Wednesday, February 27, 2008

Congress investigates Jarvic TV ad but ignores danger of killer robots

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.

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.

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.

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.

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".

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.

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.

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