Congress is looking into the TV ads starring Dr. Robert Jarvik, artificial heart valve innovator and researcher, apparently because he never was licensed to practice medicine and alarmingly the ad producers used a body double for the rowing scenes.The legislators apparently are concerned that the ads are "misleading". While protecting the public from misleading ads ( who would have thought ads could be misleading ) is a high priority there may be greater dangers.
I am not talking about the risk of receiving very bad heparin or dying in the hospital at night because all the staff are asleep or something I am talking about humanity in danger from killer robots.
Wednesday, February 27, 2008
Monday, February 25, 2008
Never can know enough
One sentence from a recent typically well written and insightful contribution by Intueri particularly resonated with me.
We [physicians] find ourselves pulled into the belief that we are squandering our skills and potential if we are not tending to our patients (through direct patient care, reading, studying, etc.) as much as we can.
I've written before ( now three years ago) about the transformation of a layperson into a physician. Much about that transformation is captured in that sentence.
That sentence describes how I felt beginning sometime in medical school and ending gradually sometime after I retired. Always the nagging fears of not knowing enough and not being alert enough and not working hard enough were there.Now since nothing I read will be translated into any real action for or to a patient( except myself and spouse) although I still read and think about medical matters a lot it as Osler said "“He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all.”
Now when I read about the latest study on ventilating patient with ARDS it is with interest but it is not with the same limbic valence as reading about something that you know "will be on the test" or that you may will really need that information as you go to sea. As much as anything that is a major part of the "transformation" back. Without that motivation to try and know enough to do the right thing for your patient and to know that you will not be regularly asked what to do by your patients really does make the transformation nearly complete. Fully complete may entail not letting that bother you so much.
We [physicians] find ourselves pulled into the belief that we are squandering our skills and potential if we are not tending to our patients (through direct patient care, reading, studying, etc.) as much as we can.
I've written before ( now three years ago) about the transformation of a layperson into a physician. Much about that transformation is captured in that sentence.
That sentence describes how I felt beginning sometime in medical school and ending gradually sometime after I retired. Always the nagging fears of not knowing enough and not being alert enough and not working hard enough were there.Now since nothing I read will be translated into any real action for or to a patient( except myself and spouse) although I still read and think about medical matters a lot it as Osler said "“He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all.”
Now when I read about the latest study on ventilating patient with ARDS it is with interest but it is not with the same limbic valence as reading about something that you know "will be on the test" or that you may will really need that information as you go to sea. As much as anything that is a major part of the "transformation" back. Without that motivation to try and know enough to do the right thing for your patient and to know that you will not be regularly asked what to do by your patients really does make the transformation nearly complete. Fully complete may entail not letting that bother you so much.
Friday, February 22, 2008
The problems of Evidence-based medicine widely accepted hierarchy of evidence
The generally (or maybe just widely) accepted formulation of the hierarchy of medical evidence that is a major construct in what has come to be known as evidence-based medicine (EBM) considers the randomized clinical trial (RCT) and the meta-analysis (MA) as the premium types of evidence capable of trumping other forms of evidence listed below them on the evidentiary ranking system. Observational studies, case reports,personal experience and notably physiologic considerations fall on the lower rungs of the ladder. According to a widely accepted and practiced version of this scheme, higher levels of evidence trump lower lower levels.
For some time I have been perplexed about this hierarchy .
This first thing that bothered me was if meta-analysis deserved such a lofty position. Two things made me decide that they definitely did not.
The important Annals of Internal Medicine Articles and editorial by Dr. Steve Goodman of Johns Hopkins made it clear to me that MAs were basically themselves observational studies in which the studies themselves were subjects. He discussed two major MAs on the value of mammograms, one which concluded they were effective and valuable and the other concluded the opposite.The major difference between the studies was their choice of studies to include and to exclude. Both sets of authors maintained their criteria for exclusion were valid and yet they were quite different and resulted in opposite conclusions. Quoting Goodman:
... this controversy shows that the justification for why studies are included or excluded from the evidence base can rest on competing claims of methodologic authority that look little different from the traditional claims of medical authority that proponents of evidence-based medicine have criticized.
Secondly, not only is the choice of inclusion rules important but so are the various statistical techniques used to analyze the data. A widely quoted MA on the use of large doses of Vitamin E published in the Annals Internal Medicine made it clear to me the importance of methodology and how impenetrable the bickering between statistical experts could be as they debate the merits of their technique of choice. In this case, the authors of the article found a tiny increase ( relative risk of 1.03) in overall deaths from the vitamin E. A flurry of letters to the editors claimed their technique was wrong and that when the "correct" method was used there was in fact no statistically significant difference. Since so much seems to depend on the investigator's choice of what studies to include and the method used to analyze the data and those actions basically takes place at least to the usual physician reader behind the thick methodological-statistical curtain that faith in the authors become very prominent.So accepting that type of evidence involves more than a little faith .
It seemed clear to me that the MA did not belong in the top of the evidence ladder and I wrote about it here.
Sometime later after I became aware of a more fundamental problem in this evidence ranking and trumping system in an 2001 article by Dr. M.R. Tonelli and after wrestling with that article for while I began to think that the construct of a hierarchy itself was in error. Tonelli said in part:
Proponents of evidence-based medicine have made a conceptual error by grouping knowledge from clinical experience and physiologic rationale under the heading of evidence and then compounded the error by developing hierarchies of evidence that relegate these forms of medical knowledge to the lowest rungs. Empirical evidence, when it exists,is viewed as the "best"evidence on which to make a clinical decision, superseding clinical experience and physiologic rationale.
More recently several articulate and thoughtful bloggers have discussed what one called the "elephant in the [EMB} room". Orac had this to say in a recent posting.
As I've come to realize, the elephant in the room when it comes to EBM is that it relegates basic science and estimates of prior probability based on that science to one of the lowest forms of evidence, to be totally trumped by clinical evidence. This may be appropriate when the clinical evidence is very compelling and shows a very large effect; in such cases we may legitimately question whether the basic science is wrong. But such is not the case for homeopathy, where the basic science evidence is exceedingly strong against it and the clinical evidence, even from the "positive" studies, generally shows small effects. EBM, however, tells us that this weak clinical evidence must trump the very strong basic science, the problem most likely being that the originators of the EBM movement never saw CAM coming and simply assumed that supporters of EBM wouldn't waste their time investigating therapeutic modalities with an infinitesimally small prior probability of working.
It seems that the elephant's cloak of invisibility was torn away when a number of small clinical trials allegedly found that such things as homeopathy and reiki ( the most improbably absurd of the improbable methods of CAM) seemed to work or at a minimum the claim was made that larger trials were needed. Perhaps worse still ,some meta-analysis of those trials by folks highly regarded in EBM circles (such as the Cochrane Collaboration)suggested there was some evidence of their efficacy , such analysis of the trials notable by the absence of any mentioning about how these techniques fly in the face of current concepts of chemistry, physics and physiology let alone contrary prior experience. The message of "trials trump basic science" seemed to have taken to heart by the folks at Cochrane.
Dr. RW had this to say
... treatments must pass not only the evidentiary test but also the test of scientific plausibility. Because EBM devalues the latter it is inadequate for the evaluation of implausible claims even though it may perform well in evaluating plausible ones. This fundamental error is built into EBM’s system of analysis as illustrated by its evidence hierarchy, which places physiologic rationale and scientific principles at the bottom of the heap...
Essential reading on this general topic must include posting by Dr. Kimball Atwood IV and the articles by Dr. Steve Goodman explicating meta-analysis and the topic of prior probability in the form of Bayesian analysis.
Goodman said "data alone cannot prove the hypothesis". It is essential to take into account biological plausibility and prior evidence.The astounding example of how sincere disciples of the extreme empiricism form of EBM "analyzed" homeopathy should be all we need to listen closely to what Goodman and Tonelli have been saying. Was is naive to think that a calculus had been devised that enabled us to make decisions simply by using a ranking system in which types of evidence higher on the pole invariably trumped those lower. To quote Goodman yet again.
Judgment determines what evidence is admissible and how strongly to weigh different forms of admissible evidence. When there is consensus on these judgments and the data are
strong, an illusion is created that the evidence is speakingfor itself and that the methods are objective. But this episode[ the mammogram controversy mentioned above] should raise awareness that judgment cannot be excised from the process of evidence synthesis and that the variation of this judgment among experts generates uncertainty just as real as the probabilistic uncertainty of statistical calculations.
I cannot help but think the EBM ranking- trumping system became for some a means to avoid the judgment that Dr. Goodman writes about, though it may have not been so intended by the founders of the movement. If medical students grow up to believe that clinical trials always trump basic science the incredible growth of CAM in main line medical schools (see here and here for how bad this is getting) will only continue to get worse and worse. Everything I have said here has been said better by the folks I quoted but I think it is important to keep the fires of protest burning.
For some time I have been perplexed about this hierarchy .
This first thing that bothered me was if meta-analysis deserved such a lofty position. Two things made me decide that they definitely did not.
The important Annals of Internal Medicine Articles and editorial by Dr. Steve Goodman of Johns Hopkins made it clear to me that MAs were basically themselves observational studies in which the studies themselves were subjects. He discussed two major MAs on the value of mammograms, one which concluded they were effective and valuable and the other concluded the opposite.The major difference between the studies was their choice of studies to include and to exclude. Both sets of authors maintained their criteria for exclusion were valid and yet they were quite different and resulted in opposite conclusions. Quoting Goodman:
... this controversy shows that the justification for why studies are included or excluded from the evidence base can rest on competing claims of methodologic authority that look little different from the traditional claims of medical authority that proponents of evidence-based medicine have criticized.
Secondly, not only is the choice of inclusion rules important but so are the various statistical techniques used to analyze the data. A widely quoted MA on the use of large doses of Vitamin E published in the Annals Internal Medicine made it clear to me the importance of methodology and how impenetrable the bickering between statistical experts could be as they debate the merits of their technique of choice. In this case, the authors of the article found a tiny increase ( relative risk of 1.03) in overall deaths from the vitamin E. A flurry of letters to the editors claimed their technique was wrong and that when the "correct" method was used there was in fact no statistically significant difference. Since so much seems to depend on the investigator's choice of what studies to include and the method used to analyze the data and those actions basically takes place at least to the usual physician reader behind the thick methodological-statistical curtain that faith in the authors become very prominent.So accepting that type of evidence involves more than a little faith .
It seemed clear to me that the MA did not belong in the top of the evidence ladder and I wrote about it here.
Sometime later after I became aware of a more fundamental problem in this evidence ranking and trumping system in an 2001 article by Dr. M.R. Tonelli and after wrestling with that article for while I began to think that the construct of a hierarchy itself was in error. Tonelli said in part:
Proponents of evidence-based medicine have made a conceptual error by grouping knowledge from clinical experience and physiologic rationale under the heading of evidence and then compounded the error by developing hierarchies of evidence that relegate these forms of medical knowledge to the lowest rungs. Empirical evidence, when it exists,is viewed as the "best"evidence on which to make a clinical decision, superseding clinical experience and physiologic rationale.
More recently several articulate and thoughtful bloggers have discussed what one called the "elephant in the [EMB} room". Orac had this to say in a recent posting.
As I've come to realize, the elephant in the room when it comes to EBM is that it relegates basic science and estimates of prior probability based on that science to one of the lowest forms of evidence, to be totally trumped by clinical evidence. This may be appropriate when the clinical evidence is very compelling and shows a very large effect; in such cases we may legitimately question whether the basic science is wrong. But such is not the case for homeopathy, where the basic science evidence is exceedingly strong against it and the clinical evidence, even from the "positive" studies, generally shows small effects. EBM, however, tells us that this weak clinical evidence must trump the very strong basic science, the problem most likely being that the originators of the EBM movement never saw CAM coming and simply assumed that supporters of EBM wouldn't waste their time investigating therapeutic modalities with an infinitesimally small prior probability of working.
