tag:blogger.com,1999:blog-1474751880645498536.post8022165802188212948..comments2023-10-10T10:14:36.340-04:00Comments on Medical Evidence Blog: The CORTICUS Trial: Power, Priors, Effect Size, and Regression to the MeanScott K. Aberegg, M.D., M.P.H.http://www.blogger.com/profile/17564774546019869201noreply@blogger.comBlogger4125tag:blogger.com,1999:blog-1474751880645498536.post-1424391625332808912008-03-15T18:21:00.000-04:002008-03-15T18:21:00.000-04:00E.A. -Your commemt brings up some interesting poin...E.A. -<BR/><BR/>Your commemt brings up some interesting points.<BR/><BR/>Firstly, it depends on whether you think a RCT is to benefit science, patients, society, or some combination.<BR/><BR/>Because a "negative" trial is often a harbinger of doom for a therapy, and because even therapies that have met the burden of proof are taken up slowly if at all (average lag stated to be 17 years from proof of efficacy to widespread adoption), I would say that a small negative trial with the trends in the right direction, while advancing science, does little to advance patient care.<BR/><BR/>And I wonder what patient enrollees in the trial would think if they knew that perhpas the majority of CC trials are underpowered and therefore negative? I dont' think that would be a good slogan for recruitment.<BR/><BR/>I understand the need for "replicability" for scientific validity. However, is it not appropriate to think of a 50 center trial with 5000 patients equivalent to 10 5-center trials with 500 patients each? Would not the external validity be about the same?<BR/><BR/>More to the point may be that we appear to have blindly followed the mantra in critical care research that states that the only legitimate and valid outcome measure is mortality. I think that in the future we will come to see this as a sophomoric perspective. Perhaps we should go the way of the cardiologists and use combined endpoints that include mortality, as well as days off pressors, days off the vent, freedom from complications. Such endpoints, I think, require greater consideration than they have heretofore been given in terms of their composition, something that I have stated on an early post on this blog. In other words, you should not get the same weight for a vent-free day as you do a survival. The problem with this is that people have not yet embraced an economic perspective when designing and interpreting RCTs, (one in which expected utility theory would be the standard for evaluating the evidnece) and this probably stems from the inherent difficulties in comparing the value of say, a death, to the value of an episode of bleeding. That would force people to consider how many times they would have to bleed before they would rather be dead. There may not ever be consensus on such an issue, but at least considering it may provide us insights into our own values that until now are implict rather than explicit.<BR/><BR/>The issues are complex. But given a paradigm for critical care research that focuses almost blindly on mortality as the only valid endpoint and that far more often than not yields null results that are of little use to patients or practitioners and generate more confusion than they resolve, I would be in favor of a re-examination of these complex issues.Scott K. Aberegg, M.D., M.P.H.https://www.blogger.com/profile/17564774546019869201noreply@blogger.comtag:blogger.com,1999:blog-1474751880645498536.post-68228908557598032652008-03-15T09:19:00.000-04:002008-03-15T09:19:00.000-04:00Dr Aberegg,You stated "...wouldn't it make sense t...Dr Aberegg,<BR/>You stated "...wouldn't it make sense to conduct 1 trial that is so robust that nobody dare repeat it in the future..." but isn't that the idea behind research--if a particular study can be repeated (assuming identical or near identical outcome) then the results are considered propitious for healthcare, which is a good thing. <BR/>Or am I way off base on this and missing the point entirely?<BR/><BR/>E.A.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1474751880645498536.post-59954606706418791992008-03-11T16:11:00.000-04:002008-03-11T16:11:00.000-04:00JMOYou should have taken the lead on this one.JMO<BR/>You should have taken the lead on this one.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-1474751880645498536.post-55963672474611971892008-03-11T11:23:00.000-04:002008-03-11T11:23:00.000-04:00Some background on CORTICUS...this study was under...Some background on CORTICUS...this study was underpowered because they ran out of money and were having a hard time recruiting patients because clinicians were giving steroids to their patients. Amazingly, the NEJM did not require the usual CONSORT figure of patients screened but not enrolled in the study. This suggests a couple of things. 1. MDs think steroids work. 2. The enrolled subjects were likely dominated by those for whom their MDs had some clinical equipoise regarding the benefit of steroids. Therefore, this may be a different population than the septic patients we see every day. Steroids benefit and suffer from their availability. Because there is no need to seek FDA approval for their use, they can be used regardless of the evidence. This is why there was a national shortage of hydrocortisone following Annane's initial study. However, without an industry interest, it is hard to fund a large, well-designed study. We get these murky results that make it hard to interpret. Part of the problem with steroids IMHO stems from the tie to the replacement of endogenous cortisol - so-called relative adrenal insufficiency. There are protean problem with this. First, we have intensivists believing they are endocrinologists - not a good sign. We know that the free cortisol fraction is the biologically active fraction - yet we measure total cortisol in the setting of extremely deranged serum protein metabolism. Also, we know that steroid resistance occurs with the inflammation of sepsis. Therefore, truly adrenally insufficient patients are those who have signs of inadequate steroid effects on cells - something not easily measured. There are also many assays in clinical labs for cortisol. The referral of all samples in CORTICUS to a central lab showed clearly that local tests are unreliable. 25% of subjects were misclassified regarding their response in total cortisol to the supraphysiologic dose of ACTH. Finally, it is impractical to think that we would get an ACTH stim test back in time to make a decision about steroids or not. There are not adequate data supporting the safety and/or efficacy of the usual practice of giving dexamethasone (which affects cortisol synthesis in response to ACTH) while and ACTH stim test is performed and stopping steroids if response is adequate. If there were resources to do a large enough study, I would suggest three arms of treatment of septic shock. Placebo, 200 mg/d hydrocortisone and 100 mg/d hydrocortisone. I would not do ACTH stim tests. I would not act like this is an effort to normalize cortisol levels (since 200 mg/d of hydrocortisone far exceeds this level). I suspect this would require something in the order of 2000 patients. At this point, most of us are sick of steroids. They make our brain hurt thinking about the lousy data we have. I doubt such a study will ever occur. I think my practice will be to give steroids to those who I think have impressive septic shock and to give it early. My first choice of therapy will remain rhAPC and steroids would be a second choice. Don't know if this is right or not. I do think we need to be more considerate about the use of etomidate. There are more options than benzo + opioid. Perhaps we should learn more from our ED and anesthesia colleagues and be quicker to consider RSI and paralytics. - JMOAnonymousnoreply@blogger.com