - in effect, all statistically significant results represent Type I errors, and the trial is useless.
(I should take a moment here to state that, ideally, the probability of Ho and Ha should both be around 50%, or not far off, representing true equipoise about the scenario being studied. Based on our data in the Delta Inflation article (see: ), it appears that at least in critical care trials evaluating comparative mortality, the prior probability of Ha is on the order of 18%, and even that figure is probably inflated because many of the trials that comprise it represent Type I errors. In any case, it is useful to consider the prior probability of Ha before considering the data from a trial, because that prior is informative. [And in the case of trials for biologics for the treatment of sepsis {be it OJ or drotrecogin, or anti-TNF-alpha}, the prior probability that any of them is efficacious is almost negligibly low.)

Which segues me to Neuromuscular Blockers (NMBs) for ARDS (see: ) - while I have several problems with this article, my most grievous concern is that we have no (in my estimation) substantive reason to believe that NMBs will improve mortality in ARDS. They may improve oxygenation, but we long ago abandoned the notion that oxygenation is a valid surrogate end-point in the management of ARDS. Indeed, the widespread abandonment of use of NMBs in ARDS reflects consensus agreement among practitioners that NMBs are on balance harmful. (Note in Figure 1 that, in contrast to the contention of the authors in the introduction that NMBs remain widely used, only 4.3% of patients were excluded because of use of NMBs at baseline.)

In short, these data fail to convince me that I should be using NMBs in ARDS. But many readers will want to know "then why was the study positive?" And I think the answer is staring us right in the face. In addition to the possibility of a simple Type I error, and the fact that the analysis was done with a Cox regression, controlling for baseline imbalances (even ones such as PF ratio which were NOT prospectively defined as variables to control for in the analysis), the study was effectively unblinded/unmasked. It is simply not possible to mask the use of NMBs, the clinicians and RNs will quickly figure out who is and is not paralyzed - paralyzed patients will "ride the vent" while unparalyzed ones will "fight the vent". And differences in care may/will arise.

It is the simplest explanation, and I wager it's correct. I will welcome data from other trials if they become available (should it even be studied further?), but in the meantime I don't think we should be giving NMBs to patients with ARDS any more than we should be praying (or avoiding prayer) for the recovery of open-heart patients.

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