It seems that the elephant's cloak of invisibility was torn away when a number of small clinical trials allegedly found that such things as homeopathy and reiki ( the most improbably absurd of the improbable methods of CAM) seemed to work or at a minimum the claim was made that larger trials were needed. Perhaps worse still ,some meta-analysis of those trials by folks highly regarded in EBM circles (such as the Cochrane Collaboration)suggested there was some evidence of their efficacy , such analysis of the trials notable by the absence of any mentioning about how these techniques fly in the face of current concepts of chemistry, physics and physiology let alone contrary prior experience. The message of "trials trump basic science" seemed to have taken to heart by the folks at Cochrane.
Dr. RW had this to say
... treatments must pass not only the evidentiary test but also the test of scientific plausibility. Because EBM devalues the latter it is inadequate for the evaluation of implausible claims even though it may perform well in evaluating plausible ones. This fundamental error is built into EBM’s system of analysis as illustrated by its evidence hierarchy, which places physiologic rationale and scientific principles at the bottom of the heap...
Essential reading on this general topic must include posting by Dr. Kimball Atwood IV and the articles by Dr. Steve Goodman explicating meta-analysis and the topic of prior probability in the form of Bayesian analysis.
Goodman said "data alone cannot prove the hypothesis". It is essential to take into account biological plausibility and prior evidence.The astounding example of how sincere disciples of the extreme empiricism form of EBM "analyzed" homeopathy should be all we need to listen closely to what Goodman and Tonelli have been saying. Was is naive to think that a calculus had been devised that enabled us to make decisions simply by using a ranking system in which types of evidence higher on the pole invariably trumped those lower. To quote Goodman yet again.
Judgment determines what evidence is admissible and how strongly to weigh different forms of admissible evidence. When there is consensus on these judgments and the data are
strong, an illusion is created that the evidence is speakingfor itself and that the methods are objective. But this episode[ the mammogram controversy mentioned above] should raise awareness that judgment cannot be excised from the process of evidence synthesis and that the variation of this judgment among experts generates uncertainty just as real as the probabilistic uncertainty of statistical calculations.
I cannot help but think the EBM ranking- trumping system became for some a means to avoid the judgment that Dr. Goodman writes about, though it may have not been so intended by the founders of the movement. If medical students grow up to believe that clinical trials always trump basic science the incredible growth of CAM in main line medical schools (see here and here for how bad this is getting) will only continue to get worse and worse. Everything I have said here has been said better by the folks I quoted but I think it is important to keep the fires of protest burning.
Tuesday, February 19, 2008
Complex trials for complex condition can be ..well complex
The history of ARDS ( acute respiratory distress syndrome) is a relatively short narrative in contrast to some other diseases and their treatments. I remember writing a review of a book about the topic as a fellow in pulmonary disease circa the early 1970s at that time very little was written about that topic, the condition having been recognized somewhere around 40 years ago.
We now talk about ALI (acute lung injury) as well as ARDS, the former being a sort of "ARDS- lite"with less severe oxgenation issues than full blown ARDS and it considered a precursor to ARDS. The "A" in ARDS first stood for "adult" and now is taken to mean " acute". Specific definitions of ALS and ARDS appeared in 1994 based on oxygenation levels defined by the ratio of arterial oxygen tension and the fraction of inspired oxygen.
Ventilatory support of these patients can be lifesaving but the optimal techniques or "settings of the ventilator" continue to be a source of controversy.Too high a tidal volume or a pressure and we risk various forms of barotrauma and too little of either seems to be associated with atelectasis ,blood shunting and another form of ventilator induced lung damage from forces related to opening and closing of gas exchange units.
Recent published clinical trials involving various techniques to ventilate these patients report in- hospital mortality rates for the treatment and the control arms in the range of 30 to 40% while a 2005 observational trial of 467 patients reported a 60% mortality rate which may well more accurately reflect real world outcomes,the old efficacy-effectiveness gap issue.
Two large clinical trials were published in the Feb. 13,2008 issue of JAMA as were as two editorials on the subject. I believe this brings to three the total of clinical trials that investigated the use of "high"er versus "low"er levels of PEEP and all found no statistically significant difference in terms of mortality although some less final measures tended to favor the higher levels. There were fewer days on ventilator support in one trial and fewer deaths from progressive hypoxemia in another.
Also favoring the higher levels are current theoretical considerations regarding what seems to be a major pathophysiological factor in ARDS. There appears to be considerable non-cardiac pulmonary edema in ARDS and the suggestion that these wet alveloi are capable of being ventilated (recruitable alveolar units) and since PEEP should enable lung unit expansion the subset of ARDS patients with more edema might significantly benefit from PEEP while other patients with less edema might not. With the now commonplace use of low tidal volumes one would expect more micro-atelectasis and it seems reasonable that higher PEEP might be needed to mitigate that tendency.
Accordingly, one editorialist suggested trials in the future might well use some measure of edema to stratify patients.The thought here is that those patients with more edema might benefit more from higher PEEP.Interestingly, in some patients PEEP seems to cause harmful overdistention without eliminating the atelectasis.
Clinical trials in complex patients pose a number of problems not seen in simpler randomized clinical trials such as those in which two medications are compared in more stable patients.
One of the editorials discusses some of the problems seen in trials such as those reported in ARDS including the necessary lack of blinding and the difficulty and traps involving in the crucial definition of exactly what the control group will be.This involves in part how much discretion are the treating docs given in the control group. Further,"inferences in causality can only be drawn about the entire intervention and not about any specific piece."
Interesting (and somewhat disconcerting to me) even though we now have three major clinical trials that all failed to demonstrate a mortality benefit to higher versus lower PEEP, all of the authors of these latest two article and one of the editorials agree that because of the compelling theoretical arguments favoring adding high PEEP to the current low tidal volume standard of care and the favorable morbidity measures that higher PEEP should be part of the de facto standard of care. If I were still twiddling the dials of the ventilators in ICU in patients with ARDS I would probably opt for higher PEEP as it seems to being about (at least in some patients) higher oxygen levels and lung docs always seem pleased with higher values and feel that we have accomplished something.
We now talk about ALI (acute lung injury) as well as ARDS, the former being a sort of "ARDS- lite"with less severe oxgenation issues than full blown ARDS and it considered a precursor to ARDS. The "A" in ARDS first stood for "adult" and now is taken to mean " acute". Specific definitions of ALS and ARDS appeared in 1994 based on oxygenation levels defined by the ratio of arterial oxygen tension and the fraction of inspired oxygen.
Ventilatory support of these patients can be lifesaving but the optimal techniques or "settings of the ventilator" continue to be a source of controversy.Too high a tidal volume or a pressure and we risk various forms of barotrauma and too little of either seems to be associated with atelectasis ,blood shunting and another form of ventilator induced lung damage from forces related to opening and closing of gas exchange units.
Recent published clinical trials involving various techniques to ventilate these patients report in- hospital mortality rates for the treatment and the control arms in the range of 30 to 40% while a 2005 observational trial of 467 patients reported a 60% mortality rate which may well more accurately reflect real world outcomes,the old efficacy-effectiveness gap issue.
Two large clinical trials were published in the Feb. 13,2008 issue of JAMA as were as two editorials on the subject. I believe this brings to three the total of clinical trials that investigated the use of "high"er versus "low"er levels of PEEP and all found no statistically significant difference in terms of mortality although some less final measures tended to favor the higher levels. There were fewer days on ventilator support in one trial and fewer deaths from progressive hypoxemia in another.
Also favoring the higher levels are current theoretical considerations regarding what seems to be a major pathophysiological factor in ARDS. There appears to be considerable non-cardiac pulmonary edema in ARDS and the suggestion that these wet alveloi are capable of being ventilated (recruitable alveolar units) and since PEEP should enable lung unit expansion the subset of ARDS patients with more edema might significantly benefit from PEEP while other patients with less edema might not. With the now commonplace use of low tidal volumes one would expect more micro-atelectasis and it seems reasonable that higher PEEP might be needed to mitigate that tendency.
Accordingly, one editorialist suggested trials in the future might well use some measure of edema to stratify patients.The thought here is that those patients with more edema might benefit more from higher PEEP.Interestingly, in some patients PEEP seems to cause harmful overdistention without eliminating the atelectasis.
Clinical trials in complex patients pose a number of problems not seen in simpler randomized clinical trials such as those in which two medications are compared in more stable patients.
One of the editorials discusses some of the problems seen in trials such as those reported in ARDS including the necessary lack of blinding and the difficulty and traps involving in the crucial definition of exactly what the control group will be.This involves in part how much discretion are the treating docs given in the control group. Further,"inferences in causality can only be drawn about the entire intervention and not about any specific piece."
Interesting (and somewhat disconcerting to me) even though we now have three major clinical trials that all failed to demonstrate a mortality benefit to higher versus lower PEEP, all of the authors of these latest two article and one of the editorials agree that because of the compelling theoretical arguments favoring adding high PEEP to the current low tidal volume standard of care and the favorable morbidity measures that higher PEEP should be part of the de facto standard of care. If I were still twiddling the dials of the ventilators in ICU in patients with ARDS I would probably opt for higher PEEP as it seems to being about (at least in some patients) higher oxygen levels and lung docs always seem pleased with higher values and feel that we have accomplished something.
Saturday, February 16, 2008
Well Point,rat-out-patients,and capitation
A number of medical blogs, including Health Care Renewal which contributed this essay have commented on the recent revelation of the dear doctor letter from Well Point requesting information from physicians regarding pre-existing conditions and their patients.
In a world where so often nothing seems to make much sense we tend to leap upon and devour ravenously a narrative that makes sense to us and explains what otherwise is a mystery.
The otherwise mystery arises in this story from the revelation that apparently such letters had been sent in large numbers and for some time and only now does a physician make public a indignant complaint.No one is surprised that a physician would complain.It seems to be a dog bites man type story.But why not before? Dr. Rich offers an explanation that resonates in our "that makes sense" gyrus located in some obscure site in the frontal lobe.
The docs who didn't complain after receiving these letters apparently were in a capitation payment system. The less illness they take care per patient the more money they get to keep. Read Dr.Rich's full entry to see how all of this seems to fit with the grand scheme of covet rationing. The story as it is unfolding looks like a "drop a dime, earn a dime situation".
In a world where so often nothing seems to make much sense we tend to leap upon and devour ravenously a narrative that makes sense to us and explains what otherwise is a mystery.
The otherwise mystery arises in this story from the revelation that apparently such letters had been sent in large numbers and for some time and only now does a physician make public a indignant complaint.No one is surprised that a physician would complain.It seems to be a dog bites man type story.But why not before? Dr. Rich offers an explanation that resonates in our "that makes sense" gyrus located in some obscure site in the frontal lobe.
The docs who didn't complain after receiving these letters apparently were in a capitation payment system. The less illness they take care per patient the more money they get to keep. Read Dr.Rich's full entry to see how all of this seems to fit with the grand scheme of covet rationing. The story as it is unfolding looks like a "drop a dime, earn a dime situation".
Monday, February 11, 2008
More crumbling dogma ? -this time lower and lower blood sugar is better
How many evening diner,CMEoid sessions included the chant, "treat to goal,treat to goal" in regard to blood sugar. As with LDl cholesterol-the goal just kept getting lower and lower.
The DPPT study seemed to provide very good evidence that the microvascular complications of type 1 diabetes could be significantly mitigated by "good"control of blood sugar.Later a follow up report from that landmark trial also provided some reasonable evidence that perhaps macrovascular disease could also be decreased.
There has been the hope that we could accomplish the same thing with the complications of type 2 diabetes by a similar surge of intensive treatment aimed at bringing about near normoglycemia. Would that life and disease and managing disease were so simple.
The UKPDS trial was-and to date is the only large trial with more or less the medications that are now used-that tried to examine whether tighter control of blood glucose would do for the type 2 diabetic patients what the DPPT trial showed that it did for type 1 patients.
