I was impressed by and wrote about an article by Dr. Croskerry who has studied how physicians think and how they can think better diagnostically when they understand their basic human tendency to think by using ad hoc rules of thumb, cognitive shortcuts or heuristics. DB's MEDICAL RANTS recently (jan. 22, 2007) referenced a great article by Jerome Groopman entitled "What's the Trouble?" which draws upon Coskerry's insights.
A more detailed treatment of these thoughts can be found here in an 2005 article by Croskerry.
I came across another related article entitled "Diagnosing Diagnostic Mistakes" which also talks about diagnostic "errors" and make the interesting and , I think, valid, point that everything called an error might not be.
Dr. Clement J. McDonald authored an excellent article over ten years ago in the Annals of Internal Medicine entitled Medical Heuristics,The silent Adjudicators of Clinical Practice",
It is available in full text on line and well worth reading.
McDonald talks about common medical heuristics some of which have been codified into aphorisms, For example Occams razor which advises to choose the simplest hypothesis (or a single disease process)to explain a set of observations.Contrasted to this is the less well know Hickam's Dictum which says a patient can have as many diagnoses as he darn well wants. Another is " treat the patient not the numbers. This adage which was quasi-dogma in my house officer days has been diluted by the development of various lines of evidence that we should in fact treat the numbers, at least when we are considering blood sugar in diabetes and blood pressure values and- at least for secondary prevention of coronary artery disease-the cholesterol level.
A more recent article by Dr. Donald Redelmeier also appears in the Annals, "The Cognitive Psychology of Missed Diagnoses"
He speaks of common heuristics: The availability heuristic-we judge the likelihood of a case by how easily examples spring to mind. The anchoring heuristic-we tend to stick with our initial impression ( this runs counter to the well established scientific principle of checking for evidence that would disprove our working hypothesis).This is also called premature closure.
Humans may well have biologically ancient neurological mechanisms that organize incomplete data into a sensible whole ( our visual system seems to do a great job of that) and gives us an reassuring sense of control and an illusion of a more accurate and more complete understanding of a given situation that we sometimes really have. These and other heuristics have survived perhaps because they do work reasonably well much of time but the missed diagnoses are reminders that much of the time is not all of the time and hopefully awareness of their existence and their potential fallibility will enable us to mentally over ride them when appropriate. This could be a simple as reconsidering the diagnosis as more clinical data becomes available.
Tuesday, January 23, 2007
Monday, January 22, 2007
Should we consider HIT (heparin induced thrombocytopenia) in cases of DVT and PE?
The answer to the title question is "yes" if the patient is receiving or has recently received unfractionated heparin(UFH) or low molecular weight heparin(LMWH).
This important point is made in an editorial in the Sept 2006 issue of Chest (subscription required) by the guru of HIT, Dr. Theodore Warkentin from Hamilton Ontario.
He quotes an accompanying article by Levine et al who did a meta-analysis that quantitated the risk of HIT in patients in whom VTE (venous thromboembolism) developed while they were taking heparin or shortly there after. ( "How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thrombocytopenia" Levin, R L et al Chest 130/3 sept 2006 pg 681). The risk was 12.8% in patients who were receiving UFH and less than 1/100 in those receiving LMWH.
Warkentin raises the important point that a DVT can develop slightly before or at the same time as the platelet count falls ( the drop in platelet count is the clue to diagnose HIT) so therapeutic doses of heparin may be given before one realizes that HIT is present. This refers to the situation in which a patient receiving heparin thromboprophylaxis develops symptomatic VTE. One way to avoid the possibility of giving a patient with heparin induced thrombocytopenia more heparin is to use fondaparinux to treat DVT and PE since it does not cross react with the HIT antibodies. One problem with this is that fondaparinux is not approved in the U.S.for treatment of HIT (only argatroban and lepirudin are).
It has become important to inquire about recent hospitalizations or medical procedures in any patient with VTE.Heparin is widely used in hospitalized patients ( keep-open I.V.'s and heparin flushes being common sources). Prior platelet counts can be critically helpful.
The pathophysiology of HIT is fascinating to internists, who always wax poetic, about the mechanism of disease.It is an immunologic attack in which the antigen is a heparin-platelet factor 4 complex which when linked with an IgG antibody activates and aggregates platelets which form microparticles and induces a thrombin storm of coagulation which must be treated by stopping the heparin and giving antithrombin agents. There is plenty of irony to go around-thrombosis being caused by giving an anticoagulant, thrombocytopenia that is associated with deleterious clotting rather than bleeding and potentially catastrophic venous and arterial thrombosis and gangrene if the old standby coumadin is given to a patient while the HIT process thunders along untreated.
Testing for the antigen-antibody complex,however, is not the basis for diagnosis which is clinical and keys on a decrease in platelets by 50% or a platelet count of less than 100,000.
This important point is made in an editorial in the Sept 2006 issue of Chest (subscription required) by the guru of HIT, Dr. Theodore Warkentin from Hamilton Ontario.
He quotes an accompanying article by Levine et al who did a meta-analysis that quantitated the risk of HIT in patients in whom VTE (venous thromboembolism) developed while they were taking heparin or shortly there after. ( "How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thrombocytopenia" Levin, R L et al Chest 130/3 sept 2006 pg 681). The risk was 12.8% in patients who were receiving UFH and less than 1/100 in those receiving LMWH.
Warkentin raises the important point that a DVT can develop slightly before or at the same time as the platelet count falls ( the drop in platelet count is the clue to diagnose HIT) so therapeutic doses of heparin may be given before one realizes that HIT is present. This refers to the situation in which a patient receiving heparin thromboprophylaxis develops symptomatic VTE. One way to avoid the possibility of giving a patient with heparin induced thrombocytopenia more heparin is to use fondaparinux to treat DVT and PE since it does not cross react with the HIT antibodies. One problem with this is that fondaparinux is not approved in the U.S.for treatment of HIT (only argatroban and lepirudin are).
It has become important to inquire about recent hospitalizations or medical procedures in any patient with VTE.Heparin is widely used in hospitalized patients ( keep-open I.V.'s and heparin flushes being common sources). Prior platelet counts can be critically helpful.
The pathophysiology of HIT is fascinating to internists, who always wax poetic, about the mechanism of disease.It is an immunologic attack in which the antigen is a heparin-platelet factor 4 complex which when linked with an IgG antibody activates and aggregates platelets which form microparticles and induces a thrombin storm of coagulation which must be treated by stopping the heparin and giving antithrombin agents. There is plenty of irony to go around-thrombosis being caused by giving an anticoagulant, thrombocytopenia that is associated with deleterious clotting rather than bleeding and potentially catastrophic venous and arterial thrombosis and gangrene if the old standby coumadin is given to a patient while the HIT process thunders along untreated.
Testing for the antigen-antibody complex,however, is not the basis for diagnosis which is clinical and keys on a decrease in platelets by 50% or a platelet count of less than 100,000.
Sunday, January 21, 2007
The"Disruptive Physician" -what is all about ?
A recent blog and a comment by a colleague stimulated my interest in the concept of "disruptive physician". Googling it quickly lead to this example of what really seems to be the peer review process being used to silence a physician who had the courage to point out a serious patient safety issue at her hospital.
The recent action of the Joint Commission regarding a disruptive hospital personnel policy indicates this issue has gone past the point of just talking about it.
Without the teeth of the Hospital Review committees, talk about the disruptive physician would mean little. However, abuse of the peer review system has been written about for a number of years. Here is a good review of the anatomy and physiology of the legal structure of the peer review world, a world that seems far remote from the usual notions of due process and innocent until proven guilty and meaningful appellate mechanisms. A key point is that federal law gives peer review committees immunity and you do not want to be on the bad side of a group of people who are not restrained by the threat of tort action.
The peer review sword can be used to remove a physician whose actions are in fact placing patients at risk but can be wielded to restrict competitors or to silence or threaten an physician whose comments are "disruptive" to a hospital administration's plan to do what it wants without bothersome input by physicians.
The recent action of the Joint Commission regarding a disruptive hospital personnel policy indicates this issue has gone past the point of just talking about it.
Without the teeth of the Hospital Review committees, talk about the disruptive physician would mean little. However, abuse of the peer review system has been written about for a number of years. Here is a good review of the anatomy and physiology of the legal structure of the peer review world, a world that seems far remote from the usual notions of due process and innocent until proven guilty and meaningful appellate mechanisms. A key point is that federal law gives peer review committees immunity and you do not want to be on the bad side of a group of people who are not restrained by the threat of tort action.
