Dr. RW and then DB's Medical Rants correctly point out that the absence of recognized ties with or support by drug companies does not insure a conflict of interest free argument or medical publication.
Dr.RW discusses what on the surface might appear to be an evidence based analysis of the end results of the US system of medical care and the single-tier,single payer system found in Canada. Several of the authors of this article which proudly announces that there are no conflicts of interest actually are quite active in the politics and lobbying efforts for a single payer system in the U.S and supporting the current system in Canada while arguing for more funding.
The lead author is the Dr. Gordon Guyatt,who could accurately be described as one of the founding guru of evidence based medicine as well as a politician.
What better form of evidence based medicine could there be for a propaganda piece than a meta-analysis? A meta-analysis is basically an observational design with the "subjects" being published studies.The authors are free to decide which studies are included and which are rejected.In the instance highlighted by Dr.RW the authors do not even tell the reader how that selection-deselection process was done.(You have to contact them to get the details.) Even when the authors disclose the process-as is typically the case- the reader must suspend concerns about possible bias -or ulterior motives-to accept the article at any approximating face value. There is more faith in the acceptance of a meta-analysis than in a randomized trial.
Dr. Steve Goodman's Annals of Internal Medicine editorial expands on the issue of what a meta-analysis really is and illustrates how two meta-analyses done by reputable researchers can reach opposite results because the authors believed or did not believe that certain studies should be included in their analysis.
Criticisms of meta-analyses aside, the major point excellently made by DR. RW is that authors who have strongly held views on social-medical issues and are actively promoting a given social or political agenda should be considered as much of a source of a conflict of interest as someone who fronts for a drug promoting article.
Monday, April 30, 2007
Tuesday, April 24, 2007
Joint Commision "fixes" four hour pneumonia rule-makes it a six hour rule
Reacting to an outpouring of criticism and valid complaints about the simplistic four hour pneumonia rule the Joint Commission ( aka JCAHO) emphatically demonstrated that they did not get the point and moved to correct the problem by increasing the time to six hours. They also amended the original rule by adding a diagnostic category called "diagnostic uncertainty", cases designated as such would not be included in the emergency department report card.
Predictably, some advocates of the rule complained that this category will set the stage for cheating.If the six hour clock has run out,those devious ER docs can place the case in that category.You just can't trust doctors, you have to watch them all the time.
Dr. Dale W. Bratzler,one of the creators of the pneumonia standards was paraphrased in the JAMA news report ( JAMA, April 25,2007-vol 297,no 16) as saying the JCAHO realizes that unintended consequences can emerge from instituting quality measures, but hospitals and ERs should not abandon attempts to improve care.That seems unlikely with the joint commission breathing down their necks.
When the planners are faced with a disconnect between their scheme and reality they amend the program but do not question their premises. Make the rules more complex, generate more stentorian admonishments, put new sheets on the Procrustean bed.
In his book "The Illusion of Technique" William Barrett said this:
"The absence of an intelligent idea in the grasp of a problem cannot be redeemed by the elaborateness of the machinery one subsequently employs"
Predictably, some advocates of the rule complained that this category will set the stage for cheating.If the six hour clock has run out,those devious ER docs can place the case in that category.You just can't trust doctors, you have to watch them all the time.
Dr. Dale W. Bratzler,one of the creators of the pneumonia standards was paraphrased in the JAMA news report ( JAMA, April 25,2007-vol 297,no 16) as saying the JCAHO realizes that unintended consequences can emerge from instituting quality measures, but hospitals and ERs should not abandon attempts to improve care.That seems unlikely with the joint commission breathing down their necks.
When the planners are faced with a disconnect between their scheme and reality they amend the program but do not question their premises. Make the rules more complex, generate more stentorian admonishments, put new sheets on the Procrustean bed.
In his book "The Illusion of Technique" William Barrett said this:
"The absence of an intelligent idea in the grasp of a problem cannot be redeemed by the elaborateness of the machinery one subsequently employs"
FDA on "trial" in the Ketek Approval matter in NEJM
In the April 19,2007 issue of NEJM,Dr. D.B. Ross a former FDA physician involved in the Ketek review process, presents what reminds me of a prosecutors closing argument critical of the FDA performance in the approval of Ketek and its response to a flawed drug trial and its slow response to increasing evidence of its liver toxicity.