The DPPT was a fairly simple trial. There were patients with a disease that seemed fairly homogenous and has relatively straightforward pathophysiology , i.e insulin lack from the get go and the treatment intervention was simply more insulin. On the other hand, the UKPDS trial involved several treatment arms and greater heterogeneity of comorbid conditions in the subjects as well as more variation in the the tempo of the various pathophysiological disturbances and the pathophysiology of type 2 is much more complex than in type 1.
With trials with more complicated conditions and multiple treatment arms there is greater likelihood of chance and confounding and various biases clouding the results. Clouded results or not the UKPDS became a major element in the argument to treat to lower blood glucose value in type 2 diabetes. The results of the UKPDS were not earth moving but were encouraging. There was some decrease in blood vessel disease on retinal exam and some decrease in the rate of progression of urinary protein leak but no change in renal failure or blindness or clinical manifestations of macrovascular disease. The benefit in terms of reduction of retinal microvascular and perhaps renal disease was arguably balanced by an almost four fold increase in serious hypoglycemia episodes ( 0.6% per year versus 2.3%). The former effect was emphasized and the later effect was not in the 2002 position paper from the American diabetes Association from which a lot of the enthusiasm for tight control arose. A somewhat less optimistic assessment of the UKPDS trial is offered here by Dr. Roy Poses and fits more with my ever increasingly cynical nature.
Now fast forward to the ACCORD trial . Here is the announcement of the cancellation of the intensive treatment arm of this large randomized trial. This was supposed to be the trial that would answer-among other questions- the question "can we decrease the macrovascular events associated with type 2 diabetes with intensive blood glucose control ?" Here the treatment goal was a HbA1C of less than 6 %, i.e. basically normal.
However,there were more overall deaths in the intensive treatment arm than in the standard treatment arm. Of those intensively treated about 1/2 had hemoglobin A1C values of less than 6.4 while in the standard treatment arm 1/2 had value less than 7.5. The mortality increase was certainly not what the investigators likely expected.The overall death rate was reported as 20% higher but there were actually fewer heart attacks in the intensive treatment arm but of those there was a higher mortality. So what is happening to cause increase mortality? The NIH announced their analysis so far has not determined what factor(s) are to blame.
Is this simply a matter of getting the glucose too low? Maybe, but an early report from the trial claimed that the excess mortality was not related to hypoglycemia although there were expectedly more hypoglycemia episodes in the intensive treatment group. Also the NIH reports the analysis so indicates no link to the use of any particular medication ,e.g. rosiglitazone.
Dr RW suggested that excessive insulin use may really be the culprit though not necessarily by precipitating hypoglycemia episodes but by fueling weight gain and the metabolic syndrome and insulin resistance. Other suggestions have been made,see here for references, including the stress placed on patients to achieve a difficult therapeutic goal and the theory that too rapid decrease in blood glucose might have played a role.
Dr. Steven Pinker has written extensively and eloquently about the human mind's mysterious and marvelous workings and has discussed how the human mind can see events in different frames. I'll bet that we be seeing the results of this trial (so far we have only a snippet of the results) spun this way and that. But deaths are not a surrogate measure and the major observation of more deaths with intensive treatment may well shift the momentum of diabetic treatment from "lower is better" to "well maybe not too low" and maybe " not necessarily the same target for everyone". A number of doctor bribe programs (A.K.A. pay for performance ) are keyed to hemoglobin A1C levels .Will we see those third party payers whose interests are claimed to be in improving quality of care quickly revise their guidelines?
Physicians want better treatments for their patients and they want results of promising treatments to be true. That desire to do good for their patients coupled with big pharma funded hype often aided by a shinny veneer pasted on by academic and other thought leaders can really energize therapeutic exuberance that may have a much less robust evidentiary base that we were lead to believe.Treating to a goal or treating the numbers can make clinical life seem simpler, sometimes too simple.
First, we find out that maybe we were giving to much EPO, and then maybe lower LDL per se is not better and now more insulin may be too much of a good thing (haven't we known that for a long time?). It is a good thing we quasi- codified all or some of those things into guidelines and pay-for-compliance programs otherwise we might not have had a chance to use them before we decided there weren't really a great idea after all. I remember as house officers we used to talk about the patient dying but the electrolytes were in balance.
The DPPT study seemed to provide very good evidence that the microvascular complications of type 1 diabetes could be significantly mitigated by "good"control of blood sugar.Later a follow up report from that landmark trial also provided some reasonable evidence that perhaps macrovascular disease could also be decreased.
There has been the hope that we could accomplish the same thing with the complications of type 2 diabetes by a similar surge of intensive treatment aimed at bringing about near normoglycemia. Would that life and disease and managing disease were so simple.
The UKPDS trial was-and to date is the only large trial with more or less the medications that are now used-that tried to examine whether tighter control of blood glucose would do for the type 2 diabetic patients what the DPPT trial showed that it did for type 1 patients.
The DPPT was a fairly simple trial. There were patients with a disease that seemed fairly homogenous and has relatively straightforward pathophysiology , i.e insulin lack from the get go and the treatment intervention was simply more insulin. On the other hand, the UKPDS trial involved several treatment arms and greater heterogeneity of comorbid conditions in the subjects as well as more variation in the the tempo of the various pathophysiological disturbances and the pathophysiology of type 2 is much more complex than in type 1.
With trials with more complicated conditions and multiple treatment arms there is greater likelihood of chance and confounding and various biases clouding the results. Clouded results or not the UKPDS became a major element in the argument to treat to lower blood glucose value in type 2 diabetes. The results of the UKPDS were not earth moving but were encouraging. There was some decrease in blood vessel disease on retinal exam and some decrease in the rate of progression of urinary protein leak but no change in renal failure or blindness or clinical manifestations of macrovascular disease. The benefit in terms of reduction of retinal microvascular and perhaps renal disease was arguably balanced by an almost four fold increase in serious hypoglycemia episodes ( 0.6% per year versus 2.3%). The former effect was emphasized and the later effect was not in the 2002 position paper from the American diabetes Association from which a lot of the enthusiasm for tight control arose. A somewhat less optimistic assessment of the UKPDS trial is offered here by Dr. Roy Poses and fits more with my ever increasingly cynical nature.
Now fast forward to the ACCORD trial . Here is the announcement of the cancellation of the intensive treatment arm of this large randomized trial. This was supposed to be the trial that would answer-among other questions- the question "can we decrease the macrovascular events associated with type 2 diabetes with intensive blood glucose control ?" Here the treatment goal was a HbA1C of less than 6 %, i.e. basically normal.
However,there were more overall deaths in the intensive treatment arm than in the standard treatment arm. Of those intensively treated about 1/2 had hemoglobin A1C values of less than 6.4 while in the standard treatment arm 1/2 had value less than 7.5. The mortality increase was certainly not what the investigators likely expected.The overall death rate was reported as 20% higher but there were actually fewer heart attacks in the intensive treatment arm but of those there was a higher mortality. So what is happening to cause increase mortality? The NIH announced their analysis so far has not determined what factor(s) are to blame.
Is this simply a matter of getting the glucose too low? Maybe, but an early report from the trial claimed that the excess mortality was not related to hypoglycemia although there were expectedly more hypoglycemia episodes in the intensive treatment group. Also the NIH reports the analysis so indicates no link to the use of any particular medication ,e.g. rosiglitazone.
Dr RW suggested that excessive insulin use may really be the culprit though not necessarily by precipitating hypoglycemia episodes but by fueling weight gain and the metabolic syndrome and insulin resistance. Other suggestions have been made,see here for references, including the stress placed on patients to achieve a difficult therapeutic goal and the theory that too rapid decrease in blood glucose might have played a role.
Dr. Steven Pinker has written extensively and eloquently about the human mind's mysterious and marvelous workings and has discussed how the human mind can see events in different frames. I'll bet that we be seeing the results of this trial (so far we have only a snippet of the results) spun this way and that. But deaths are not a surrogate measure and the major observation of more deaths with intensive treatment may well shift the momentum of diabetic treatment from "lower is better" to "well maybe not too low" and maybe " not necessarily the same target for everyone". A number of doctor bribe programs (A.K.A. pay for performance ) are keyed to hemoglobin A1C levels .Will we see those third party payers whose interests are claimed to be in improving quality of care quickly revise their guidelines?
Physicians want better treatments for their patients and they want results of promising treatments to be true. That desire to do good for their patients coupled with big pharma funded hype often aided by a shinny veneer pasted on by academic and other thought leaders can really energize therapeutic exuberance that may have a much less robust evidentiary base that we were lead to believe.Treating to a goal or treating the numbers can make clinical life seem simpler, sometimes too simple.
First, we find out that maybe we were giving to much EPO, and then maybe lower LDL per se is not better and now more insulin may be too much of a good thing (haven't we known that for a long time?). It is a good thing we quasi- codified all or some of those things into guidelines and pay-for-compliance programs otherwise we might not have had a chance to use them before we decided there weren't really a great idea after all. I remember as house officers we used to talk about the patient dying but the electrolytes were in balance.
Tuesday, February 05, 2008
Three years of blogging-a look back and a happy blog birthday to me
Some of things I have learned about and written about in my blog over the past three years I would have never imagined three years ago let alone forty years ago when I was handed a MD diploma. Here are some of them.
1.Alternative medicine, AKA integrative medicine, AKA woo . This is many ways may be the most mind boggling. Whatever you want to call it, Dr RW called is quackademics, "it" has moved into the medical school curriculum, research activities and the accepting mind sets of many medical students. We see large numbers of government funded research grants and for many of the projects all you can say is "you've got to be kidding me".
2.The role of the AMA in damaging primary care through its development and continuing support of an advisory group that virtually sets fees from CMS and does so in such a way as to denigrate primary care and elevate procedure based medical specialists.Three years ago I had not even heard about the RUC ( Relative value scale update committee) and paid too little attention to the RBRVS (Resource Based Relative Value Scale ). With friends like the AMA...
3. Three years ago I had not heard of DrRich's thoughts regarding "covert rationing". Now that I have I cannot think of medical practice in the same way. His thoughts can be found at his web site and more completely in his book docs and I believe medical students and physicians alike should read what he is saying before they do anything else. On the insight scale this would be a ten.
4.The downward spiral of primary care. No. 2 above plays a role here but a major culprit is the price controls that are part of the Medicare system which I ranted about here.
5.Pay for performance (P4P) as absurd and wrong on so many levels as seems to be to me it continues to thrive and I believe make matters even worse in primary care. Physicians accepting bribes to do their job is just another example of the continuing loss of pride and ethical demise.
How to apply group data to individual patients, the potential pitfalls and traps and tricks of evidence based medicine (EBM) and how some can pervert the sound principles of EMB to their own ends are some of the thoughts that have recurred in my mind and in my blog. Thanks to those who have commented on my comments, some of which were laudatory and a few of which were not and the occasional one who missed the point or whose mind set is imbued with a different vision. I know I have learned more from other blogs than they have from mine but it has been and I hope will continue to be a blast.
1.Alternative medicine, AKA integrative medicine, AKA woo . This is many ways may be the most mind boggling. Whatever you want to call it, Dr RW called is quackademics, "it" has moved into the medical school curriculum, research activities and the accepting mind sets of many medical students. We see large numbers of government funded research grants and for many of the projects all you can say is "you've got to be kidding me".
2.The role of the AMA in damaging primary care through its development and continuing support of an advisory group that virtually sets fees from CMS and does so in such a way as to denigrate primary care and elevate procedure based medical specialists.Three years ago I had not even heard about the RUC ( Relative value scale update committee) and paid too little attention to the RBRVS (Resource Based Relative Value Scale ). With friends like the AMA...
3. Three years ago I had not heard of DrRich's thoughts regarding "covert rationing". Now that I have I cannot think of medical practice in the same way. His thoughts can be found at his web site and more completely in his book docs and I believe medical students and physicians alike should read what he is saying before they do anything else. On the insight scale this would be a ten.