The peer review sword can be used to remove a physician whose actions are in fact placing patients at risk but can be wielded to restrict competitors or to silence or threaten an physician whose comments are "disruptive" to a hospital administration's plan to do what it wants without bothersome input by physicians.
Wednesday, January 17, 2007
Observational data is important but how do we analyze the data.
Here is a summary of a recent JAMA article that should make it clear that the statistical techniques on which a study result may turn are definitely not your father's t test, p-values and simple regression equations any more.
Here is a summary of the JAMA article by Stukel et.al.
My simplistic "understanding" of all of this follows.
Randomized clinical trials (RCTs) are the best way to measure treatment effects because they reduce or ideally eliminate selection bias making the treatment and control group equal in regard to all features. If done properly the study should be protected from known and unknown confounders eliminating the need for statistical manipulations.
There is an important difference between the outcome of a RCT wherein the patient self selects to be randomized and there are often many criteria which exclude subjects such as age, sex, other medical conditions present, etc. and the outcome that occurs when the treatment is applied to patients in the more real ,non-RCT world of medical practice. This is often called the "effficacy (RCT results) -effectiveness (real world results) gap. Observational studies relate to the second.
Observational studies- though plagued by selection bias-can be valuable:they provide data when there are no relevant RCTs and they are capable of finding deleterious treatment effects in the longer run with more patients.RCTs are not the end-all in regard to side effects with recent examples being cardiac outcomes of selective NSAIDs and the long term occlusion of drug eluting stents.
So we need observational data but statisticians have to deal with selection bias.
Stukel and co-workers compared various statistical methods to address these selection biases using Medicare data on the use and outcomes of cardiac catheterizations following myocardial infarctions.
They compared something called "propensity score methods" with "instrumental variable methods". As explained in an accompanying editorial by Drs. D'Agostino, Stukel's group maintained that the instrumental methods were better because they produces an answer closer to RCTs and they eliminated bias due to unobserved variables.
The editorialists seem to cast doubt on that conclusion with statistical arguments that quickly escalate from my level of understanding but they did share my concern with the authors's comment " instrumental variable analyses...are more suited to answer policy questions than to provide insight into a specific clinical question for a specific patient." The D'Agostinos say "treatment effects should deal with effects relevant to patients." Of course, what else could it be all about? How can policy decisions not affect patient management decisions?
If you juxtapose the article with editorial you quickly see that experts in the field of statistics differ in major ways about the the best way(s) to analyze observational data to mitigate the potentially misleading effect of selection bias but both groups agree that the choice of analytic method can have major effects regarding the conclusion as to what the data are thought demonstrate. So it is important how you analyze the data but statisticians differ as to how to do it. The devil seems to be in the details of analysis but the intricacies and understanding of these details seem increasingly to be beyond the reach of many practicing physicians.
I seem to stumble across more and more studies whose conclusions seem to vary by the choice of statistical technique and the discussions regarding the choice of techniques seem to get more and more obtuse.
Here is a summary of the JAMA article by Stukel et.al.
My simplistic "understanding" of all of this follows.
Randomized clinical trials (RCTs) are the best way to measure treatment effects because they reduce or ideally eliminate selection bias making the treatment and control group equal in regard to all features. If done properly the study should be protected from known and unknown confounders eliminating the need for statistical manipulations.
There is an important difference between the outcome of a RCT wherein the patient self selects to be randomized and there are often many criteria which exclude subjects such as age, sex, other medical conditions present, etc. and the outcome that occurs when the treatment is applied to patients in the more real ,non-RCT world of medical practice. This is often called the "effficacy (RCT results) -effectiveness (real world results) gap. Observational studies relate to the second.
Observational studies- though plagued by selection bias-can be valuable:they provide data when there are no relevant RCTs and they are capable of finding deleterious treatment effects in the longer run with more patients.RCTs are not the end-all in regard to side effects with recent examples being cardiac outcomes of selective NSAIDs and the long term occlusion of drug eluting stents.
So we need observational data but statisticians have to deal with selection bias.
Stukel and co-workers compared various statistical methods to address these selection biases using Medicare data on the use and outcomes of cardiac catheterizations following myocardial infarctions.
They compared something called "propensity score methods" with "instrumental variable methods". As explained in an accompanying editorial by Drs. D'Agostino, Stukel's group maintained that the instrumental methods were better because they produces an answer closer to RCTs and they eliminated bias due to unobserved variables.
The editorialists seem to cast doubt on that conclusion with statistical arguments that quickly escalate from my level of understanding but they did share my concern with the authors's comment " instrumental variable analyses...are more suited to answer policy questions than to provide insight into a specific clinical question for a specific patient." The D'Agostinos say "treatment effects should deal with effects relevant to patients." Of course, what else could it be all about? How can policy decisions not affect patient management decisions?
If you juxtapose the article with editorial you quickly see that experts in the field of statistics differ in major ways about the the best way(s) to analyze observational data to mitigate the potentially misleading effect of selection bias but both groups agree that the choice of analytic method can have major effects regarding the conclusion as to what the data are thought demonstrate. So it is important how you analyze the data but statisticians differ as to how to do it. The devil seems to be in the details of analysis but the intricacies and understanding of these details seem increasingly to be beyond the reach of many practicing physicians.
I seem to stumble across more and more studies whose conclusions seem to vary by the choice of statistical technique and the discussions regarding the choice of techniques seem to get more and more obtuse.
Tuesday, January 16, 2007
Combining CABG with carotid endarterectomy-good or bad idea?
A recent article in Neurology suggests that the combination of coronary artery bypass surgery with carotid endarterectomy may not be a good idea.
Dr. Wes takes this article on in his blog and provides a very insightful analysis of the issue and delves into the problems that are involved with this type of retrospective analysis of administrative data. This is the type study that I like to call a "coarse grain" study, a satellite view of the forest providing no essential data about the individual trees.
Dr. Wes says it well when he speaks of the study as:
"... a retrospective chart review of computer-code data set....in an attempt to glean a flicker of data with which to draw a glimmer of a trend-NOT a conclusion."
In regard to the authors's disclaimer regarding "the limitations to the use of administrative data sets" his translation nails it:
"we know the data are poor and we fixed them a bit to clean them up and erased some data, but don't worry about that."
When the odds ratio is corrected for the various things that epidemiologists like to think they can correct for it shrinks from a value of 2.25 to an unimpressive 1.38. The uncorrected odds ratio is the one that will get the emphasis in the lay press and will serve to worry and frustrate patients and their physicians particularly since this study seems to not support the current position of the American College of Cardiology and American Heart Association. One retrospective, administrative coding analysis should not have the evidentiary weight to effectively contradict the ACCP/AHA position. Calls for a randomized clinical trial to "settle" this issue appeared quickly.
Dr. Wes takes this article on in his blog and provides a very insightful analysis of the issue and delves into the problems that are involved with this type of retrospective analysis of administrative data. This is the type study that I like to call a "coarse grain" study, a satellite view of the forest providing no essential data about the individual trees.
Dr. Wes says it well when he speaks of the study as:
"... a retrospective chart review of computer-code data set....in an attempt to glean a flicker of data with which to draw a glimmer of a trend-NOT a conclusion."
In regard to the authors's disclaimer regarding "the limitations to the use of administrative data sets" his translation nails it:
"we know the data are poor and we fixed them a bit to clean them up and erased some data, but don't worry about that."
When the odds ratio is corrected for the various things that epidemiologists like to think they can correct for it shrinks from a value of 2.25 to an unimpressive 1.38. The uncorrected odds ratio is the one that will get the emphasis in the lay press and will serve to worry and frustrate patients and their physicians particularly since this study seems to not support the current position of the American College of Cardiology and American Heart Association. One retrospective, administrative coding analysis should not have the evidentiary weight to effectively contradict the ACCP/AHA position. Calls for a randomized clinical trial to "settle" this issue appeared quickly.
Monday, January 15, 2007
More important caveats re: generalizing from Randomized trials
In the Jan. 9, 2007 issue of the Archives of Internal Medicine, there is an interesting article regarding the external validity of randomized clinical trials. External validity refers to the ability of results of a trial or experiment to generalize to the real world population.
There has been much written about how often the elderly (usually 65 and over) and women are excluded from trials. Clinician have been frequently admonished to be careful about extrapolating results of trials to their patients who differ from the those eligible to have participated in the particular trial. This article raises interesting questions suggesting that those patients who apparently did not differ and were eligible but did not participate in the trial had a higher baseline risk and worse results. Of course, those who were not eligible had a even higher baseline risk and outcome.