He is critical of the way that the FDA handled the entire matter and seems to present a very fact oriented argument absent of emotional laden rhetoric. NEJM features his commentary and also present the "defense closing argument" penned by five current FDA physicians somewhat less prominently in the correspondence section. So the interested reader can study both sides of the issue "did the FDA do its job appropriately?"
For a more detailed and nuanced personal view the audio interview with Dr. Ross is available on the NEJM site . He opines that the culture of the FDA changed about ten years ago and now a "culture of approval" is found. A significant percentage of FDA operating funds derives from drug companies and the incentive arrow points in the direction of faster rather than slower approval.Dr. Ross presents instances where pressure from above serves to discourage criticism of trials and more rather than less scrutiny.
Part of the FDA mission ( or at least their mission statement as the two need not necessarily coincide completely) is to "speed innovations".Ross believes that the speed imperative and the driver of big pharma funding may at least be part of what seems to be a problem at this agency.
While the word speed may be instructive in this instance, in general I believe that Thomas Sowell's insight regarding institutions and organizations (any decision making unit) works best. Do not look at what an organization says it is doing, look instead to the incentives and constraints it faces and the feedback it can receive. There does seem to be an incentive to speed innovations (it may not just be mission statement verbiage) and there is a budgetary restraint and at least until recently( when senate committees have investigated) much of the feedback was from the drug companies.
We now have testimony from two long time FDA physicians (remember Dr.David Graham and the Vioxx saga) which have seriously damaged the reputation of the FDA and our belief that a drug is safe and effective because the FDA says it is. Still more concern is raised in another Perspective Commentary in the same issue of NEJM by Dr.Mirian Shuchman which discusses the approval process of the vagus-nerve simulation for treatment of depression.
He is critical of the way that the FDA handled the entire matter and seems to present a very fact oriented argument absent of emotional laden rhetoric. NEJM features his commentary and also present the "defense closing argument" penned by five current FDA physicians somewhat less prominently in the correspondence section. So the interested reader can study both sides of the issue "did the FDA do its job appropriately?"
For a more detailed and nuanced personal view the audio interview with Dr. Ross is available on the NEJM site . He opines that the culture of the FDA changed about ten years ago and now a "culture of approval" is found. A significant percentage of FDA operating funds derives from drug companies and the incentive arrow points in the direction of faster rather than slower approval.Dr. Ross presents instances where pressure from above serves to discourage criticism of trials and more rather than less scrutiny.
Part of the FDA mission ( or at least their mission statement as the two need not necessarily coincide completely) is to "speed innovations".Ross believes that the speed imperative and the driver of big pharma funding may at least be part of what seems to be a problem at this agency.
While the word speed may be instructive in this instance, in general I believe that Thomas Sowell's insight regarding institutions and organizations (any decision making unit) works best. Do not look at what an organization says it is doing, look instead to the incentives and constraints it faces and the feedback it can receive. There does seem to be an incentive to speed innovations (it may not just be mission statement verbiage) and there is a budgetary restraint and at least until recently( when senate committees have investigated) much of the feedback was from the drug companies.
We now have testimony from two long time FDA physicians (remember Dr.David Graham and the Vioxx saga) which have seriously damaged the reputation of the FDA and our belief that a drug is safe and effective because the FDA says it is. Still more concern is raised in another Perspective Commentary in the same issue of NEJM by Dr.Mirian Shuchman which discusses the approval process of the vagus-nerve simulation for treatment of depression.
Monday, April 23, 2007
American Heart Association's 10 th version on infective endocarditis prophylaxis
The ninth version of the AHA's recommendations for prevention of IE was published in 1997-now we have the tenth and if followed there will be many fewer patients taking antibiotics before dental procedures. To the credit of the AHA the full text version is available on line and as well as being interesting reading from an historical and an analytic point of view it is something physicians need to know.
It looks like we don't have to fret about the patient who might have mitral value prolapse (MVP) and what type she/he was supposed to have because now we told it doesn't matter anyway. The authors point out that these guidelines " may violate long standing expectations and practice patterns " held by physicians,dentists and patients.I used to spend time trying to figure out what exactly the physician had told the patient about the type of MVP he had and what I really thought I needed was the echo report.
With some patients now being told they don't have to take antibiotics when they previously were told the opposite, will some be asking if the doctor/dentist was wrong then or is he wrong now? Probably some will but such is the half-life of medical truth.