4.The downward spiral of primary care. No. 2 above plays a role here but a major culprit is the price controls that are part of the Medicare system which I ranted about here.
5.Pay for performance (P4P) as absurd and wrong on so many levels as seems to be to me it continues to thrive and I believe make matters even worse in primary care. Physicians accepting bribes to do their job is just another example of the continuing loss of pride and ethical demise.
How to apply group data to individual patients, the potential pitfalls and traps and tricks of evidence based medicine (EBM) and how some can pervert the sound principles of EMB to their own ends are some of the thoughts that have recurred in my mind and in my blog. Thanks to those who have commented on my comments, some of which were laudatory and a few of which were not and the occasional one who missed the point or whose mind set is imbued with a different vision. I know I have learned more from other blogs than they have from mine but it has been and I hope will continue to be a blast.
Friday, February 01, 2008
we all love a good story but it is not the way of science
Here is a great posting by Steve Novella entitled "Role of Anecdotes in Science-Based Medicine".
Understanding the world through stories was a good strategy in the environment of our evolutionary history but is far too flawed to deal with the complex world we live in today. In fact, the discipline of science developed as a tool to go beyond the efficient but flawed techniques we evolved .
Generalization and quick and dirty induction may well have been part of the survival package that our ancestors used to good advantage as they tried to avoid predators and gather together to hunt and gather but in dealing with the complex and nuanced world we now try to describe and unravel we need other tools and to be aware of the pitfalls and traps to which some of our mental apparatus makes us prone.
Novella gives a good briefing on why is it that anecdotes do not form the basis for sound conclusions . He give us the top 9 (or 8 depending on how you count) reasons for one to be skeptical about anecdotes including:
The phenomenon of regression to the mean, confirmation bias, and reporting bias-to name a few.
If medical students ( or docs for that matter) understood what Dr. Novella is saying we would not have med students writing nonsense about- for example-reike referenced on Jan. 30,2008 here by Dr. RW.
Dr. Robert Centor has recently been writing about the medical school and pre-med curriculum and what it should include. I was pleased to see this sentence in his latest effort along those lines.
I would add a cognition course throughout the first year. This course would teach logic, evidence based medicine and principles of cognition (as Jerome Groopman champions.) The course would stress thinking.
I agree completely.If medical students were made aware of the mental foibles that lead some presumably educated people to believe in such utter non-sense as reiki maybe we would not continue to see the acceptance and sad defenses of that and other versions of quackery in medical student organization's publications . As things stand now,I'm afraid that more medical students than medical educators would like to admit would not appreciate the on-target satire of altie medicine and post modernism found here
Understanding the world through stories was a good strategy in the environment of our evolutionary history but is far too flawed to deal with the complex world we live in today. In fact, the discipline of science developed as a tool to go beyond the efficient but flawed techniques we evolved .
Generalization and quick and dirty induction may well have been part of the survival package that our ancestors used to good advantage as they tried to avoid predators and gather together to hunt and gather but in dealing with the complex and nuanced world we now try to describe and unravel we need other tools and to be aware of the pitfalls and traps to which some of our mental apparatus makes us prone.
Novella gives a good briefing on why is it that anecdotes do not form the basis for sound conclusions . He give us the top 9 (or 8 depending on how you count) reasons for one to be skeptical about anecdotes including:
The phenomenon of regression to the mean, confirmation bias, and reporting bias-to name a few.
If medical students ( or docs for that matter) understood what Dr. Novella is saying we would not have med students writing nonsense about- for example-reike referenced on Jan. 30,2008 here by Dr. RW.
Dr. Robert Centor has recently been writing about the medical school and pre-med curriculum and what it should include. I was pleased to see this sentence in his latest effort along those lines.
I would add a cognition course throughout the first year. This course would teach logic, evidence based medicine and principles of cognition (as Jerome Groopman champions.) The course would stress thinking.
I agree completely.If medical students were made aware of the mental foibles that lead some presumably educated people to believe in such utter non-sense as reiki maybe we would not continue to see the acceptance and sad defenses of that and other versions of quackery in medical student organization's publications . As things stand now,I'm afraid that more medical students than medical educators would like to admit would not appreciate the on-target satire of altie medicine and post modernism found here
Tuesday, January 29, 2008
Word of the month(well the year so far) is Quackademics
Hats off to Dr. RW for his coining of the term quackademics. His relentless battles against the forces of altie medicine and quackery sliding into the halls and curriculum of medical school and in the mind sets of at least some members of the SAMA is appreciated. ORAC has been doggedly pursuing this issue for some time and keeps us up to date with his Academic Woo Aggregator which list the academic centers who have their fingers in the altie pie and there are more than one web sites devoted to the exposing of medical quackeries and woo. Alumni of a number of very well known and respected medical schools cannot be happy when they see their schools teaching reiki which may not be the most absurd thing ever but it is close.Orac gives some alarming information about where reiki can be found.
The phenomenon of the establishment of so-called alternative medicine into a number of medical schools itself is perplexing. How, why ? Dr RW offers some reasonable explanations for this with money leading the list. I've wondered about the role of political correctness and the influence of post-modernistic thought as has RW and a recent commenter to his blog about the state of affairs in some medical school down under. I hope things aren't as absurd there as the commenter relates.
The medical blog world has been percolating various thoughts about this issue for some time which is a good thing but as Dr RW points out a larger movement is needed if this absurd trend is to be reversed. The choir is convinced . A recent discussion on Medscape might have helped a bit and alerted more physicians to the issue and I think the ire of well healed alumni putting pressure on their alma matters might not hurt although I am not aware of much of that actually happening. However, the combination of money ( from patient services paid for in cash and the infusion of grant money) plus the effect of the rhetoric of political correctness and post modernism BS are formidable forces pushing things very much in the wrong direction. I fear that we are not that close to a tripping point to turn the tide. If any one has any ideas, let me know; we retired folks have time on our hands.
The phenomenon of the establishment of so-called alternative medicine into a number of medical schools itself is perplexing. How, why ? Dr RW offers some reasonable explanations for this with money leading the list. I've wondered about the role of political correctness and the influence of post-modernistic thought as has RW and a recent commenter to his blog about the state of affairs in some medical school down under. I hope things aren't as absurd there as the commenter relates.
The medical blog world has been percolating various thoughts about this issue for some time which is a good thing but as Dr RW points out a larger movement is needed if this absurd trend is to be reversed. The choir is convinced . A recent discussion on Medscape might have helped a bit and alerted more physicians to the issue and I think the ire of well healed alumni putting pressure on their alma matters might not hurt although I am not aware of much of that actually happening. However, the combination of money ( from patient services paid for in cash and the infusion of grant money) plus the effect of the rhetoric of political correctness and post modernism BS are formidable forces pushing things very much in the wrong direction. I fear that we are not that close to a tripping point to turn the tide. If any one has any ideas, let me know; we retired folks have time on our hands.
The ABIM's certification in Comprehensive Internal Medicine -too silly even for the ACP?
The American College of Physicians (ACP) apparently has problems with the latest proposal from the American Board of Internal Medicine (ABIM) which involves the concept of the Comprehensive Care Internist (CCIM). I have written about this before when details were few but now the plan has been revealed-although some particulars remain to be worked out.
Here is the executive summary of the proposal and from that the interested reader can access all the details. When I read the details I concluded that ABIM is proposing certification for a type practice that really doesn't exist which will involve assessment of various skills and roles for which they have no assessment tools. ACP addresses that fact in more polite understatement;
"The lack of valid and reliable assessment tools for CCIM competencies is a substantial limitation."
Yes, not having the tools to assess the competencies on which the certification is based would be a limitation -actually it would be impossible.
Internists who earn this new certificate would be referred to a "Comprehensive Care Internists". The standard dictionary definition of the word comprehensive is including all or everything.
Since the comprehensive care internist would be basically an physician doing office work and not taking care of sick patients in the hospital ( an activity once associated with internists) the designation "comprehensive" seems off base. I suggest the term Non-comprehensive Care Internist would be more appropriate. Although the "comprehensive" internist would not take care of sick patients in the hospital she would be certified as a "change agent" and a "team leader" -that is once they figure out how to assess those skills. I feel confident that if my very elderly but still very savvy and sharp aunt were asked what she wants in her physician what she would not say is that she wanted someone who was a change agent and a team leader.
In summary, then we have a proposal for a board certification for a comprehensive internist whose practice is really not comprehensive that envisions a type of practice that really does quite exist yet and for which the set of tools to carry out the assessment do not exist. Sounds like a plan.
Here is the executive summary of the proposal and from that the interested reader can access all the details. When I read the details I concluded that ABIM is proposing certification for a type practice that really doesn't exist which will involve assessment of various skills and roles for which they have no assessment tools. ACP addresses that fact in more polite understatement;
"The lack of valid and reliable assessment tools for CCIM competencies is a substantial limitation."
Yes, not having the tools to assess the competencies on which the certification is based would be a limitation -actually it would be impossible.
Internists who earn this new certificate would be referred to a "Comprehensive Care Internists". The standard dictionary definition of the word comprehensive is including all or everything.
Since the comprehensive care internist would be basically an physician doing office work and not taking care of sick patients in the hospital ( an activity once associated with internists) the designation "comprehensive" seems off base. I suggest the term Non-comprehensive Care Internist would be more appropriate. Although the "comprehensive" internist would not take care of sick patients in the hospital she would be certified as a "change agent" and a "team leader" -that is once they figure out how to assess those skills. I feel confident that if my very elderly but still very savvy and sharp aunt were asked what she wants in her physician what she would not say is that she wanted someone who was a change agent and a team leader.
In summary, then we have a proposal for a board certification for a comprehensive internist whose practice is really not comprehensive that envisions a type of practice that really does quite exist yet and for which the set of tools to carry out the assessment do not exist. Sounds like a plan.
Just when you thought we were through with Ketex
I have ranted about various aspects of the Ketex saga before-fatal liver side effects and bogus clinical trial data and a major thought leader enabled , pseudo-CME, hyped up, thinly disguised advertisement campaign for a medication which, in my humble opinion, served no rational purpose in a doc's antibiotic quiver.
Now a House Panel is busy looking into some of the "data integrity " problems that would appear to be mainly yesterday's news but now apparently the FDA is being accused of not supplying material for an House subcommittee investigation investigation. See here for some thoughts on how bad the integrity problem was and here for a WSJ blog article on the House activities in that regard.
Now a House Panel is busy looking into some of the "data integrity " problems that would appear to be mainly yesterday's news but now apparently the FDA is being accused of not supplying material for an House subcommittee investigation investigation. See here for some thoughts on how bad the integrity problem was and here for a WSJ blog article on the House activities in that regard.
Wednesday, January 23, 2008
How the world works-should be part of med school curriculum
I am quoting this paragraph from Health Care Renewal because it is such an excellent sketch of the outrageous situation that now exists with a certain type of medication marketing that holds itself out as CME. Read about how the players in this scenario are interrelated and how everyone benefits, well almost everyone, the docs who at best gets a little wink-wink-nudge-nudge- "CME credit" are mislead and we can guess what the results might be for the patients of the docs who are mislead.
... The standard formula calls for corporate sponsorship channeled through an “unrestricted educational grant” to a medical education communications company (MECC). The MECC employs writers to prepare the “educational content,” and academic KOLs are recruited to deliver this content. The KOLs are chosen for their willingness to be “on message” for the corporate sponsor. If they go “off message” they know they will not be invited back. The talk of “unrestricted grants” is window dressing. The MECC also secures the imprimatur of a nationally accredited CME sponsor, typically an academic institution. The sponsor is paid to certify that the CME program meets the standards of the Accreditation Council on Continuing Medical Education (ACCME). Everybody turns a buck: the MECC and its staff are handsomely paid (CME is now a multi-billion dollar business); the KOLs are generously rewarded with honoraria and perquisites; the academic sponsor is well paid by the MECC; the ACCME receives dues from the academic sponsor; the audience obtains free CME credits rather than having to pay for these required educational experiences; and the corporate sponsor gets what it considers value for its marketing dollar.