Dr.Steg and a group of international investigators divided patients in the GRACE registry (which forms a large multi-national cohort,) into three groups,RCT participants, eligible patients not enrolled in a trial, and ineligible patients. Not only was there a gradient of baseline risk with those participating in RCTs having the lowest, those eligible but not participatng the next lowest and those not eligible the highest but an important observation was that the RCT participants had half the hospital mortality of the eligible, nonparticipating group. (3.6% versus 7.1%)
The authors offered several possible interpretations.The one that strikes my eye is that the better results of the trial patients is due to the "closer medical attention" possibly provided in the trial,e.g perhaps more regular use of the other treatment modalities-aspirin, beta-blockers, reperfusion therapies). Apparently, they had some evidence that this was a factor.In addition, as always, the specter of "unknown confounders" is raised which in statistic-speak means "it could be something else but we don't know what".
What are the implications of this? One is that the treatment groups outcomes would be better irrespective of the benefit derived from the particular therapy at issue.The results of thrombolysis in S-T segment elevated M.I.,for example, may be less impressive even in those patients who characteristics closely resemble those of the patients treated in the trial.
The authors seem to provide evidence for still another reason for the effectiveness-efficacy gap. Even if the direction of the results of a RCT may be correct, we should not expect the results to be as impressive when the therapies are applied to patients even if their clinical characteristics closely mirror those who participated in the trial.
There has been much written about how often the elderly (usually 65 and over) and women are excluded from trials. Clinician have been frequently admonished to be careful about extrapolating results of trials to their patients who differ from the those eligible to have participated in the particular trial. This article raises interesting questions suggesting that those patients who apparently did not differ and were eligible but did not participate in the trial had a higher baseline risk and worse results. Of course, those who were not eligible had a even higher baseline risk and outcome.
Dr.Steg and a group of international investigators divided patients in the GRACE registry (which forms a large multi-national cohort,) into three groups,RCT participants, eligible patients not enrolled in a trial, and ineligible patients. Not only was there a gradient of baseline risk with those participating in RCTs having the lowest, those eligible but not participatng the next lowest and those not eligible the highest but an important observation was that the RCT participants had half the hospital mortality of the eligible, nonparticipating group. (3.6% versus 7.1%)
The authors offered several possible interpretations.The one that strikes my eye is that the better results of the trial patients is due to the "closer medical attention" possibly provided in the trial,e.g perhaps more regular use of the other treatment modalities-aspirin, beta-blockers, reperfusion therapies). Apparently, they had some evidence that this was a factor.In addition, as always, the specter of "unknown confounders" is raised which in statistic-speak means "it could be something else but we don't know what".
What are the implications of this? One is that the treatment groups outcomes would be better irrespective of the benefit derived from the particular therapy at issue.The results of thrombolysis in S-T segment elevated M.I.,for example, may be less impressive even in those patients who characteristics closely resemble those of the patients treated in the trial.
The authors seem to provide evidence for still another reason for the effectiveness-efficacy gap. Even if the direction of the results of a RCT may be correct, we should not expect the results to be as impressive when the therapies are applied to patients even if their clinical characteristics closely mirror those who participated in the trial.
Friday, January 05, 2007
Federal Trade Commission and physician group negotiation
It seems- at least from this account of recent FTC action-the likelihood of groups of physicians banding together to successfully negotiate with third party payers, is either very low or non existent. This is because the FTC considers such action on the part of docs as violating the antitrust laws.
Here is the FTC news release outlining the complaint against a number of groups that represent a large number of physicians in the Chicago area. Appeal of the FTC ruling seems to be an often futile exercise in paying large fees to attorneys with little likelihood of success and very real legal risk. A listing of the large number of physicians who have felt the impact of FTC actions can be found at this site, which also describes the continuing legal battle of one group, North Texas specialty Physicians,whose case is to be heard by the Fifth Circuit Court. Physicians alarmed by the stance of the FTC will not be surprised that both unions and hospitals are apparently exempt from antitrust laws. For a discussion of how the FTC manages instances of alleged "horizontal price fixing" by physician groups from a libertarian, Austrian Economic School point of view go here.
As long as the "negotiation" between third party payers and individual doctors is of the type "here is our offer (based on CMS Medicare numbers),take it or leave it" we have de-facto price controls. Price controls tend to have four consequences: increased demand, decreased supply, poorer quality,and the emergence of a black market. It seems to me that in the medical world of the U.S. we are seeing all but the fourth. See Scalpel for some cogent comments about quality and price controls in medicine.
As long as insurers set the prices for medical services and the FTC prohibits physician groups from negotiating for fees, efforts by physicians to support and take part in P4P programs in the hope that the downward spiral of fees for primary care will be halted will be less effective than rearranging deck chairs on a sinking ship.
Here is the FTC news release outlining the complaint against a number of groups that represent a large number of physicians in the Chicago area. Appeal of the FTC ruling seems to be an often futile exercise in paying large fees to attorneys with little likelihood of success and very real legal risk. A listing of the large number of physicians who have felt the impact of FTC actions can be found at this site, which also describes the continuing legal battle of one group, North Texas specialty Physicians,whose case is to be heard by the Fifth Circuit Court. Physicians alarmed by the stance of the FTC will not be surprised that both unions and hospitals are apparently exempt from antitrust laws. For a discussion of how the FTC manages instances of alleged "horizontal price fixing" by physician groups from a libertarian, Austrian Economic School point of view go here.
As long as the "negotiation" between third party payers and individual doctors is of the type "here is our offer (based on CMS Medicare numbers),take it or leave it" we have de-facto price controls. Price controls tend to have four consequences: increased demand, decreased supply, poorer quality,and the emergence of a black market. It seems to me that in the medical world of the U.S. we are seeing all but the fourth. See Scalpel for some cogent comments about quality and price controls in medicine.
As long as insurers set the prices for medical services and the FTC prohibits physician groups from negotiating for fees, efforts by physicians to support and take part in P4P programs in the hope that the downward spiral of fees for primary care will be halted will be less effective than rearranging deck chairs on a sinking ship.
Tuesday, January 02, 2007
Great review of major Hospital Medicine issues-Go Web 2
Dr. R.W. has posted a useful series of essays highlighting his version of the top issues for 2006 in the field of hospital medicine. Anyone who is interested in hospital based care will find these entries valuable sources of information and analysis. I found his most recent posting fascinating as it touches on the issue of how a "feel good" project can develop a mind all of its own even while seemingly forsaking basic principles of evidence based thinking in an effort to claim success in achieving its stated goals. I am referring to the widely hyped Institute for Health Care improvement (IHI) Save 100,000 Lives initiative and their claim for success even though the evidence supporting that claim is not only weak but there are good reasons to believe that some of their efforts may be counterproductive. Details can be found in his posts and more late breaking news regarding heart failure performance measures and their lack of correlation with outcomes can be found here.
I continue to be impressed with how rich and valuable the new or virtual doctor's lounge(i.e.the medical blogosphere) can be. The blogs are only part of the so-called WEB-2 which I believe is really changing the way physicians can obtain medical information.
I continue to be impressed with how rich and valuable the new or virtual doctor's lounge(i.e.the medical blogosphere) can be. The blogs are only part of the so-called WEB-2 which I believe is really changing the way physicians can obtain medical information.
Saturday, December 30, 2006
The Limits of Risk Factor Epidemiology
First a great quote, from Michale Thun, VP of Epidemiology and Surveillance Research at the American Cancer society:
With epidemiology you can tell a little thing from a big thing.What's very hard to do is to tell a little thing from nothing at all.
Gary Taubes in his widely cited article,"Epidemiology Faces Its Limits",Science, Vol 269,p. 164,July 1995, followed that quote with this comment:
...journals today are full of studies suggesting that a little risk is not nothing at all.
There is no basic law of science or statistics or epidemiology or metaphysics which will define how large a relative risk or a odds ratio has to be before physicians and patients need be concerned. Here we are talking about the interpretation or weighing of the evidence that accrues in the quest for evidence on which to base medicine.
Committees that author guidelines typically outline for the reader what their evidentiary hierarchy will be, usually randomized clinical trials at the top etc. But what are the rules for judging individual studies particularly the observational ones, e.g. case control studies and cohort studies.How big should a RR (or ORs for case-control studies) be before they consider that study worthy of adding to the pile of evidence worth of consideration ?
To get a sense of what the professionals do in that regard we could survey experts and see rules of thumb they use in knowing when to consider an observational study worthy of worrying about or suitable for publication. What we learn is that it may not be just the size of the RR but the overall context.
Robert Temple of the FDA is quoted by Taubes as saying:
My basic rule is if the relative risk isn't at least 3 or 4, forget it.