It looks like we don't have to fret about the patient who might have mitral value prolapse (MVP) and what type she/he was supposed to have because now we told it doesn't matter anyway. The authors point out that these guidelines " may violate long standing expectations and practice patterns " held by physicians,dentists and patients.I used to spend time trying to figure out what exactly the physician had told the patient about the type of MVP he had and what I really thought I needed was the echo report.
With some patients now being told they don't have to take antibiotics when they previously were told the opposite, will some be asking if the doctor/dentist was wrong then or is he wrong now? Probably some will but such is the half-life of medical truth.
Wednesday, April 18, 2007
JAMA editorial critical of how ESAs have been used-
Few of the participants in the national dialysis scene escape the overt or implied criticism in comments found in an editorial by Dr. Daniel W. Coyne, a professor of medicine and nephologist at Washington University School of Medicine, in the April 18,2007 issue of JAMA. This is one of a number of articles and commentaries that have the same too-much-of-a-good-thing theme namely that the erythropoeisis stimulating agents(ESAs) have been over used both in renal failure patients and in patients with malignancies.
The medications on the table are:
epoetin alfa (branded as Epogen and Procrit)
darbepoetin (branded as Aranesp)
The recipients of criticism are:
1.The for-profit dialysis centers: An article in the same issue finds that the for-profits use more EPO and try to keep the hemoglobin levels higher than do the not for profit dialysis centers..The editorialist points out the profit margin for use of these drugs and possible marketing and rebate arrangements with the drugs manufacturer and distributors. Data from observational studies which have provided evidence for the improved quality of life associated with higher levels of hemoglobin are said by the editorial author are to be seriously confounded and he presents an array of selected data from several studies (some of which are randomized trials) which seem to indicate that mortality wise just the opposite is true.The increased mortality data associated with higher achieved hemoglobin levels was a key factor in the FDA's recent actions (see below)
2.The National Kidney Foundation and particularly its KDOQI (Kidney Disease Outcomes Quality Initiative). In this regard ,we are reminded that Amgen and other corporate contributors donate a good deal of money to the organization and that the chairman of the anemia working group works part time for a large for-profit dialysis company and 11/16 members of the work groups reportedly have conflicts of interest with the EPO producer.The reader is left to infer that the panel's recommendations may have been less influenced by sound data than by the source of funding. Dr. Coyne asserts that the panel's recommendations are based solely on quality of life studies. The NKF is expected to release new recommendations but Coyne believes that physicians "should not wait for the NKF opinions ,or necessarily trust of follow them."
Strong words, indeed.A reply from the Kidney Assocation folks surely will follow and I await their reply.
3.The nephrologists. While the practicing renal disease specialist does not make more money for using more EPO, he too does not appear blameless based on this editorial. Why? Even though he followed the guidelines (isn't this what everyone want doctors to do?) and even though he may have honestly believed there was the evidence base to support higher hemoglobin levels, he should have carefully analyzed the data and appropriately discounted the observational data and gone with what RCTs. Perhaps he should have concluded that contrary to the widely used guidelines, higher hemoglobin levels are not better. (OK Dr. Coyne didn't say any of those things, but I cannot help but think there is an undercurrent of unspoken criticism). I have to believe that most renal docs have acted in good faith here i.e.doing what they thought would benefit their patients and acting according to national guidelines.
I do not know if the data used to conclude that higher hemoglobin levels are better is so flawed as to conclude it should be discounted and I do not know if the conflicting data is so sound that clearly we should go with lower goals. But, I will admit Dr. Coyne's arguments seem persuasive and I would have to agree with the lower goals now recommended by the FDA. I obviously also do not know if the NKF panel was acting in anyway other than honestly and analysed the available data they had access to at the time in any way other fairly and appropriately. There is the perception of conflict of interest but concern about that should not be determinative. Analysis of the relevant data ideally should not factor in the possible conflict of interest but being human it is hard to not let that issue influence one's opinion. Moreover, I worry that we have been so guideline oriented and so herded by the views of organizations whose motives at times seem at best suspect that we really can't win.Go by the guidelines and then we learn the guidelines are thought to be bogus; don't comply with them and you are not practicing quality medicine and won't recieve your bribe (a.k.a. pay for performance.) We are learning how goldfish feel.
The FDA has also spoken on this topic and makes 3 points:
1.Use the lowest dose of an ESA to gradually increase the hemoglobin to the lowest level necessary to avoid a transfusion.
2.Realize that raising the hemoglobin level to greater than 12 increases the risk for cardiovascular events.