I have been invited to a number of these events and with the lure of a good meal and nothing else to do I have attended more than one. There was a time when I was not aware of what the above description depicts but now I know how to follow the money.
I have written before about how the tools and verbiage of evidence based medicine can be misused (Note I am not degrading the value of honest proper application of EBM principles or the principles themselves) and the above scenario has to be about as bad as that gets .
Bernard Carroll's paragraph quoted from HCR should be part of the basic curriculum of every medical school, every nursing school, every PA school , and every residency program.
With this concise but detailed description of the anatomy of what passes for CME in mind, one would expect growing support for the Macy Foundation report which calls for the abolition of commercial interest sponsored CME but also we can expect resistance from the well funded interested parties and some of the recipients of those funds.
We find a interesting turn described in this blog posting by Dr. Carlat who knows a little about some of the aspects of commercial interested sponsored CME. He describes a meeting he attended at Harvard and the comments made there by Dr. Martin Samuels. Anyone who has heard a lecture by Dr. Samuels will be very favorably impressed and since I have heard several( and remember much of what he said) I have to take what he says seriously.
Martin Samuels describes the Macy Report as a "house of cards" made less credible by the self interest of some of the participants. He asserts that Denise Basow who was one of the organizing committee members of the Macy Report is a principal in the online medical education endeavor known at UpToDate and that the report's recommendations fit nicely with the commercial interests of UpToDate. Let me make it clear- I am not critical of the educational value or usefulness of the UpToDate product.Everything I have heard about it indicates it is a good product.
Samuels also defends one particular MECC with which he is involved, Pri-Med. I have heard his talks on dizziness and the heart and brain interrelationships at Pri-Med meetings and in those there was no promoting of any particular product and as with all of his talks they were brilliant. Maybe Pri-Med is different from the usual MECC but I have attended 3 Primed conferences ( I plan no others) and in my opinion, some of the other talks were very little disguised drug advertisements while others appeared as valid education sessions with drug promotion either absent or so subtle I missed it. I like to think I can tell one type from the other but... It should be noted Samuels did not defend MECCs in general and also called for the abolition of the quite popular satellite educational sessions that latch onto national medical meetings.
As usual things get hard to sort out but to my thinking it is clear that much of the industry sponsored medical education is nothing more than product promotion given a veneer of respectability by their affiliation with medical school KOLs and the schools themselves and the CME certification organization known as ACCME,whose credibility also is at risk.
... The standard formula calls for corporate sponsorship channeled through an “unrestricted educational grant” to a medical education communications company (MECC). The MECC employs writers to prepare the “educational content,” and academic KOLs are recruited to deliver this content. The KOLs are chosen for their willingness to be “on message” for the corporate sponsor. If they go “off message” they know they will not be invited back. The talk of “unrestricted grants” is window dressing. The MECC also secures the imprimatur of a nationally accredited CME sponsor, typically an academic institution. The sponsor is paid to certify that the CME program meets the standards of the Accreditation Council on Continuing Medical Education (ACCME). Everybody turns a buck: the MECC and its staff are handsomely paid (CME is now a multi-billion dollar business); the KOLs are generously rewarded with honoraria and perquisites; the academic sponsor is well paid by the MECC; the ACCME receives dues from the academic sponsor; the audience obtains free CME credits rather than having to pay for these required educational experiences; and the corporate sponsor gets what it considers value for its marketing dollar.
I have been invited to a number of these events and with the lure of a good meal and nothing else to do I have attended more than one. There was a time when I was not aware of what the above description depicts but now I know how to follow the money.
I have written before about how the tools and verbiage of evidence based medicine can be misused (Note I am not degrading the value of honest proper application of EBM principles or the principles themselves) and the above scenario has to be about as bad as that gets .
Bernard Carroll's paragraph quoted from HCR should be part of the basic curriculum of every medical school, every nursing school, every PA school , and every residency program.
With this concise but detailed description of the anatomy of what passes for CME in mind, one would expect growing support for the Macy Foundation report which calls for the abolition of commercial interest sponsored CME but also we can expect resistance from the well funded interested parties and some of the recipients of those funds.
We find a interesting turn described in this blog posting by Dr. Carlat who knows a little about some of the aspects of commercial interested sponsored CME. He describes a meeting he attended at Harvard and the comments made there by Dr. Martin Samuels. Anyone who has heard a lecture by Dr. Samuels will be very favorably impressed and since I have heard several( and remember much of what he said) I have to take what he says seriously.
Martin Samuels describes the Macy Report as a "house of cards" made less credible by the self interest of some of the participants. He asserts that Denise Basow who was one of the organizing committee members of the Macy Report is a principal in the online medical education endeavor known at UpToDate and that the report's recommendations fit nicely with the commercial interests of UpToDate. Let me make it clear- I am not critical of the educational value or usefulness of the UpToDate product.Everything I have heard about it indicates it is a good product.
Samuels also defends one particular MECC with which he is involved, Pri-Med. I have heard his talks on dizziness and the heart and brain interrelationships at Pri-Med meetings and in those there was no promoting of any particular product and as with all of his talks they were brilliant. Maybe Pri-Med is different from the usual MECC but I have attended 3 Primed conferences ( I plan no others) and in my opinion, some of the other talks were very little disguised drug advertisements while others appeared as valid education sessions with drug promotion either absent or so subtle I missed it. I like to think I can tell one type from the other but... It should be noted Samuels did not defend MECCs in general and also called for the abolition of the quite popular satellite educational sessions that latch onto national medical meetings.
As usual things get hard to sort out but to my thinking it is clear that much of the industry sponsored medical education is nothing more than product promotion given a veneer of respectability by their affiliation with medical school KOLs and the schools themselves and the CME certification organization known as ACCME,whose credibility also is at risk.
Tuesday, January 22, 2008
Now allegations of conflict of interest in advocates of CT scanning for lung cancer
Probably every lung doc in his career has seen a patient who has been apparently cured ( at least has gone over five years without evidence of disease) after a lung cancer was incidentally detected and then resected . The typical scenario was that an incidental chest xray demonstrated a solitary pulmonary nodule (SNP). ( A single nodule less than 3 cm in diameter) With the prognosis of lung cancer detected at a symptomatic stage so dismal it is understandable that we would yearn for some method of early detection.There is no general agreement that such a method has been found and some wonder if it is even possible.
The clinical trials that examined results of screening with annual chest x-rays have not clearly shown benefit and arguably suggested harm. This has resulted in most groups not recommending periodic chest film screening even in smokers.
Lung CTs are the latest candidate for a early detector of lung cancer and that technique has not been warmly received even though pulmonary physicians certainly would welcome something to make the prognosis of detected lung cancer much better as progress in that area is not one of the cancer cure success stories of modern medicine.
A number of articles have been published in which the authors concluded that CTs are very helpful and have recommended their application. Now in the WSJ health blog we are given some details of what seems like fairly big red flag involving conflicts of interests and failure to disclose those potential conflicts in some of these researchers who have written and spoken widely advocating CT screening.
One of the major "pro-screening" articles was published in the NEJM and I have commented about that before as well as delving into the issue of "how do we decide if screening really works ?" I think much of that answer depends on if you think survival rates ( e.g five year survival rates) or cause specific mortality for a specific cancer (I am note sure if we can ask that about cancers in general as I believe it depends on the natural history of the cancer) should be the statistical arbiter. Most people who write about this favor cause specific mortality and that is the conventional wisdom but there is at least one articulate advocate of the other view mentioned in my above self reference. Which view I take seems to depend on whose article I have read most recently.
The contrarian in this regard is Dr. Gay M. Strauss from Dana-Farber Cancer Institute.He presents his case in Chest 1997:112 216 s-228s ) "Measuring Effectiveness in Lung cancer Screening." I think a subscription is required. Anyone interested in this issue will find his argument either interesting but flawed or convincing and spot on or will be unable to decide which assessment is correct.
His argument suggesting that RCTs may not be the final answer regarding the efficacy of screening for various cancers does not convince me because I really don't understand it. Whose fault is that? He asserts that small absolute differences in disease risk between screened and control group often persist after randomization and translate in large proportional difference in the size of sub groups at risk for disease specific mortality and may give misleading results when a randomized clinical trial (RCT) is applied in the preventive medicine arena. He is not arguing against the value of RCTs in other contexts.
One of his other arguments resonates with me to a much greater degree. One anti-screening argument is that survival rates look favorable for screening while mortality rates do not is explained by the detection of large numbers of indolent lung cancers which really did not need to be treated. This argument is commonly made in regard to prostate cancer. Strauss argues that this is not valid as regards lung cancer. Now if this "lead time bias" is at work here, he continues,therapy would irrelevant to outcome. So let us look at the outcome of those stage 1,non-small cell cancer patients who were screened but did not undergo surgical resection .What is their outlook. Five year survival was 5%- rather low survival for supposed indolent cancers. This is far less than the what we see with resected lung cancers that present clinically as SNPs.
Prostate cancer is not rare in autopsy series-some have shown over 50% prevalence of latent prostate cancer so the concept of indolent or very slow growing prostate cancer is very reasonable while "surprise" lung cancer at autopsy , according to Strauss, has a prevalence of 0.8%. Again if we are detecting this not clinically important entity by CTs , why do we not see large numbers of lung cancers at autopsy? ( It should be noted that at least one autopsy series showed a much higher number of previously undetected lung cancers.)
So who is right? I don't have the answer but I believe that there is more to it than simply closing the debate by shouting firmly " Lead time bias ".
Now entering the discourse is the accusation of possible conflict of interest in some of those who are recommending lung CT screening.In a world where decisions were made with the pure logic of a Mr. Spock the possibility that someone taking a particular position possibly gaining from acceptance of that position should not be determinative in the debate about the truth of that argument, but in the non Spock world thorough we pass people who have no Vulcan genes definitely take into account the "credibility of the witnesses". ( In some settings Spock would consider that also).
As pointed out by Dr. Howard Brody, conflict of interest is not localized to Big Pharma and
"Nothing like knocking public trust in academic medicine and medical research down a few more notches."
The clinical trials that examined results of screening with annual chest x-rays have not clearly shown benefit and arguably suggested harm. This has resulted in most groups not recommending periodic chest film screening even in smokers.
Lung CTs are the latest candidate for a early detector of lung cancer and that technique has not been warmly received even though pulmonary physicians certainly would welcome something to make the prognosis of detected lung cancer much better as progress in that area is not one of the cancer cure success stories of modern medicine.
A number of articles have been published in which the authors concluded that CTs are very helpful and have recommended their application. Now in the WSJ health blog we are given some details of what seems like fairly big red flag involving conflicts of interests and failure to disclose those potential conflicts in some of these researchers who have written and spoken widely advocating CT screening.
One of the major "pro-screening" articles was published in the NEJM and I have commented about that before as well as delving into the issue of "how do we decide if screening really works ?" I think much of that answer depends on if you think survival rates ( e.g five year survival rates) or cause specific mortality for a specific cancer (I am note sure if we can ask that about cancers in general as I believe it depends on the natural history of the cancer) should be the statistical arbiter. Most people who write about this favor cause specific mortality and that is the conventional wisdom but there is at least one articulate advocate of the other view mentioned in my above self reference. Which view I take seems to depend on whose article I have read most recently.
The contrarian in this regard is Dr. Gay M. Strauss from Dana-Farber Cancer Institute.He presents his case in Chest 1997:112 216 s-228s ) "Measuring Effectiveness in Lung cancer Screening." I think a subscription is required. Anyone interested in this issue will find his argument either interesting but flawed or convincing and spot on or will be unable to decide which assessment is correct.