However, Dr. John Bailar,from McGill,believes there is no magic dividing line.
If it's a 1.5 relative risk and it's only one study and even a very good one, you scratch your chin and say maybe.
It is not size of the RR alone ( but we have to agree at some point low is too low say 1.03 relative risk) but the results of other studies addressing the same issue and concerns about scientific in general and in specific biological plausibility have to be factored in. Even though the size of the RR or OR ( odds ratio) is not necessarily determinative it is easy to cite a number of experts in the field who favor the notion that RR less than 2 should be- if not dismissed- at least looked at with a very skeptical eye.
While size of the relative risk is not the end of the analysis, it is the case that small RRs are more likely to be generated by undetected systematic error(s) than are large one. A RR of 1.2 should be much more suspect than a RR of 3.2
The observational studies can be considered coarse-grained instruments with bias and confounding being the basis for the coarseness,the hidden variables that can lead to an association that is not real. While calculating a confidence interval takes random variation in the data into account , bias and confounding lie outside its reach.
Sophisticated (and to many medical readers-mysterious) statistical methods such as various types of mathematical modeling may serve to eliminate or minimize some of the systematic errors but in the final analysis the reader or researcher still does not know to what extent biases are not controlled. I have yet to read the discussion section of an observational study in which the authors did not believe that they had "controlled" for sources of bias and confounding even when that study contradicted an earlier one whose authors also believed their methods likely excluded bias.
I believe that the best an ordinary medical reader -one whose wall is not decorated with an advanced degree in epidemiology or statistics-can do is:
1.Be very skeptical of Relative Risks less than 2 and particularly less than 1.5
2.Look in the articles' discussion sections for citation of confirming or contradictory studies.
3.Consider whether the findings fit some concept of reasonable biological plausibility.
With epidemiology you can tell a little thing from a big thing.What's very hard to do is to tell a little thing from nothing at all.
Gary Taubes in his widely cited article,"Epidemiology Faces Its Limits",Science, Vol 269,p. 164,July 1995, followed that quote with this comment:
...journals today are full of studies suggesting that a little risk is not nothing at all.
There is no basic law of science or statistics or epidemiology or metaphysics which will define how large a relative risk or a odds ratio has to be before physicians and patients need be concerned. Here we are talking about the interpretation or weighing of the evidence that accrues in the quest for evidence on which to base medicine.
Committees that author guidelines typically outline for the reader what their evidentiary hierarchy will be, usually randomized clinical trials at the top etc. But what are the rules for judging individual studies particularly the observational ones, e.g. case control studies and cohort studies.How big should a RR (or ORs for case-control studies) be before they consider that study worthy of adding to the pile of evidence worth of consideration ?
To get a sense of what the professionals do in that regard we could survey experts and see rules of thumb they use in knowing when to consider an observational study worthy of worrying about or suitable for publication. What we learn is that it may not be just the size of the RR but the overall context.
Robert Temple of the FDA is quoted by Taubes as saying:
My basic rule is if the relative risk isn't at least 3 or 4, forget it.
However, Dr. John Bailar,from McGill,believes there is no magic dividing line.
If it's a 1.5 relative risk and it's only one study and even a very good one, you scratch your chin and say maybe.
It is not size of the RR alone ( but we have to agree at some point low is too low say 1.03 relative risk) but the results of other studies addressing the same issue and concerns about scientific in general and in specific biological plausibility have to be factored in. Even though the size of the RR or OR ( odds ratio) is not necessarily determinative it is easy to cite a number of experts in the field who favor the notion that RR less than 2 should be- if not dismissed- at least looked at with a very skeptical eye.
While size of the relative risk is not the end of the analysis, it is the case that small RRs are more likely to be generated by undetected systematic error(s) than are large one. A RR of 1.2 should be much more suspect than a RR of 3.2
The observational studies can be considered coarse-grained instruments with bias and confounding being the basis for the coarseness,the hidden variables that can lead to an association that is not real. While calculating a confidence interval takes random variation in the data into account , bias and confounding lie outside its reach.
Sophisticated (and to many medical readers-mysterious) statistical methods such as various types of mathematical modeling may serve to eliminate or minimize some of the systematic errors but in the final analysis the reader or researcher still does not know to what extent biases are not controlled. I have yet to read the discussion section of an observational study in which the authors did not believe that they had "controlled" for sources of bias and confounding even when that study contradicted an earlier one whose authors also believed their methods likely excluded bias.
I believe that the best an ordinary medical reader -one whose wall is not decorated with an advanced degree in epidemiology or statistics-can do is:
1.Be very skeptical of Relative Risks less than 2 and particularly less than 1.5
2.Look in the articles' discussion sections for citation of confirming or contradictory studies.
3.Consider whether the findings fit some concept of reasonable biological plausibility.
Thursday, December 28, 2006
Proton pump inhibitors, hip fracture and small relative risks
A JAMA article has generated considerable media attention citing a case control study that linked PPIs (proton pump inhibitors) to an increased risk of hip fracture.
The overall adjusted odds ratio was 1.44 with a confidence interval of 1.3-1.59. There was a dose response relationship demonstrated with duration of therapy.
Observational studies, such as this case-control study, are generally accepted to be so-called "hypothesis generating" studies rather than studies that more suggest a causative relationship (o.k. I'll stipulate causation is a deep, complicated philosophical issue and I use the word here just to indicate that case-control studies are just the beginning of efforts to demonstrate likely causal relationships).
A dramatic example of how observational trials can be misleading can be found in the juxtaposition of two studies in the New England Journal of Medicine dealing with relationship between hormone replacement therapy and coronary artery disease. One study demonstrated a two fold increase in coronary disease risk while the companion article showed a coronary artery risk reduction of 50% in those who used HRT.
There has been a number of conflicting case control studies regarding the relationship between statin use and colon cancer risk which again points our the problems involved when you take the results of one such study too seriously.
Let's quickly apply Bradford Hill's criteria to the PPI-hip fracture issue. The temporal relationship is there. There is a dose response relationship is a reasonable biological plausibility- low stomach acid conditions can interfere with absorption of some forms of calcium.
However, the association (1.44. OR) is not very large and there is not a strong consistency of results in other observational studies. (The JAMA article quote another study with similar results and one that did not demonstrate the association). At the end of the mini-analysis we still don't know if the reported relationship is valid or really know if we should somehow change our practice in regard to PPIs.
How big should the relative risk (RR) or odds ratio (OR) be for us to be concerned with the results? This is the very question asked by Dr. David Sackett in his book " Evidence-Based Medicine. How to practice and Teach EBM", Churchill Livingtone. Second edition,pg 162).For an answer to this the pioneers in EBM turn to argument by authority as opposed to an evidence based reason.
In regard to a case control study he said
We might not want to label an odds ratio from a case-control study as impressive unless it is greater than 4 for minor adverse events and set this value progressively lower [for more serious events].
Further, he says in regard to a cohort study, where there is less potential bias , that a relative risk of greater than 3 might be convincing for a more serious adverse event.I have posted before on the issue of RR in the 1-2 range.
John Ioannidis stirred up the medical community a bit in his article "Why Most Published Research Findings are False" and in regard to small relative risk determinations he is quoted as saying:
The smaller the effect sizes in a scientific field, the less likely the research findings are to be true...more likely true in scientific fields with ...relative risks [ in the 3- 20 range] ...than in scientific fields where the postulated effects are small [in the 1.1-1.5 range]
Could this study, and so many more with RRs less than 2 hit that hit the headline news, not really be worth much concern at all since the reported increased risk is so small ?
Dr. Marcia Angell, NEJM editor, has been quoted as saying that generally they only accept papers if the relative risk is 3 or more, particularly if it is biologically implausible or if it's a brand new finding. In the PPI case, there is some biological plausibility and occurs in the context of at least one study with findings pointing in the same direction.
In some legal venues, a relative risk of 2 or more is required to meet the legal standard of "more likely than not".
The PPI study authors suggest we should recommend that calcium supplements be taken with meals and I would add recommend adequate amounts of vitamin D ( thought to be about 800-1000 units per day now) and to perhaps have a looser trigger finger on the indications for measurement of bone density in those patients who are on long term PPI therapy and/or higher dose. However, I do not think patients whose GERD symptoms have been controlled by PPIs-and sometimes this change has been dramatic-should throw away their pills.
The overall adjusted odds ratio was 1.44 with a confidence interval of 1.3-1.59. There was a dose response relationship demonstrated with duration of therapy.