3.Realize that there has been reported a higher incidence of deep vein thrombosis in patients receiving epoetin preop to avoid blood transfusion.
ESAs are approved by the FDA for:
1.treatment of anemia in chronic kidney failure patients.
2.treatment of cancer patient whose chemotherapy has caused anemia.
The medications on the table are:
epoetin alfa (branded as Epogen and Procrit)
darbepoetin (branded as Aranesp)
The recipients of criticism are:
1.The for-profit dialysis centers: An article in the same issue finds that the for-profits use more EPO and try to keep the hemoglobin levels higher than do the not for profit dialysis centers..The editorialist points out the profit margin for use of these drugs and possible marketing and rebate arrangements with the drugs manufacturer and distributors. Data from observational studies which have provided evidence for the improved quality of life associated with higher levels of hemoglobin are said by the editorial author are to be seriously confounded and he presents an array of selected data from several studies (some of which are randomized trials) which seem to indicate that mortality wise just the opposite is true.The increased mortality data associated with higher achieved hemoglobin levels was a key factor in the FDA's recent actions (see below)
2.The National Kidney Foundation and particularly its KDOQI (Kidney Disease Outcomes Quality Initiative). In this regard ,we are reminded that Amgen and other corporate contributors donate a good deal of money to the organization and that the chairman of the anemia working group works part time for a large for-profit dialysis company and 11/16 members of the work groups reportedly have conflicts of interest with the EPO producer.The reader is left to infer that the panel's recommendations may have been less influenced by sound data than by the source of funding. Dr. Coyne asserts that the panel's recommendations are based solely on quality of life studies. The NKF is expected to release new recommendations but Coyne believes that physicians "should not wait for the NKF opinions ,or necessarily trust of follow them."
Strong words, indeed.A reply from the Kidney Assocation folks surely will follow and I await their reply.
3.The nephrologists. While the practicing renal disease specialist does not make more money for using more EPO, he too does not appear blameless based on this editorial. Why? Even though he followed the guidelines (isn't this what everyone want doctors to do?) and even though he may have honestly believed there was the evidence base to support higher hemoglobin levels, he should have carefully analyzed the data and appropriately discounted the observational data and gone with what RCTs. Perhaps he should have concluded that contrary to the widely used guidelines, higher hemoglobin levels are not better. (OK Dr. Coyne didn't say any of those things, but I cannot help but think there is an undercurrent of unspoken criticism). I have to believe that most renal docs have acted in good faith here i.e.doing what they thought would benefit their patients and acting according to national guidelines.
I do not know if the data used to conclude that higher hemoglobin levels are better is so flawed as to conclude it should be discounted and I do not know if the conflicting data is so sound that clearly we should go with lower goals. But, I will admit Dr. Coyne's arguments seem persuasive and I would have to agree with the lower goals now recommended by the FDA. I obviously also do not know if the NKF panel was acting in anyway other than honestly and analysed the available data they had access to at the time in any way other fairly and appropriately. There is the perception of conflict of interest but concern about that should not be determinative. Analysis of the relevant data ideally should not factor in the possible conflict of interest but being human it is hard to not let that issue influence one's opinion. Moreover, I worry that we have been so guideline oriented and so herded by the views of organizations whose motives at times seem at best suspect that we really can't win.Go by the guidelines and then we learn the guidelines are thought to be bogus; don't comply with them and you are not practicing quality medicine and won't recieve your bribe (a.k.a. pay for performance.) We are learning how goldfish feel.
The FDA has also spoken on this topic and makes 3 points:
1.Use the lowest dose of an ESA to gradually increase the hemoglobin to the lowest level necessary to avoid a transfusion.
2.Realize that raising the hemoglobin level to greater than 12 increases the risk for cardiovascular events.
3.Realize that there has been reported a higher incidence of deep vein thrombosis in patients receiving epoetin preop to avoid blood transfusion.
ESAs are approved by the FDA for:
1.treatment of anemia in chronic kidney failure patients.
2.treatment of cancer patient whose chemotherapy has caused anemia.
more on the 4-hour pneumonia antibiotic rule
Here are still more negative comments about the famous four hour rule.Patients with a discharge diagnosis of pneumonia are supposed to have received antibiotics within four hours to receive a gold star on their quality score sheet. This "quality indicator" is a core quality measure for CMS and JCAHO and according to Health Care Renewal at least in some hospitals may be one of the determinants of physician reimbursement.