His argument suggesting that RCTs may not be the final answer regarding the efficacy of screening for various cancers does not convince me because I really don't understand it. Whose fault is that? He asserts that small absolute differences in disease risk between screened and control group often persist after randomization and translate in large proportional difference in the size of sub groups at risk for disease specific mortality and may give misleading results when a randomized clinical trial (RCT) is applied in the preventive medicine arena. He is not arguing against the value of RCTs in other contexts.
One of his other arguments resonates with me to a much greater degree. One anti-screening argument is that survival rates look favorable for screening while mortality rates do not is explained by the detection of large numbers of indolent lung cancers which really did not need to be treated. This argument is commonly made in regard to prostate cancer. Strauss argues that this is not valid as regards lung cancer. Now if this "lead time bias" is at work here, he continues,therapy would irrelevant to outcome. So let us look at the outcome of those stage 1,non-small cell cancer patients who were screened but did not undergo surgical resection .What is their outlook. Five year survival was 5%- rather low survival for supposed indolent cancers. This is far less than the what we see with resected lung cancers that present clinically as SNPs.
Prostate cancer is not rare in autopsy series-some have shown over 50% prevalence of latent prostate cancer so the concept of indolent or very slow growing prostate cancer is very reasonable while "surprise" lung cancer at autopsy , according to Strauss, has a prevalence of 0.8%. Again if we are detecting this not clinically important entity by CTs , why do we not see large numbers of lung cancers at autopsy? ( It should be noted that at least one autopsy series showed a much higher number of previously undetected lung cancers.)
So who is right? I don't have the answer but I believe that there is more to it than simply closing the debate by shouting firmly " Lead time bias ".
Now entering the discourse is the accusation of possible conflict of interest in some of those who are recommending lung CT screening.In a world where decisions were made with the pure logic of a Mr. Spock the possibility that someone taking a particular position possibly gaining from acceptance of that position should not be determinative in the debate about the truth of that argument, but in the non Spock world thorough we pass people who have no Vulcan genes definitely take into account the "credibility of the witnesses". ( In some settings Spock would consider that also).
As pointed out by Dr. Howard Brody, conflict of interest is not localized to Big Pharma and
"Nothing like knocking public trust in academic medicine and medical research down a few more notches."
Friday, January 18, 2008
Is it too soon to say we were off base on the heart attack cholesterol deal?
Several thoughtful bloggers, on the heels of the Enhance trial, have raised the question and given their views of the issue of "should the cholesterol -coronary artery disease hypothesis be re-visited and perhaps revised." Dr. DB correctly, in my view, suggests that we may have been too literal and dogmatic about the LDL "targets" and Dr. Howard Brody is a bit more sweeping in his foray into revisionism but both make good points.
It is certainty possible that the well proven reduction in CAD incidence may be due at least in part to an effect or effects of the statins apart from their ability to lower the LDL cholesterol. The Enhance trial failed to show that a more marked LDL cholesterol lowering brought about a greater reduction in blood vessel wall thickness and in a study not powered to show it did not show any changes in the attack rate of CAD in its various clinical presentations. So, I would characterize this as a failure to demonstrate that greater lowering of LDL was associated with a beneficial change in a CAD surrogate and really nothing more.
If memory serves lowering the LDL with niacin and by certain types of bariatric surgery have also been associated with lowering of the incidence of coronary artery diseases indicating that the correlation of lowering LDL and decreased heart attacks is not unique to the statins.
Could the maxim that the decrease in CD is proportional to decrement in LDL be a oversimplification? Of course, the magical linearity of CAD and LDL level with the claim that a x change in LDL brings about y change in CAD always did seem a little to pat to really tell the whole story.
But again I have to bring up that Enhance dealt with a surrogate marker whose ultimately relationship to what we probably really care about ( number of heart attacks etc) is not known and we continue to learn how reliance on surrogates can get us in trouble.
Now, both the American College of Cardiology and The American Heart Association have advised us all to just sit there and not do anything which probably makes sense. Even so, the speed with which they presumed to advise us all not only struck me as at least interesting and stimulated Dr. Roy Poses to point out some interesting things about those advisories and the folks responsible for them. In this regard and in numerous others he has done a yeoman's job of educating his readers about the "pervasive web of conflicts" that involve so many physicians many of whom are labeled as thought leaders and various types of medical organizations that many of us have generally relied upon to give good sound, unbiased advice and recommendations.
Steve Lucas, in a comment to DR DB's posting on the Enhance trial, makes a very quotable comment - namely that this is another instance of marketing overtaking science.
And it is not only the medical bloggers that are contemplating what we may really maybe doing with statins for almost everyone, Business Week has a lengthy article on statins as well, raising the question of oversell- replete with NNT numbers.
It is certainty possible that the well proven reduction in CAD incidence may be due at least in part to an effect or effects of the statins apart from their ability to lower the LDL cholesterol. The Enhance trial failed to show that a more marked LDL cholesterol lowering brought about a greater reduction in blood vessel wall thickness and in a study not powered to show it did not show any changes in the attack rate of CAD in its various clinical presentations. So, I would characterize this as a failure to demonstrate that greater lowering of LDL was associated with a beneficial change in a CAD surrogate and really nothing more.
If memory serves lowering the LDL with niacin and by certain types of bariatric surgery have also been associated with lowering of the incidence of coronary artery diseases indicating that the correlation of lowering LDL and decreased heart attacks is not unique to the statins.
Could the maxim that the decrease in CD is proportional to decrement in LDL be a oversimplification? Of course, the magical linearity of CAD and LDL level with the claim that a x change in LDL brings about y change in CAD always did seem a little to pat to really tell the whole story.
But again I have to bring up that Enhance dealt with a surrogate marker whose ultimately relationship to what we probably really care about ( number of heart attacks etc) is not known and we continue to learn how reliance on surrogates can get us in trouble.
Now, both the American College of Cardiology and The American Heart Association have advised us all to just sit there and not do anything which probably makes sense. Even so, the speed with which they presumed to advise us all not only struck me as at least interesting and stimulated Dr. Roy Poses to point out some interesting things about those advisories and the folks responsible for them. In this regard and in numerous others he has done a yeoman's job of educating his readers about the "pervasive web of conflicts" that involve so many physicians many of whom are labeled as thought leaders and various types of medical organizations that many of us have generally relied upon to give good sound, unbiased advice and recommendations.
Steve Lucas, in a comment to DR DB's posting on the Enhance trial, makes a very quotable comment - namely that this is another instance of marketing overtaking science.
And it is not only the medical bloggers that are contemplating what we may really maybe doing with statins for almost everyone, Business Week has a lengthy article on statins as well, raising the question of oversell- replete with NNT numbers.
Thursday, January 17, 2008
"The silent evidence"-unpublished "negative trials"
Here is a recent WSJ article in which we read about drug trials ( in this instance antidepressants) that do not see the published light of day. WSJ is quoting from a NEJM article a summary of which can be found here.
This is another example of how the solid and valid methods of EBM ( evidence based medicine) can be corrupted and misused to serve a particular end-in this case one that can be discerned by application of the old Mafia rule-follow the money. A number of RCTs are done,which can be done absolutely correctly, but only those trials that support superiority over placebo of the a given drug are submitted for publication. Then, in support of the given drug only the published trials are mentioned.
Note: This is not an indictment of proper application of EBM methods and principles and not an indictment against EBM in general but an indictment against lying and cheating. I only mention the obvious because of what I hope to be a misunderstanding of what I have said from time to time. I have been accused of a paranoid,off the deep end attack against the principles of EBM itself. This was never my intent. Back to the main point-
The lead sentence in the NEJM article nails it- if in a bit understated fashion:
Evidence-based medicine is valuable to the extent that the evidence base is complete and unbiased.
Publication bias is nothing new but perhaps with the impact factor of the NEJM more folks will become aware of the issue and carry a bit more skepticism with them as they attempt to evaluate the efficacy of various medications. Obviously, it is difficult ( more understatement) to evaluate evidence that is unpublished.
The term silent evidence comes from a book I am currently enjoying, entitled "Fooled by Randomness" by a former securities trader named Nassim Taleb. which I have mentioned before. More details and commentary regarding the silent evidence regarding antidepressant trials can be found here at the ever alert blog,Clinical Psychology and Psychiatry:A closer look.
This is another example of how the solid and valid methods of EBM ( evidence based medicine) can be corrupted and misused to serve a particular end-in this case one that can be discerned by application of the old Mafia rule-follow the money. A number of RCTs are done,which can be done absolutely correctly, but only those trials that support superiority over placebo of the a given drug are submitted for publication. Then, in support of the given drug only the published trials are mentioned.
Note: This is not an indictment of proper application of EBM methods and principles and not an indictment against EBM in general but an indictment against lying and cheating. I only mention the obvious because of what I hope to be a misunderstanding of what I have said from time to time. I have been accused of a paranoid,off the deep end attack against the principles of EBM itself. This was never my intent. Back to the main point-
The lead sentence in the NEJM article nails it- if in a bit understated fashion:
Evidence-based medicine is valuable to the extent that the evidence base is complete and unbiased.
Publication bias is nothing new but perhaps with the impact factor of the NEJM more folks will become aware of the issue and carry a bit more skepticism with them as they attempt to evaluate the efficacy of various medications. Obviously, it is difficult ( more understatement) to evaluate evidence that is unpublished.
The term silent evidence comes from a book I am currently enjoying, entitled "Fooled by Randomness" by a former securities trader named Nassim Taleb. which I have mentioned before. More details and commentary regarding the silent evidence regarding antidepressant trials can be found here at the ever alert blog,Clinical Psychology and Psychiatry:A closer look.
Wednesday, January 16, 2008
The Enhance trial,ACC quick action to allay "panic" and Wittgenstein's Ruler
In the wonderful age of the recursive, self amplifying, instant news Internet few people have yet to comment on the Enhance trial which failed to show enhanced reduction in vessel wall thickness by the addition of Zetia to simvastatin in patients with heterozygous hypercholestrolemia.
The media shy Steven Nissen tells us what the study "showed". "The study showed it matters how you lower cholesterol -not just how much you lower cholesterol." As indicated below I am not sure what it showed.
In record time, the American College of Cardiology (ACC) has issued reassurance that we should not panic. Since apparently no one was harmed in the trial,it is not clear to me who would panic anyway except the drug company that makes Vytorin. See here for the ACC summary of the trial and here for the ACC 's comments on the trial and the non-panic advisory.
This was a trial that looked at a surrogate maker-what the bottom line is regarding the drugs that lower cholesterol is the reduction of heart attacks or cardiac events. Enhance looked at vessel wall thickness and there was no shrinkage in the Vytorin group over that seen in the simavastatin alone group. Since we have been warned to not take trials that look at surrogate markers too seriously we should not maybe take any of this too seriously. Had a marked advantage accrued to the Vytorin group we would have been appropriately warned by whomever to not go wild and prescribe Vyotrin to everyone we see on the basis of a surrogate marker trial. Similarly with a negative trial we perhaps should restrain ourselves from calling all the patients on Vytorin and urging them to stop the pills.
All of which gets us to Wittgensteine's ruler.
Unless you have confidence in the ruler's reliability, if you use a ruler to measure a table you may also be using the table to measure the ruler."
Note: I cannot find that Wittgenstein actually said that.I am quoting from a delightful book by Nassim N. Taleb, entitled "Fooled by Randomness" onto whose trail I was put by the blog Healthcare Epistemocrat.
The media shy Steven Nissen tells us what the study "showed". "The study showed it matters how you lower cholesterol -not just how much you lower cholesterol." As indicated below I am not sure what it showed.
In record time, the American College of Cardiology (ACC) has issued reassurance that we should not panic. Since apparently no one was harmed in the trial,it is not clear to me who would panic anyway except the drug company that makes Vytorin. See here for the ACC summary of the trial and here for the ACC 's comments on the trial and the non-panic advisory.