Observational studies, such as this case-control study, are generally accepted to be so-called "hypothesis generating" studies rather than studies that more suggest a causative relationship (o.k. I'll stipulate causation is a deep, complicated philosophical issue and I use the word here just to indicate that case-control studies are just the beginning of efforts to demonstrate likely causal relationships).
A dramatic example of how observational trials can be misleading can be found in the juxtaposition of two studies in the New England Journal of Medicine dealing with relationship between hormone replacement therapy and coronary artery disease. One study demonstrated a two fold increase in coronary disease risk while the companion article showed a coronary artery risk reduction of 50% in those who used HRT.
There has been a number of conflicting case control studies regarding the relationship between statin use and colon cancer risk which again points our the problems involved when you take the results of one such study too seriously.
Let's quickly apply Bradford Hill's criteria to the PPI-hip fracture issue. The temporal relationship is there. There is a dose response relationship is a reasonable biological plausibility- low stomach acid conditions can interfere with absorption of some forms of calcium.
However, the association (1.44. OR) is not very large and there is not a strong consistency of results in other observational studies. (The JAMA article quote another study with similar results and one that did not demonstrate the association). At the end of the mini-analysis we still don't know if the reported relationship is valid or really know if we should somehow change our practice in regard to PPIs.
How big should the relative risk (RR) or odds ratio (OR) be for us to be concerned with the results? This is the very question asked by Dr. David Sackett in his book " Evidence-Based Medicine. How to practice and Teach EBM", Churchill Livingtone. Second edition,pg 162).For an answer to this the pioneers in EBM turn to argument by authority as opposed to an evidence based reason.
In regard to a case control study he said
We might not want to label an odds ratio from a case-control study as impressive unless it is greater than 4 for minor adverse events and set this value progressively lower [for more serious events].
Further, he says in regard to a cohort study, where there is less potential bias , that a relative risk of greater than 3 might be convincing for a more serious adverse event.I have posted before on the issue of RR in the 1-2 range.
John Ioannidis stirred up the medical community a bit in his article "Why Most Published Research Findings are False" and in regard to small relative risk determinations he is quoted as saying:
The smaller the effect sizes in a scientific field, the less likely the research findings are to be true...more likely true in scientific fields with ...relative risks [ in the 3- 20 range] ...than in scientific fields where the postulated effects are small [in the 1.1-1.5 range]
Could this study, and so many more with RRs less than 2 hit that hit the headline news, not really be worth much concern at all since the reported increased risk is so small ?
Dr. Marcia Angell, NEJM editor, has been quoted as saying that generally they only accept papers if the relative risk is 3 or more, particularly if it is biologically implausible or if it's a brand new finding. In the PPI case, there is some biological plausibility and occurs in the context of at least one study with findings pointing in the same direction.
In some legal venues, a relative risk of 2 or more is required to meet the legal standard of "more likely than not".
The PPI study authors suggest we should recommend that calcium supplements be taken with meals and I would add recommend adequate amounts of vitamin D ( thought to be about 800-1000 units per day now) and to perhaps have a looser trigger finger on the indications for measurement of bone density in those patients who are on long term PPI therapy and/or higher dose. However, I do not think patients whose GERD symptoms have been controlled by PPIs-and sometimes this change has been dramatic-should throw away their pills.
Sunday, December 24, 2006
Is being a hospitalist the only way to still be a old time internist?
Dr. Laurence Wellikson seems to believe that the only way -at least a way-to recapture the core of what internist used to do (care for the patient with the complex problem(s))is to become a hospitalist.
Here is a point-counterpoint presentation by Dr. Willikson,CEO of the Society of Hospital Medicine,and Dr. Robert Centor,President of the Society of General Internal Medicine on the topic of "What is an Internist?"
Willikson seems right on target when he speaks about "internists [having] devolved into gatekepers and primary care physicians" ...[and] competing with Family Practitioners and Nurse Practitioners to be the traffic cop for resource use and burgeoning specialization."
He then inserts some of the current- in- vogue- jargon of the business consultants and speaks about the importance of preparing a "value proposition" and then makes what I consider to be a "boil the oceans" type suggestion namely to "reset the reimbursement system".
Given the current power relationship between third party payers and physicians it hard to conceive of what doctors could do to change the system. Hospitalists are either employees of the hospitals in which they practice or are contractors. The only tool either group has to bring about change is the strike, an action that physicians have rarely participated in. Changing the current medical care-reimbursement system is going to take more than hospitalists or internists writing a value statement, which I understand to be a statement made by a business explaining what they do and why the targeted customer should by it. (It occurs to me what if other specialists were exhorted to author a value statement.Perhaps neurosurgeons would propose "We take out brain tumors better than anybody."
Hospitalists do seem to spend most of their work day doing what many of us wanted to do when we decided to become internists and I hate to think the only avenue for the Oslerian type internist to travel is that of the hospitalist but that may be the reality though we have not quite arrived at that point yet. I hate to think that because an important part of what I used to do was not only caring for the complicated case in the hospital but also as an outpatient. This was a common occurence with COPD patients with exacerbations requiring hospital and often ICU type care. Internists should be the ones caring for patients with complex medical problems in and out of a hospital setting. There are still internists who care for the complex cases as in and out patients but clearly it is getting harder to do that. Dr. Wellikson seems to think internists should care for complex cases outside the hospital as well but leaves me wondering how he thinks that will happen.
Here is a point-counterpoint presentation by Dr. Willikson,CEO of the Society of Hospital Medicine,and Dr. Robert Centor,President of the Society of General Internal Medicine on the topic of "What is an Internist?"
Willikson seems right on target when he speaks about "internists [having] devolved into gatekepers and primary care physicians" ...[and] competing with Family Practitioners and Nurse Practitioners to be the traffic cop for resource use and burgeoning specialization."
He then inserts some of the current- in- vogue- jargon of the business consultants and speaks about the importance of preparing a "value proposition" and then makes what I consider to be a "boil the oceans" type suggestion namely to "reset the reimbursement system".
Given the current power relationship between third party payers and physicians it hard to conceive of what doctors could do to change the system. Hospitalists are either employees of the hospitals in which they practice or are contractors. The only tool either group has to bring about change is the strike, an action that physicians have rarely participated in. Changing the current medical care-reimbursement system is going to take more than hospitalists or internists writing a value statement, which I understand to be a statement made by a business explaining what they do and why the targeted customer should by it. (It occurs to me what if other specialists were exhorted to author a value statement.Perhaps neurosurgeons would propose "We take out brain tumors better than anybody."
Hospitalists do seem to spend most of their work day doing what many of us wanted to do when we decided to become internists and I hate to think the only avenue for the Oslerian type internist to travel is that of the hospitalist but that may be the reality though we have not quite arrived at that point yet. I hate to think that because an important part of what I used to do was not only caring for the complicated case in the hospital but also as an outpatient. This was a common occurence with COPD patients with exacerbations requiring hospital and often ICU type care. Internists should be the ones caring for patients with complex medical problems in and out of a hospital setting. There are still internists who care for the complex cases as in and out patients but clearly it is getting harder to do that. Dr. Wellikson seems to think internists should care for complex cases outside the hospital as well but leaves me wondering how he thinks that will happen.
Tuesday, December 19, 2006
Sowell's "Conflict of Visions" and medicine
Thomas Sowell's book "Conflict of Visions" is one of the most insightful and intellectually satisfying books I have ever read.It deals with the ways in which people differ in their fundamental view of the world.
Sowell observes that "reality is far too complex to be comprehended by any given mind" and therefore humans need maps, or a sense of how the world works to enable them to make sense of it all; he describes these maps as visions or pre-analytic cognitive constructs.
These visions differ about the basic nature of man. Sowell considers that this visions can be categorized into two broad categories are the "constrained view" also called the Tragic view and the "unconstrained view" also called the Utopian view.
In the Tragic view, man is constrained by his moral limitations and his egocentricity. The social challenge is how to work with those limitations rather than engage in energy wasting and ultimately futile efforts to change human nature.In this view, one deals with trade-offs and not solutions. Benefits to society derive from actions largely unintended but emerging from market actions which derive from the pressures of the incentives for individual gain which include the monetary and the psychic. Much of the meat of the constrained view can be picked from Adam Smith's "The Wealth of Nations". In a scheme that values trade offs , prudence assumes a high position. Burke said "Nothing is good but in proportion and with reference."
Steven Pinker in his book, 'The Blank slate' expresses the differences between the visions in this way :
In the tragic vision, humans are inherently limited in knowledge,wisdom and virtue and all social arrangements must acknowledge those limits....in the utopian, psychological limitations are artifacts that come from our social arrangements and we should not allow them to restrict our gaze from what is possible in a better world."
