In this week's NEJM, (http://content.nejm.org/cgi/content/short/358/22/2344) Camilleri (of the Mayo Clinic) and comrades from Movetis (a pharmaceutical company) report the results of a study of Prucalopride, a prokinetic agent, for the treatment of chronic constipation. What is striking about this study is not the agent's relation to Ciaspride (Propulsid, an agent removed from the market a number of years ago because of QTc prolongation and associated cardiac risk) but rather the fact that this study was completed nearly a decade ago, and was only just now published. Such a delay is certainly worthy of concern as astutely pointed out by an editorialist (http://content.nejm.org/cgi/content/short/358/22/2402).
A colleague and I recently pointed out the unethical practice of witholding the results of negative trials from the scientific community (see http://ccmjournal.com/pt/re/ccm/fulltext.00003246-200803000-00060.htm;jsessionid=L2bQSl9ygT9BzlZq81qlnJGfyfG2Jh2f2qQvP4XTp0YqMQ1ZD3T1!195308708!181195628!8091!-1?index=1&database=ppvovft&results=1&count=10&searchid=2&nav=search#P6), but the Prucalopride trial takes the cake. Here, positive results were either intentionally witheld from that community or by happenstance were omitted from publication, delaying further study of this agent (if it is indeed even warranted) and undermining the altruistic basis of subjects' participation in the trial, which, ostensibly, was to advance science (unless they participated for financial incentives, which I might argue [as others already have] should be disclosed in the reporting of a trial - see http://content.nejm.org/cgi/content/extract/358/22/2316.)
I will leave it to other bloggers and commentators to speculate whether the profit or other motives were the impetus behind this delay and whether medical ghostwriting was in any way involved in the publication of this article. Suffice it to say that there are certain irregularities in the way a trial is reported (in addition to those with which it was conducted) that should give us pause. Prucalopride has now shown itself to be worthy of a bright spotlight of intense scrutiny.
Thursday, May 29, 2008
Wednesday, May 14, 2008
Troponin Predicts Outcome in Heart Failure - But So What?
In today's NEJM, Peacock and others (http://content.nejm.org/cgi/content/short/358/20/2117 ) report that cardiac troponin is STATISTICALLY associated with hospital mortality in patients with acute decompensated heart failure, and that this association is independent of other predictive variables. Let us assume that we take the results for granted, and that this is an internally and externally valid study with little discernible bias.
In the first paragraph of the discussion, the authors state that "These results suggest that measurement of troponin adds important prognostic information to the initial evaluation of patients with acute decompensated heart failure and should be considered as part of an early assessment of risk."
Really?
The mortality in patients in the lowest quartile of troponin I was 2.0% and that in the highest quartile was 5.3%. If we make the common mistake of comparing things on a relative scale, this is in an impressive difference - in excess of a twofold increase in mortality. But that is like saying that I saved 50% off the price of a Hershey Kiss which costs 5 cents - so I saved 3 cents! As we approach zero, smaller and smaller absolute differences can appear impressive on a relative scale. But health should not be appraised that way. If you are "buying" something, be it health or some other commodity, you shouldn't care about your relative return on your investment, only the absolute return. You have after all, only some absolute quantity of money. Charlie (from the Chocolate Factory) may find 3 cents to be meaningful, but we are not here talking about getting a 3% reduction in mortality - we are talking about predicting for Charlie whether he will have to pay $0.05 for his kiss or $0.02 for it, and even if our prediction is accurate, we do not know how to help him get the discounted kiss - he's either lucky or he's not.
Imagine that you are a patient hospitalized for acute decompensated heart failure. Does it matter to you if your physician comes to you carrying triumphantly the results of your troponin I test and informs you that because it is low, your mortality is 2% rather than 5%? It probably matters very little. It matters even less if your physician is not going to do anything differently given the results of that test. Two percent, 5 percent, it doesn't matter if it can't be changed.
Then there is the cost associated with this test. My hospital charges on the order of $200 for this test. Consider the opportunity costs - what else could that $200 be spent on, in the care of American patients, and perhaps even more importantly in the context of global health and economics? Also consider the value of the test to a patient who might have to pay out of pocket for it - is it worth $200 to discriminate within an in-hospital mortality range of 2-5%?
This study, while meticulously conducted and reported, underscores the important distinction between statistical significance and clinical significance. With the aid of a ginormous patient registry, the authors clearly demonstrated a statistically significant result that is at least mildly interesting from a biological perspective (is it interesting that a failing heart spills some of its contents into the blodstream and that they can be detected by a highly sensitive assay?) But the clinical significance of the findings appears to be negligible, and I worry that this report will encourate the already rampant mindless use of this expensive test which, outside of the context of clinical pre-test probabilities, already serves to misguide care and run up healthcare costs in a substantial proportion of the patients in whom it is ordered.
In the first paragraph of the discussion, the authors state that "These results suggest that measurement of troponin adds important prognostic information to the initial evaluation of patients with acute decompensated heart failure and should be considered as part of an early assessment of risk."
Really?
The mortality in patients in the lowest quartile of troponin I was 2.0% and that in the highest quartile was 5.3%. If we make the common mistake of comparing things on a relative scale, this is in an impressive difference - in excess of a twofold increase in mortality. But that is like saying that I saved 50% off the price of a Hershey Kiss which costs 5 cents - so I saved 3 cents! As we approach zero, smaller and smaller absolute differences can appear impressive on a relative scale. But health should not be appraised that way. If you are "buying" something, be it health or some other commodity, you shouldn't care about your relative return on your investment, only the absolute return. You have after all, only some absolute quantity of money. Charlie (from the Chocolate Factory) may find 3 cents to be meaningful, but we are not here talking about getting a 3% reduction in mortality - we are talking about predicting for Charlie whether he will have to pay $0.05 for his kiss or $0.02 for it, and even if our prediction is accurate, we do not know how to help him get the discounted kiss - he's either lucky or he's not.
Imagine that you are a patient hospitalized for acute decompensated heart failure. Does it matter to you if your physician comes to you carrying triumphantly the results of your troponin I test and informs you that because it is low, your mortality is 2% rather than 5%? It probably matters very little. It matters even less if your physician is not going to do anything differently given the results of that test. Two percent, 5 percent, it doesn't matter if it can't be changed.
Then there is the cost associated with this test. My hospital charges on the order of $200 for this test. Consider the opportunity costs - what else could that $200 be spent on, in the care of American patients, and perhaps even more importantly in the context of global health and economics? Also consider the value of the test to a patient who might have to pay out of pocket for it - is it worth $200 to discriminate within an in-hospital mortality range of 2-5%?
This study, while meticulously conducted and reported, underscores the important distinction between statistical significance and clinical significance. With the aid of a ginormous patient registry, the authors clearly demonstrated a statistically significant result that is at least mildly interesting from a biological perspective (is it interesting that a failing heart spills some of its contents into the blodstream and that they can be detected by a highly sensitive assay?) But the clinical significance of the findings appears to be negligible, and I worry that this report will encourate the already rampant mindless use of this expensive test which, outside of the context of clinical pre-test probabilities, already serves to misguide care and run up healthcare costs in a substantial proportion of the patients in whom it is ordered.
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