This was a trial that looked at a surrogate maker-what the bottom line is regarding the drugs that lower cholesterol is the reduction of heart attacks or cardiac events. Enhance looked at vessel wall thickness and there was no shrinkage in the Vytorin group over that seen in the simavastatin alone group. Since we have been warned to not take trials that look at surrogate markers too seriously we should not maybe take any of this too seriously. Had a marked advantage accrued to the Vytorin group we would have been appropriately warned by whomever to not go wild and prescribe Vyotrin to everyone we see on the basis of a surrogate marker trial. Similarly with a negative trial we perhaps should restrain ourselves from calling all the patients on Vytorin and urging them to stop the pills.
All of which gets us to Wittgensteine's ruler.
Unless you have confidence in the ruler's reliability, if you use a ruler to measure a table you may also be using the table to measure the ruler."
Note: I cannot find that Wittgenstein actually said that.I am quoting from a delightful book by Nassim N. Taleb, entitled "Fooled by Randomness" onto whose trail I was put by the blog Healthcare Epistemocrat.
Monday, January 14, 2008
AMA President delcares war on "disease of social injustice"
The comments published by Dr. Ronald M. Davis, President of AMA, published in the AMA News were not the reason I opted not to continue my membership in AMA but they did reinforce my decision.
In a commentary (Jan 21,2007) he outlined the actions the AMA has taken regarding the "disease of social injustice". Dr. Davis is a specialist in preventive medicine. A review of the bio published by the AMA indicates he has spent his entire medical career in preventive medicine and I could find no reference to any clinical practice. ( I do not rule out there was some,but if, so it was not mentioned in the biography).
The preventive medicine vision is one in which it seems reasonable to support and believe in the concept of social justice where in one is concerned about equality of outcome as opposed to the quality of opportunity.There are endless opportunities to monitor for various inequalities and offer mitigating proposals. Job security written in capital letters. One expects to hear comments such as those by Dr. Davis in the publications of various public health organizations, in some of which Dr. Davis has been active. From the preventive medicine world we are used to hearing various issues characterized as disease. These strained metaphors of "disease-ifying" have including the diseases of spousal abuse, child abuse and illiteracy to name a few.
I believe the membership of the AMA to mainly consist of practicing clinical doctors rather than preventive medicine specialists.I am unsure what the role of a preventive medicine specialist is in leading such an organization or how appropriate is such a background to lead a group largely composed of physicians who actually practice medicine.
Dr. Davis outlines some of the AMA's accomplishments in this battle against social injustice including arranging seminars on the topic and urging the restriction of sodium in food products.
One of the most striking inequalities that practicing internists and family physicians might notice is that authored, encouraged and abetted by the AMA's RBRVS Committee (RVC) namely the delta between the CMS's compensation for the procedurists and the non-procedurists. An excellent review of that issue can be found here. I believe this to be a major factor in the worsening crisis in primary care.
Dr. Davis might do well to realize that as more and more docs opt out of primary care it will not be the more affluent population who suffers the most-although they ultimately will suffer too- and that the AMA has played a major role in that demise of primary care, seminars about inequality and campaigns to decrease dietary salt intake notwithstanding. I have made my views of the social justice issue clear before.Now I am suggesting that if Dr. Davis is concerned with improving health care for all -not just certain pre-defined demographic categories-he should focus some effort on correcting a major part of the problem caused by the AMA. If the ship sinks there should be little satisfaction in noticing the ultimate equality evident in that everyone is deprived a a life preserver.
In a commentary (Jan 21,2007) he outlined the actions the AMA has taken regarding the "disease of social injustice". Dr. Davis is a specialist in preventive medicine. A review of the bio published by the AMA indicates he has spent his entire medical career in preventive medicine and I could find no reference to any clinical practice. ( I do not rule out there was some,but if, so it was not mentioned in the biography).
The preventive medicine vision is one in which it seems reasonable to support and believe in the concept of social justice where in one is concerned about equality of outcome as opposed to the quality of opportunity.There are endless opportunities to monitor for various inequalities and offer mitigating proposals. Job security written in capital letters. One expects to hear comments such as those by Dr. Davis in the publications of various public health organizations, in some of which Dr. Davis has been active. From the preventive medicine world we are used to hearing various issues characterized as disease. These strained metaphors of "disease-ifying" have including the diseases of spousal abuse, child abuse and illiteracy to name a few.
I believe the membership of the AMA to mainly consist of practicing clinical doctors rather than preventive medicine specialists.I am unsure what the role of a preventive medicine specialist is in leading such an organization or how appropriate is such a background to lead a group largely composed of physicians who actually practice medicine.
Dr. Davis outlines some of the AMA's accomplishments in this battle against social injustice including arranging seminars on the topic and urging the restriction of sodium in food products.
One of the most striking inequalities that practicing internists and family physicians might notice is that authored, encouraged and abetted by the AMA's RBRVS Committee (RVC) namely the delta between the CMS's compensation for the procedurists and the non-procedurists. An excellent review of that issue can be found here. I believe this to be a major factor in the worsening crisis in primary care.
Dr. Davis might do well to realize that as more and more docs opt out of primary care it will not be the more affluent population who suffers the most-although they ultimately will suffer too- and that the AMA has played a major role in that demise of primary care, seminars about inequality and campaigns to decrease dietary salt intake notwithstanding. I have made my views of the social justice issue clear before.Now I am suggesting that if Dr. Davis is concerned with improving health care for all -not just certain pre-defined demographic categories-he should focus some effort on correcting a major part of the problem caused by the AMA. If the ship sinks there should be little satisfaction in noticing the ultimate equality evident in that everyone is deprived a a life preserver.
Tight blood sugar control in the critically ill-maybe not too tight
What the New England Journal can give it can take back.
In 2001 the Journal published what can be called the first Van den Berghe study in which it was demonstrated that in critically ill surgical patients intensive insulin therapy had a beneficial effect. It was a large trial and the results seemed impressive and from the data the authors presented they recommended that blood glucose be targeted to be less than 110 in critically ill patient in the surgical intensive care unit. We love to extrapolate- maybe it would be just as good for medical ICU patients. So another trial was launched.
The second Van den Berghe paper appeared in 2006 and investigated blood glucose control in medical ICU patients with different and somewhat puzzling results. Different in that the over all morality benefit to the tight control group did not occur and puzzling in that a subset ( those with ICU stays greater than 3 days) showed benefit while the complementary subgroup ( those
with stays less than 3 days) showed detriment. This lead some observers to recommend a middle ground namely treat to a a blood glucose of less than 150 for first few days and then go for more intense control ( 110) after that.
Maybe this is reasonable but I am always suspicious of subgroup analysis as some strange findings can appear and the more subgroups you look at the greater the likelihood of a false positive result misleading you. ( My favorite subgroup analysis story can be found here in the discussion of how the benefits found in the landmark thrombolysis trial (ISIS-2) trial did not apply to those patients unlucky enough to have been born under the sign of Gemini or Libra). We are not told about the astrological signs of the participants in the Van den Berghe study.
It has been pointed out that the benefits effects of intensive insulin therapy on postoperative survival was mainly seen in post-op surgical patients who were given rather large glucose loads on admission to the surgical ICU and it makes sense they needed more insulin to mitigate the potential harm of overzealous sugar loading.
In still another NEJM article on intensive insulin therapy in the critically ill published in the Jan 10,2007 issue we are told that the use of "intensive insulin therapy place critically ill patients with sepsis at increased risk for serious adverse effects related to hypoglycemia " and that there was no difference in mortality at 28 days. The authors of this article conclude that when one takes into account both of the Van den Berghe articles and their publication that
" intensive insulin therapy has no measurable,consistent benefit in critically ill patients in a medical ICU, regardless of whether the patients have severe sepsis..."
In what could be characterized as a effectiveness study using historical controls ( i.e. not a randomized trial) treating to a blood glucose of less than 140 it was demonstrated that that regimen seemed doable and was associated to a number of measurable benefits. Comparing results then and now is tricky business as many variables change over time and how well they can be controlled for is really never known.
DR RW gives a nice review of the glucose issue here.
The 2004 Surviving sepsis Guidelines suggest a blood glucose target of less than 150
using an infusion of glucose and insulin. The 140 to 150 range seems a reasonable and reasonably safe approach-pushing to the arbitrary 110 may well cause hypoglycemia episodes and do more harm than good.
In 2001 the Journal published what can be called the first Van den Berghe study in which it was demonstrated that in critically ill surgical patients intensive insulin therapy had a beneficial effect. It was a large trial and the results seemed impressive and from the data the authors presented they recommended that blood glucose be targeted to be less than 110 in critically ill patient in the surgical intensive care unit. We love to extrapolate- maybe it would be just as good for medical ICU patients. So another trial was launched.
The second Van den Berghe paper appeared in 2006 and investigated blood glucose control in medical ICU patients with different and somewhat puzzling results. Different in that the over all morality benefit to the tight control group did not occur and puzzling in that a subset ( those with ICU stays greater than 3 days) showed benefit while the complementary subgroup ( those
with stays less than 3 days) showed detriment. This lead some observers to recommend a middle ground namely treat to a a blood glucose of less than 150 for first few days and then go for more intense control ( 110) after that.
Maybe this is reasonable but I am always suspicious of subgroup analysis as some strange findings can appear and the more subgroups you look at the greater the likelihood of a false positive result misleading you. ( My favorite subgroup analysis story can be found here in the discussion of how the benefits found in the landmark thrombolysis trial (ISIS-2) trial did not apply to those patients unlucky enough to have been born under the sign of Gemini or Libra). We are not told about the astrological signs of the participants in the Van den Berghe study.
It has been pointed out that the benefits effects of intensive insulin therapy on postoperative survival was mainly seen in post-op surgical patients who were given rather large glucose loads on admission to the surgical ICU and it makes sense they needed more insulin to mitigate the potential harm of overzealous sugar loading.
In still another NEJM article on intensive insulin therapy in the critically ill published in the Jan 10,2007 issue we are told that the use of "intensive insulin therapy place critically ill patients with sepsis at increased risk for serious adverse effects related to hypoglycemia " and that there was no difference in mortality at 28 days. The authors of this article conclude that when one takes into account both of the Van den Berghe articles and their publication that
" intensive insulin therapy has no measurable,consistent benefit in critically ill patients in a medical ICU, regardless of whether the patients have severe sepsis..."
In what could be characterized as a effectiveness study using historical controls ( i.e. not a randomized trial) treating to a blood glucose of less than 140 it was demonstrated that that regimen seemed doable and was associated to a number of measurable benefits. Comparing results then and now is tricky business as many variables change over time and how well they can be controlled for is really never known.
DR RW gives a nice review of the glucose issue here.
The 2004 Surviving sepsis Guidelines suggest a blood glucose target of less than 150
using an infusion of glucose and insulin. The 140 to 150 range seems a reasonable and reasonably safe approach-pushing to the arbitrary 110 may well cause hypoglycemia episodes and do more harm than good.
Friday, January 11, 2008
Corticosteroids in septic shock-the wheel keeps turning
I remember forty years ago as a house office that we used steroids in patients with septic shock. We also used antibiotics,fluids and vasopressors. There were no large randomized clinical trials (RCT) whose results formed the basis of our treatment plans. The age of evidence based medicine (EBM) had not yet arrived.
Since then we have had RCTs that demonstrated the benefit of high dose steroids followed by larger trials that showed no benefit. Was that the end of steroid use ?No it was not. The stage shifted to the use of low dose or so-called physiological dose steroids.It seemed we were giving too much and perhaps we were not selective enough . Enter the phase of testing for adrenal function in spesis patients.
A trial by Annane et al published in JAMA in 2002 used a corticotrophin stimulation test to divide sepsis patient into those who responded with a cortisol increase to some decided upon cut off and those who did not. The latter group appeared to benefit from corticosteroid treatment.This was not the only trial suggesting the value of low dose steroid and testing for adrenal function,there were several others but the Annane number may have determined the meta-analysis outcome.