In the Utopian view, social inequalities such poverty,uninsured patients,drug addiction, racial or gender imbalances are seen as resulting from faults in society and therefore warrant that social targets be developed and plans made to rectify the social problems. The tragic Visionist would be concerned with the self interested motive of the people who are tasked with carrying out the programs and also with the unforeseen and unintended consequences that such projects seem to invariably entail.
Uneven distribution of wealth as brought about by a market economy in the unconstrained view is thought of as being unjust and in need of remedy in the name of social justice. The constrained view would argue that the notion of justice does not make sense when applied to an abstraction as society and would speak of justice only in the context of human decisions in a framework of laws.
So what has all of this to do with medicine? I believe the current iteration of Medical Professionalism ( Medical Professionalism in the New Millenium.A Physician Charter.Ann. Int. Med 5 Feb 2002, Vol. 136, pg 243-246) reflects the Utopian View and to a degree I find distressing has become part of the medical education agenda and the writing and speech of academic and organizational physicians. In this new charter, justice is emphasized and the justice proposed in their construct of social justice involves concern about "allocation of medical resources" and physicians considered stewards of society's resources.It talks about "commitment to a just distribution of finite resources" and to be committed to "develop guidelines for cost effective care".
Of course, concern for the individual patient's welfare has not be abolished and the "primacy of the patient welfare " is still said to be fundamental. However, a potentially conflicting principle,the social justice imperative, has been added the physician's obligation list.
I grew up medically with notion of concern for the individual patient being primary-first do no harm and to act always in the interest of the patient. Fiduciary duty was the decision trump card. I wonder at what point the imperative of "just allocation of resources" trumps concern for the welfare of the individual patient. The front line physician battered back and forth in the moment to moment flurry of phone calls, lab tests, patient problems, managed care restraints and hassels will have little time, energy or the tools to somehow factor into his patient decisions concern about "society's resources".
Sowell observes that "reality is far too complex to be comprehended by any given mind" and therefore humans need maps, or a sense of how the world works to enable them to make sense of it all; he describes these maps as visions or pre-analytic cognitive constructs.
These visions differ about the basic nature of man. Sowell considers that this visions can be categorized into two broad categories are the "constrained view" also called the Tragic view and the "unconstrained view" also called the Utopian view.
In the Tragic view, man is constrained by his moral limitations and his egocentricity. The social challenge is how to work with those limitations rather than engage in energy wasting and ultimately futile efforts to change human nature.In this view, one deals with trade-offs and not solutions. Benefits to society derive from actions largely unintended but emerging from market actions which derive from the pressures of the incentives for individual gain which include the monetary and the psychic. Much of the meat of the constrained view can be picked from Adam Smith's "The Wealth of Nations". In a scheme that values trade offs , prudence assumes a high position. Burke said "Nothing is good but in proportion and with reference."
Steven Pinker in his book, 'The Blank slate' expresses the differences between the visions in this way :
In the tragic vision, humans are inherently limited in knowledge,wisdom and virtue and all social arrangements must acknowledge those limits....in the utopian, psychological limitations are artifacts that come from our social arrangements and we should not allow them to restrict our gaze from what is possible in a better world."
In the Utopian view, social inequalities such poverty,uninsured patients,drug addiction, racial or gender imbalances are seen as resulting from faults in society and therefore warrant that social targets be developed and plans made to rectify the social problems. The tragic Visionist would be concerned with the self interested motive of the people who are tasked with carrying out the programs and also with the unforeseen and unintended consequences that such projects seem to invariably entail.
Uneven distribution of wealth as brought about by a market economy in the unconstrained view is thought of as being unjust and in need of remedy in the name of social justice. The constrained view would argue that the notion of justice does not make sense when applied to an abstraction as society and would speak of justice only in the context of human decisions in a framework of laws.
So what has all of this to do with medicine? I believe the current iteration of Medical Professionalism ( Medical Professionalism in the New Millenium.A Physician Charter.Ann. Int. Med 5 Feb 2002, Vol. 136, pg 243-246) reflects the Utopian View and to a degree I find distressing has become part of the medical education agenda and the writing and speech of academic and organizational physicians. In this new charter, justice is emphasized and the justice proposed in their construct of social justice involves concern about "allocation of medical resources" and physicians considered stewards of society's resources.It talks about "commitment to a just distribution of finite resources" and to be committed to "develop guidelines for cost effective care".
Of course, concern for the individual patient's welfare has not be abolished and the "primacy of the patient welfare " is still said to be fundamental. However, a potentially conflicting principle,the social justice imperative, has been added the physician's obligation list.
I grew up medically with notion of concern for the individual patient being primary-first do no harm and to act always in the interest of the patient. Fiduciary duty was the decision trump card. I wonder at what point the imperative of "just allocation of resources" trumps concern for the welfare of the individual patient. The front line physician battered back and forth in the moment to moment flurry of phone calls, lab tests, patient problems, managed care restraints and hassels will have little time, energy or the tools to somehow factor into his patient decisions concern about "society's resources".
Now American College of Surgeons favor P4P-say it isn't so ,Joe.
Seemingly following in the footsteps of the American College of Physicians (ACP) the executive director of the American College of Surgeons (ACS) has written a letter to the NY Times advocating P4P. Dr. Thomas Russell wrote in part:
"Many physicians have long encouraged efforts to advance evidence-based care such as Medicare's "pay for performance" system. They do so because such steps are in the best interest of patients."
His comments seem mainly to be gratuitous asssertions which can be countered by equally gratuitous denials since he offers no arguments in support.Those of us who have serious questions about P4P and believe it to be simply wrong on many levels believe that is not in the interests of patients and that it will not advance evidence-based care.I have been of the opinion that the majority of real life internists in private practice do not share many of the policy decisions of ACP, I would like to hear from the prolific and articulate surgeons bloggers if a similar situation exists in the surgical world. I suspect it does.
"Many physicians have long encouraged efforts to advance evidence-based care such as Medicare's "pay for performance" system. They do so because such steps are in the best interest of patients."
His comments seem mainly to be gratuitous asssertions which can be countered by equally gratuitous denials since he offers no arguments in support.Those of us who have serious questions about P4P and believe it to be simply wrong on many levels believe that is not in the interests of patients and that it will not advance evidence-based care.I have been of the opinion that the majority of real life internists in private practice do not share many of the policy decisions of ACP, I would like to hear from the prolific and articulate surgeons bloggers if a similar situation exists in the surgical world. I suspect it does.
Monday, December 18, 2006
More accusations of big pharma behaving very badly
The ethics of business is not the same as the ethics of medicine but if recent accusations against Lilly are true you might conclude that in regard to some businesses the word does not even apply. I have quoted Dr. Patricia Illingworth before:
...some commonly accepted principles of business ethics are fundamentally incompatible with traditional medical ethics...,
These practices include spinning and playing down the negative aspects of your product and intentionally misleading customers and maybe that is why we have laws against deceptive trade practices.
Reuters today published an article saying that the NY Times web site describes Lilly's activities promoting off label use of Zyprexa (olanzapine) and acting to play down Zyprexa's known side effects of significant weight gain and increased risk of diabetes. They are accused of a stealth campaign to promote the drug's use in dementia. Olanzapine has FDA approval for use only in Bipolar disease and schizophrenia.
NY Times writes about internal Lilly documents that suggest Zyprexa be promoted to primary care docs for use in dementia noting that psychiatrists are the physicians who mainly treat schizophrenia and bipolar disorder and primary docs do not feel confident is managing those conditions but they do manage many elderly patients with varying degrees of dementia.
Evidence is presented that indicates sales reps did in fact promote the drug for the off label use with the result of a significant increase in sales and were given monetary incentives for those activities. The promotional program was known as "Viva Zyprexa". A representative for Lilly denies claims of promoting the drug use for non approved indications and is quoted as stating that a Zyprexa-diabetes link has not been proven.
...some commonly accepted principles of business ethics are fundamentally incompatible with traditional medical ethics...,
These practices include spinning and playing down the negative aspects of your product and intentionally misleading customers and maybe that is why we have laws against deceptive trade practices.
Reuters today published an article saying that the NY Times web site describes Lilly's activities promoting off label use of Zyprexa (olanzapine) and acting to play down Zyprexa's known side effects of significant weight gain and increased risk of diabetes. They are accused of a stealth campaign to promote the drug's use in dementia. Olanzapine has FDA approval for use only in Bipolar disease and schizophrenia.
NY Times writes about internal Lilly documents that suggest Zyprexa be promoted to primary care docs for use in dementia noting that psychiatrists are the physicians who mainly treat schizophrenia and bipolar disorder and primary docs do not feel confident is managing those conditions but they do manage many elderly patients with varying degrees of dementia.
Evidence is presented that indicates sales reps did in fact promote the drug for the off label use with the result of a significant increase in sales and were given monetary incentives for those activities. The promotional program was known as "Viva Zyprexa". A representative for Lilly denies claims of promoting the drug use for non approved indications and is quoted as stating that a Zyprexa-diabetes link has not been proven.
Saturday, December 16, 2006
FDA relegates Ketek to second line treatment for community acquired pneumonia
The FDA seems to making some progress in the Ketek matter.Maybe now we will be seeing less of the ubiquitous Ketex advertising owl on the back of medical journals.
I have been concerned with the Ketek issue for some time and have blogged on and on about it on several occasions.I expressed the opinion that there was little if any indication for that drug.It had been approved and marketed for sinusitis,bronchitis and community acquired pneumonia (CAP).Now the FDA panel says use it only as a second line drug for CAP.At least they are heading in the right direction. The risk of liver disease seems real (I believe at least 12 fatal cases so far) and why anyone would use it to treat sinusitis escapes me.
ADDENDUM:(12/19/06) Thanks to an alert reader I was informed I had misspelled the brand name of the drug in question when this message was first published.Since one who controls the present controls the past I am now going to at least partially control the past and republish the corrected posting with the explanatory addendum. James Gaulte
I have been concerned with the Ketek issue for some time and have blogged on and on about it on several occasions.I expressed the opinion that there was little if any indication for that drug.It had been approved and marketed for sinusitis,bronchitis and community acquired pneumonia (CAP).Now the FDA panel says use it only as a second line drug for CAP.At least they are heading in the right direction. The risk of liver disease seems real (I believe at least 12 fatal cases so far) and why anyone would use it to treat sinusitis escapes me.
ADDENDUM:(12/19/06) Thanks to an alert reader I was informed I had misspelled the brand name of the drug in question when this message was first published.Since one who controls the present controls the past I am now going to at least partially control the past and republish the corrected posting with the explanatory addendum. James Gaulte
Friday, December 15, 2006
Post-modernism,EBM and George Orwell
Dr. Roy Poses in his Dec.01,2006 posting on Health Care Renewal tackled the topic of the attack of the post-modernists on Evidence Based Medicine (EBM). From time to time, I have written about the mis-use of EBM to cook the RCT books and hype the results and about how some may misunderstand EBM but the post-modernists attack on EBM seems to be basically self contradictory.
As pointed out by Steven Pinker (pg 426 ," The Blank Slate, the modern denial of human nature")
"It is ironic that a philosophy that prides itself on deconstructing the accoutrement's of power should embrace a relativism that makes challenges to power impossible, because it denies that there are objective benchmarks against which the deceptions of the powerful can be evaluated."
Pinker prefaces those remarks by discussing the totalitarian regime found in "Nineteen Eighty Four" and by describing their philosophy as "thoroughly postmodernist".
He quotes from the government agent, O' Brien, as he lectures the protagonist, Winston Smith, who is strapped to a table and tortured and "educated ".
"You believe that reality is something objective,external, existing in its own right. ...But I tell you, Winston, that reality is not external .[it exists] only in the mind of the party, which is collective and immortal"
When there is no objective truth and no means of obtaining the truth,whoever is in charge determines what it true or not. "Who controls the past controls the future:who controls the present controls the past."
A frontal attack on the science of medicine or on science in general is fairly easily beaten back.Nonsense tends to fall on its own weight even if sometimes that fall may take longer than we would like. In regard to medicine and medical education the greater danger seems to be in the infiltration of alternative medicine elements-and its philosophic underpinnings,Post Modernism- into the curriculum of medical schools and even into the clinical services they offer. Dr. RW relentlessly keeps us well informed about the alarming instances of medical schools offering courses and sponsoring clinics for practitioners of the various categories of altie hokum.
As pointed out by Steven Pinker (pg 426 ," The Blank Slate, the modern denial of human nature")
"It is ironic that a philosophy that prides itself on deconstructing the accoutrement's of power should embrace a relativism that makes challenges to power impossible, because it denies that there are objective benchmarks against which the deceptions of the powerful can be evaluated."
Pinker prefaces those remarks by discussing the totalitarian regime found in "Nineteen Eighty Four" and by describing their philosophy as "thoroughly postmodernist".
He quotes from the government agent, O' Brien, as he lectures the protagonist, Winston Smith, who is strapped to a table and tortured and "educated ".
"You believe that reality is something objective,external, existing in its own right. ...But I tell you, Winston, that reality is not external .[it exists] only in the mind of the party, which is collective and immortal"
When there is no objective truth and no means of obtaining the truth,whoever is in charge determines what it true or not. "Who controls the past controls the future:who controls the present controls the past."
A frontal attack on the science of medicine or on science in general is fairly easily beaten back.Nonsense tends to fall on its own weight even if sometimes that fall may take longer than we would like. In regard to medicine and medical education the greater danger seems to be in the infiltration of alternative medicine elements-and its philosophic underpinnings,Post Modernism- into the curriculum of medical schools and even into the clinical services they offer. Dr. RW relentlessly keeps us well informed about the alarming instances of medical schools offering courses and sponsoring clinics for practitioners of the various categories of altie hokum.
Doctors fight back, Insurance company capitulates
The above headline was inspired by a news report in the daily email I get from AMA ( one of the few perks of membership). I had blogged previously about the Blue Shield matter in Seattle.
Apparently, something call the "AMA Litigation Center" joined in a legal action with the Washington State Medical Society and six physicians against the "Select Network Plan" devised by Regence Blueshield. I had not heard of the Litigation Center, but it seems that for the past 10 years it has been involved in legal actions that look after the interests of physicians and has a new initiative to fight back against insurers who play fast and loose with bogus guidelines and performance indicators "delisting" docs and damaging their reputations and practices.
The insurer dropped the plan.
Dr. Pleasted, president of AMA, is quoted as saying:
"A patient's choice of a physician must not be influenced by a health insurer's mistaken assumption that low cost is the only acceptable measure of quality."
Physicians should not neglect the powerful effect that legal action that sometimes have but what happens now is not clear.What about the patients that received letters from the insurance company informing them that their doctors were not practicing according to some standards? They were said to not be practicing "quality and efficient " medicine. What reparations will be made for lost patients,damaged reputations and lost income? According to AMA websites ,( I believe membership is required to access) the law suit continues in an effort to obtain monetary damages.
Apparently, something call the "AMA Litigation Center" joined in a legal action with the Washington State Medical Society and six physicians against the "Select Network Plan" devised by Regence Blueshield. I had not heard of the Litigation Center, but it seems that for the past 10 years it has been involved in legal actions that look after the interests of physicians and has a new initiative to fight back against insurers who play fast and loose with bogus guidelines and performance indicators "delisting" docs and damaging their reputations and practices.
The insurer dropped the plan.
Dr. Pleasted, president of AMA, is quoted as saying:
"A patient's choice of a physician must not be influenced by a health insurer's mistaken assumption that low cost is the only acceptable measure of quality."
Physicians should not neglect the powerful effect that legal action that sometimes have but what happens now is not clear.What about the patients that received letters from the insurance company informing them that their doctors were not practicing according to some standards? They were said to not be practicing "quality and efficient " medicine. What reparations will be made for lost patients,damaged reputations and lost income? According to AMA websites ,( I believe membership is required to access) the law suit continues in an effort to obtain monetary damages.
Wednesday, December 13, 2006
JAMA article considers Hospital Performance Measures and mortality rates
In the December 13, 2006 issue of JAMA, Drs. Rachel Werner and Eric Bradlow analyzed data from 3657 acute care hospitals looking at the relationship between certain performance measures and mortality rates. They used 10 measures which are available from CMS and the Joint Commission 's web site. For example, in regard to pneumonia the measures are: 1) timing of initial antibiotic administration, 2) pneumococcal vaccination and 3)whether oxygenation was measured in the first 24 hours.
The authors concluded that:
"hospital performance measures predict small differences in hospital risk-adjusted mortality rates"
and said further:
"Based on these results, the ability of performance measures to detect clinically meaningful differences in quality across hospitals is questionable"
Dr. Susan Horn in her related editorial makes several good points:
1.If these performance measures are not strongly associated with outcomes, why should we bother with them either as basis for P4P of for consumers to use as tools for judging hospitals?
2.Since many( but not all) of these measures were chosen,at least,in part because of the results of RCTs, why are these interventions not associated with better outcomes in practice?