RCTS work best in studying treatment effects in a relatively homogeneous,relatively clinically stable conditions where there are not be-deviling co morbidities and a rapidly changing clinical picture in which the timing of various intervention may be determinative. In sepsis small clinical trials and reliance on adding up those trials which may vary in critical ways and calling it a meta-analysis may well lead to recommendations that are faulty because of all the reasons we learn in epidemiology 101 that cause clinical studies to be misleading.
RCTs are often small and fail to capture the perplexing diversity of relevant variables (known and unknown) that lurk in complex, hospitalized patients. It is the sickest patients that simplistic rules formulated by committees harm the most and in whom the pathophysiological diversity is likely to overwhelm premature generalizations and an overly eager rush to mandate treatment rules.
Now the evidence wheel is turning back over to the " no significant difference" marking regarding the use of low dose steroids. This "negative study" appears in the Jan 10,2008 issue of the New England Journal of Medicine. This study, the Corticus study, gives results markedly different from the Annane trial. See here for a discussion of the trial. A brief review of the discussion section informs us that there were major differences in the two trials.These included difference in entry requirements, duration of therapy and a major difference in the survival rate in the placebo group to name a few of those factors discussed in the article. As if that were not enough to muddy the waters the authors tell us about the "lack of adequate power" and say further:
On the basis of the current data,however, the likelihood of seeing any differences in outcomes between the two study group was unlikely.
(Apparently the trial was stopped because they ran out of money and they are telling us they did not round up enough patients to show a difference if one really existed. Is there something wrong here?
So we are told the Corticus trial was quite different from the Annane trial in a number of possibly important procedural matters and it was too underpowered to show a difference.
The authors are not deterred from making a recommendation anyway-at least in sort of a negative way. They say that "hydrocortisone cannot be recommended as a general adjuvant therapy for septic shock nor can corticotrophin testing be recommended." However, they admit hydrocortisone may have role if given early to patients in whom the administration of high dose pressors does not raise the blood pressure. Isn't evidence based medicine great? I think that is what we did forty years.
Another important point was mentioned in the companion editorial by Dr. Simon Finfer. Apparently one of the problems in recruiting patients for the trial was the fact that earlier guidelines had already enshrined the used of steroids in septic shock. Finfer said:
...apparently authoritative guidelines may make the conduct of important confirmatory trials more difficult.
So it looks like small clinical trials may give apparent positive results that then may get incorporated into guidelines whose controlling effect on clinical practice may inhibit or even foreclose on larger trials that might correct the earlier faulty false positive trials.
Since then we have had RCTs that demonstrated the benefit of high dose steroids followed by larger trials that showed no benefit. Was that the end of steroid use ?No it was not. The stage shifted to the use of low dose or so-called physiological dose steroids.It seemed we were giving too much and perhaps we were not selective enough . Enter the phase of testing for adrenal function in spesis patients.
A trial by Annane et al published in JAMA in 2002 used a corticotrophin stimulation test to divide sepsis patient into those who responded with a cortisol increase to some decided upon cut off and those who did not. The latter group appeared to benefit from corticosteroid treatment.This was not the only trial suggesting the value of low dose steroid and testing for adrenal function,there were several others but the Annane number may have determined the meta-analysis outcome.
RCTS work best in studying treatment effects in a relatively homogeneous,relatively clinically stable conditions where there are not be-deviling co morbidities and a rapidly changing clinical picture in which the timing of various intervention may be determinative. In sepsis small clinical trials and reliance on adding up those trials which may vary in critical ways and calling it a meta-analysis may well lead to recommendations that are faulty because of all the reasons we learn in epidemiology 101 that cause clinical studies to be misleading.
RCTs are often small and fail to capture the perplexing diversity of relevant variables (known and unknown) that lurk in complex, hospitalized patients. It is the sickest patients that simplistic rules formulated by committees harm the most and in whom the pathophysiological diversity is likely to overwhelm premature generalizations and an overly eager rush to mandate treatment rules.
Now the evidence wheel is turning back over to the " no significant difference" marking regarding the use of low dose steroids. This "negative study" appears in the Jan 10,2008 issue of the New England Journal of Medicine. This study, the Corticus study, gives results markedly different from the Annane trial. See here for a discussion of the trial. A brief review of the discussion section informs us that there were major differences in the two trials.These included difference in entry requirements, duration of therapy and a major difference in the survival rate in the placebo group to name a few of those factors discussed in the article. As if that were not enough to muddy the waters the authors tell us about the "lack of adequate power" and say further:
On the basis of the current data,however, the likelihood of seeing any differences in outcomes between the two study group was unlikely.
(Apparently the trial was stopped because they ran out of money and they are telling us they did not round up enough patients to show a difference if one really existed. Is there something wrong here?
So we are told the Corticus trial was quite different from the Annane trial in a number of possibly important procedural matters and it was too underpowered to show a difference.
The authors are not deterred from making a recommendation anyway-at least in sort of a negative way. They say that "hydrocortisone cannot be recommended as a general adjuvant therapy for septic shock nor can corticotrophin testing be recommended." However, they admit hydrocortisone may have role if given early to patients in whom the administration of high dose pressors does not raise the blood pressure. Isn't evidence based medicine great? I think that is what we did forty years.
Another important point was mentioned in the companion editorial by Dr. Simon Finfer. Apparently one of the problems in recruiting patients for the trial was the fact that earlier guidelines had already enshrined the used of steroids in septic shock. Finfer said:
...apparently authoritative guidelines may make the conduct of important confirmatory trials more difficult.
So it looks like small clinical trials may give apparent positive results that then may get incorporated into guidelines whose controlling effect on clinical practice may inhibit or even foreclose on larger trials that might correct the earlier faulty false positive trials.
Monday, January 07, 2008
Retainer Medicine,Social Justice and the importance of framing the debate
In the not too distant past, but well before the current generation of medical students and house officers were born, a person might go to a physician with some medical problem and be charged for the medical services and then pay for the service either out of pocket or out of pocket and then file with an insurer to get or all some of that reimbursed. It was a private transaction between two persons in a country in which private transaction between individuals was so normal as to not attract any attention. The ethics or justice of such a transaction was simply not a topic for discourse.
In the not too distant past, the ethics of the medical profession was generally well defined and could be expressed in a few simple sentences and seemed to be firmly imprinted in the physician's mind as part of the transition process from a lay person to a physician.
Respect for autonomy, beneficence, and non-maleficence. It was all about the physician and the patient-do no harm, act in the patient's best interest and respect the patient's views and wishes . It was a two party deal.
The AMA 2001 published version of the ethical principles is a bit more detailed but contained little to be contentious about and does not contain the word "justice". More on that latter.
Later, a fourth major principle was grafted on the the ethical framework-justice. In the beginning there could have been a bit of ambiguity as there are many definitions of justice. But it became quite clear what was mean by justice with the publication of the Medical Professionalism in the New Millennium.A Physician Charter.( Annals of Internal Medicine 5 Feb. 2002, vol 136 pg 243-246.
The justice of which they spoke was social justice. Thomas Sowell makes the distinction between the traditional American society's version of justice and social justice in this way. On the one hand, we have justice as basically applying the same rules and standards to everyone -equality of opportunity or equality under the law. On the other hand, we have the redressing of those inequalities that proponents characterize as the fault of society-equality of outcome. In the latter, whatever characteristics at issue are thought to be unequally "distributed" between various groups (income,medical care,access to swimming pools) should be "redistributed". Whatever may have been distributed by acts of God, accidents of history, an uncaring society , or whatever, to achieve social justice someone or something needs to correct the mal-distribution. When redistribution is needed, force or the threat of it is required.
Making everything right would appear to be quite a task to assign to busy, working in the trenches docs, so one should not be surprised by the results of a survey,that I talk about here, that indicated that concern for social justice does not take up a large amount of a physician's times or enter heavily into his daily clinical decisions and activities.
Not only it is quite a task, proponents of new professionalism tell us in August 2007 JAMA article that after "further reading" of the tenets of the new professionalism that physicians alone cannot do it. So who should do it? We are told it should be a medical societal alliance. My translation is that again we told medicine is far too important to be left to the individual patient and the individual physician and we need more powerful players, probably the government,likely big insurance and well connected medical academic intellectuals, such as those who write such articles to mobilize things and makes the inequities right.
Thomas Sowell writes about a "moralistic approach to public policy" in the concluding section of his book, "Knowledge and Decisions". I characterize the authors of the New Medical Professionalism with their insistence of physician's allegiance to social justice - in a society where there is no dominant secular view of justice at all-as medical moralists.
In Sowell's section entitled "Embattled Freedom" we read ...The desire for freedom and its opposite,power, are as universal as any human attributes....The moralistic approach to public policy is not merely a political advantage for those seeking concentration of power. Moralism in itself implies a concentration of power...The reach of national political power into every nook and cranny has proceed in step with campaigns for greater "social justice".
The recent, at-times heated,discussions (see here for some links) about the ethics of retainer practices illustrate how the concept of social justice as an alleged medical ethical imperative as promulgated by the medical moralists has framed the discussion and attempts to control the dialog.
In the not too distant past, the ethics of the medical profession was generally well defined and could be expressed in a few simple sentences and seemed to be firmly imprinted in the physician's mind as part of the transition process from a lay person to a physician.
Respect for autonomy, beneficence, and non-maleficence. It was all about the physician and the patient-do no harm, act in the patient's best interest and respect the patient's views and wishes . It was a two party deal.
The AMA 2001 published version of the ethical principles is a bit more detailed but contained little to be contentious about and does not contain the word "justice". More on that latter.
Later, a fourth major principle was grafted on the the ethical framework-justice. In the beginning there could have been a bit of ambiguity as there are many definitions of justice. But it became quite clear what was mean by justice with the publication of the Medical Professionalism in the New Millennium.A Physician Charter.( Annals of Internal Medicine 5 Feb. 2002, vol 136 pg 243-246.
The justice of which they spoke was social justice. Thomas Sowell makes the distinction between the traditional American society's version of justice and social justice in this way. On the one hand, we have justice as basically applying the same rules and standards to everyone -equality of opportunity or equality under the law. On the other hand, we have the redressing of those inequalities that proponents characterize as the fault of society-equality of outcome. In the latter, whatever characteristics at issue are thought to be unequally "distributed" between various groups (income,medical care,access to swimming pools) should be "redistributed". Whatever may have been distributed by acts of God, accidents of history, an uncaring society , or whatever, to achieve social justice someone or something needs to correct the mal-distribution. When redistribution is needed, force or the threat of it is required.
Making everything right would appear to be quite a task to assign to busy, working in the trenches docs, so one should not be surprised by the results of a survey,that I talk about here, that indicated that concern for social justice does not take up a large amount of a physician's times or enter heavily into his daily clinical decisions and activities.
Not only it is quite a task, proponents of new professionalism tell us in August 2007 JAMA article that after "further reading" of the tenets of the new professionalism that physicians alone cannot do it. So who should do it? We are told it should be a medical societal alliance. My translation is that again we told medicine is far too important to be left to the individual patient and the individual physician and we need more powerful players, probably the government,likely big insurance and well connected medical academic intellectuals, such as those who write such articles to mobilize things and makes the inequities right.
Thomas Sowell writes about a "moralistic approach to public policy" in the concluding section of his book, "Knowledge and Decisions". I characterize the authors of the New Medical Professionalism with their insistence of physician's allegiance to social justice - in a society where there is no dominant secular view of justice at all-as medical moralists.
In Sowell's section entitled "Embattled Freedom" we read ...The desire for freedom and its opposite,power, are as universal as any human attributes....The moralistic approach to public policy is not merely a political advantage for those seeking concentration of power. Moralism in itself implies a concentration of power...The reach of national political power into every nook and cranny has proceed in step with campaigns for greater "social justice".
The recent, at-times heated,discussions (see here for some links) about the ethics of retainer practices illustrate how the concept of social justice as an alleged medical ethical imperative as promulgated by the medical moralists has framed the discussion and attempts to control the dialog.
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