Her answer to the second question is that improving outcomes in actual real world practice is much more complex and multidimensional than using a few, discrete interventions that seemed efficacious and safe in RCTs that typically focus on a single condition in a fairly homogeneous population. In part, it is the question of efficacy versus effectiveness. Measuring quality of care is much more complex and slippery than the ten measures analyzed in their study.
In an earlier article Dr. Werner pointed out some possible unintended consequences of hospital "report card" including treating the chart and excluding sicker patients.
One message should be: we have no business using simple and simplistic measures as a basis for pay for performance or for claiming to be able to distinguish between different hospitals quality of care. Not only may they not deliver on what they promise, they may be harmful.
The authors concluded that:
"hospital performance measures predict small differences in hospital risk-adjusted mortality rates"
and said further:
"Based on these results, the ability of performance measures to detect clinically meaningful differences in quality across hospitals is questionable"
Dr. Susan Horn in her related editorial makes several good points:
1.If these performance measures are not strongly associated with outcomes, why should we bother with them either as basis for P4P of for consumers to use as tools for judging hospitals?
2.Since many( but not all) of these measures were chosen,at least,in part because of the results of RCTs, why are these interventions not associated with better outcomes in practice?
Her answer to the second question is that improving outcomes in actual real world practice is much more complex and multidimensional than using a few, discrete interventions that seemed efficacious and safe in RCTs that typically focus on a single condition in a fairly homogeneous population. In part, it is the question of efficacy versus effectiveness. Measuring quality of care is much more complex and slippery than the ten measures analyzed in their study.
In an earlier article Dr. Werner pointed out some possible unintended consequences of hospital "report card" including treating the chart and excluding sicker patients.
One message should be: we have no business using simple and simplistic measures as a basis for pay for performance or for claiming to be able to distinguish between different hospitals quality of care. Not only may they not deliver on what they promise, they may be harmful.
Friday, December 08, 2006
AMA President nails P4P for what it is at AMA Interim meeting
Dr. William G. Plested III, president of the AMA had this to say regarding pay for performance at the recent Interim meeeting;
I will point out that-reminiscent of the managed care debachle-P4P will allow insurers to dictate the treatment that we give our patients and will publicly label any physician foolish enough to contract with them and not follow their dictates as nonpreferred, substandard or some such label.
This is not just speculation as the physicians in the state of Washington had exactly that happen to them.
Further, he said that he was unaware of any P4P program in place that was in compliance with the AMA suggested guidelines for P4P.
A proposal was made for the AMA to launch a campaign to discredit P4P and correctly label it as economic credentialing. Unfortunately, no resolution was passed. At least, the president of the AMA recognizes P4P for what it is which much more than can be said for the leadership of the American College of Physicians who seem to be working with the third payers payers to move ahead with this very bad idea. ACP seems to believe-or at least their rhetoric suggests-that they can "work with" third payers to ensure that P4P program will improve quality and not just lower costs.
I will point out that-reminiscent of the managed care debachle-P4P will allow insurers to dictate the treatment that we give our patients and will publicly label any physician foolish enough to contract with them and not follow their dictates as nonpreferred, substandard or some such label.
This is not just speculation as the physicians in the state of Washington had exactly that happen to them.
Further, he said that he was unaware of any P4P program in place that was in compliance with the AMA suggested guidelines for P4P.
A proposal was made for the AMA to launch a campaign to discredit P4P and correctly label it as economic credentialing. Unfortunately, no resolution was passed. At least, the president of the AMA recognizes P4P for what it is which much more than can be said for the leadership of the American College of Physicians who seem to be working with the third payers payers to move ahead with this very bad idea. ACP seems to believe-or at least their rhetoric suggests-that they can "work with" third payers to ensure that P4P program will improve quality and not just lower costs.
Monday, December 04, 2006
Randomized trials are wonderful but beware of "evidence based paralysis"
The term "evidence based paralysis" came to my attention in a letter to the editor in the Archives of Internal Medicine in the Aug 14/28 2006 Letter to the Editor section. Drs. David Ziemer and Lawrence S. Phillips from Emory used it in their reply to a comment about an article concerning the issue of whether tight control of type 2 diabetic patients is " evidence based ". They also used to term "RCTomyopia" to refer to an " unwillingness to take action without incontrovertible proof from controlled trials".
RCTs and meta-analyses are considered the most reliable tools in the hierarchy of EBM.(For some time I have questioned whether MA belong in that position.) Because of this, some make the mistake of jumping to the position that if there are no RCTs that there is no evidence based reason for action.
Of course, RCTs are good, but there are not good for everything.They cannot answer all the questions physicians need/want to have answered.
They are great for discrete interventions in carefully defined, relatively homogeneous conditions in terms of determining efficacy. They are clearly less good for determining harm and for determining how to diagnosis conditions and for determining prognosis. In regard to harm, RCTs can recognize relatively common adverse effects that occur fairly soon after a medication is started but are less useful in detecting less common and/or delayed side effects.
However, when the questions to be answered arise in and from more complex patient populations in which the patient characteristics and interventions are more complex and heterogeneous it become much more difficult to separate out causality from bias,confounding and even random variation.In fact, some times it is more than difficult in that after the trial has been done and analyzed we still do not know the answer we were searching for. Case in point is the recent back surgery for herniated disc versus conservative management RCT published in JAMA. In this instance, there was so much cross over between the two groups as they were randomized that the "intent to treat" analysis was not considered valid and the "as treated analysis" suffers from the very real risk of selection bias which is why we have randomization in the first place. One is left with the disturbing thought that it may not be possible to solve this clinical issue by doing a randomized trial as long as we deal with patients who are free to do what they think is best for them.
It is important to know the limitations of the RCTs and that the very nature of certain clinical problems may be too complex for RCTs to be of use. Further, RCTs can never be done for all the problems that they are suitable to analyze.There are too many questions, often too little money and interest and with new drugs, procedures and testing methods always evolving-or at least changing-older RCTs lose relevance and the newer treatments may be years away from RCT results.
In treating patients with serious illnesses often we have to act not just sit there. We have to go with the evidence we have not the evidence we would like to have.
Ziemer and Philips had this to say in their letter to editor:
We believe that responsible physicians and patients should make decisions based on the best available evidence-including cell and animal studies, observational studies and controlled trials if available-and the strengths and weaknesses of the findings with each approach should be given due consideration.
I cannot resist when discussing this general topic to throw in the parachute-gravitational challenge comment that I quoted last year.
RCTs and meta-analyses are considered the most reliable tools in the hierarchy of EBM.(For some time I have questioned whether MA belong in that position.) Because of this, some make the mistake of jumping to the position that if there are no RCTs that there is no evidence based reason for action.
Of course, RCTs are good, but there are not good for everything.They cannot answer all the questions physicians need/want to have answered.
They are great for discrete interventions in carefully defined, relatively homogeneous conditions in terms of determining efficacy. They are clearly less good for determining harm and for determining how to diagnosis conditions and for determining prognosis. In regard to harm, RCTs can recognize relatively common adverse effects that occur fairly soon after a medication is started but are less useful in detecting less common and/or delayed side effects.
However, when the questions to be answered arise in and from more complex patient populations in which the patient characteristics and interventions are more complex and heterogeneous it become much more difficult to separate out causality from bias,confounding and even random variation.In fact, some times it is more than difficult in that after the trial has been done and analyzed we still do not know the answer we were searching for. Case in point is the recent back surgery for herniated disc versus conservative management RCT published in JAMA. In this instance, there was so much cross over between the two groups as they were randomized that the "intent to treat" analysis was not considered valid and the "as treated analysis" suffers from the very real risk of selection bias which is why we have randomization in the first place. One is left with the disturbing thought that it may not be possible to solve this clinical issue by doing a randomized trial as long as we deal with patients who are free to do what they think is best for them.
It is important to know the limitations of the RCTs and that the very nature of certain clinical problems may be too complex for RCTs to be of use. Further, RCTs can never be done for all the problems that they are suitable to analyze.There are too many questions, often too little money and interest and with new drugs, procedures and testing methods always evolving-or at least changing-older RCTs lose relevance and the newer treatments may be years away from RCT results.
In treating patients with serious illnesses often we have to act not just sit there. We have to go with the evidence we have not the evidence we would like to have.
Ziemer and Philips had this to say in their letter to editor:
We believe that responsible physicians and patients should make decisions based on the best available evidence-including cell and animal studies, observational studies and controlled trials if available-and the strengths and weaknesses of the findings with each approach should be given due consideration.
I cannot resist when discussing this general topic to throw in the parachute-gravitational challenge comment that I quoted last year.
Subscribe to:
Posts (Atom)