To the quality police it may not matter if the rule they seek to enforce is not feasible which is what the above referenced article indicates.Unintended consequences of this rule have been written about by others
Rough cut, broad rules which ignore individual particulars and substitute a rule or algorithm for an individual expert's opinion and simplify things for ease of counting will naturally have consequences that the rule makers did not intend.
It is part of the mentality and hubris of the central planner to deny the expertise and value of the expert in the field familiar with case at hand.
To the quality police it may not matter if the rule they seek to enforce is not feasible which is what the above referenced article indicates.Unintended consequences of this rule have been written about by others
Rough cut, broad rules which ignore individual particulars and substitute a rule or algorithm for an individual expert's opinion and simplify things for ease of counting will naturally have consequences that the rule makers did not intend.
It is part of the mentality and hubris of the central planner to deny the expertise and value of the expert in the field familiar with case at hand.
Tuesday, April 17, 2007
More evidence favoring use of inhaled steroid in severe COPD
An randomized clinical trial (RCT) in the Annals of Internal Medicine provides evidence favoring use of inhaled corticosteroids (ICS) for moderate and severe COPD. Entry criteria included: fev1 less than 65% predicted, at least 10 pack years of cigarette use, and a history of at least one exacerbation of COPD in the preceding year.
Three groups ( about 150 patients per group) were compared:
tiotropium plus placebo
tiotropium plus salmeterol
tiotropium plus salmeterol-futicasone (Advair)
The third group had fewer hospitalizations, improved lung function and a better score on a quality of life question indicator.Numerically there were fewer exacerbations in the triple therapy group but it did not reach statistical significance.
The Advair manufacturers have to be pleased with some relatively good news after bad publicity generated by the SMART trial and subsequent publications by the Salpter family in regard to the use of ICS inhalers in asthma.
I suspect this trial will not bring about any major change in the way pulmonary physicians treat COPD. The recent well publicized TORCH trial compared salmeterol,fluticasone and the combination of the two and demonstrated fewer exacerbations with the combo treatment but did find more pneumonia in the group that received the ICS. The GOLD guidelines already have recommended adding a ICS to COPD patients with severe disease who have a history of repeated exacerbations. ("Severe" according to GOLD is less than 50% fev1 and very severe is less than 30%)
Both the TORCH trial and the current one included patients with FEV1 values greater than 50% of predicted which is the GOLD cut point for severe COPD so possibly more patients may be thought to be candidates for ICS according to the results of these two studies.
Three groups ( about 150 patients per group) were compared:
tiotropium plus placebo
tiotropium plus salmeterol
tiotropium plus salmeterol-futicasone (Advair)
The third group had fewer hospitalizations, improved lung function and a better score on a quality of life question indicator.Numerically there were fewer exacerbations in the triple therapy group but it did not reach statistical significance.
The Advair manufacturers have to be pleased with some relatively good news after bad publicity generated by the SMART trial and subsequent publications by the Salpter family in regard to the use of ICS inhalers in asthma.
I suspect this trial will not bring about any major change in the way pulmonary physicians treat COPD. The recent well publicized TORCH trial compared salmeterol,fluticasone and the combination of the two and demonstrated fewer exacerbations with the combo treatment but did find more pneumonia in the group that received the ICS. The GOLD guidelines already have recommended adding a ICS to COPD patients with severe disease who have a history of repeated exacerbations. ("Severe" according to GOLD is less than 50% fev1 and very severe is less than 30%)
Both the TORCH trial and the current one included patients with FEV1 values greater than 50% of predicted which is the GOLD cut point for severe COPD so possibly more patients may be thought to be candidates for ICS according to the results of these two studies.
Chondroitin takes a hit joining glucosamine hydrochloride
An Annals of Internal Medicine meta-analysis and an accompanying editorial argue strongly for the lack of efficacy of chondroitin for the treatment of osteoarthritis of the knee and hip. Last year, folks were talking about the GAIT trial which seemed to show that the hydrochloride form of glucosamine plus chondroitin did not help overall in that RCT but it might have helped in those with moderate or severe pain.An editorial paired with the NEJM article reporting on the GAIT trial reminded readers that previously data has suggested that the sulfate form of glucosamine seemed to work while the hydrochloride form perhaps did not.
Now it looks like there is little or no reason to add chondroitin to glucosamine sulfate even though many of the available preparations combine the two if we are to accept the results of the meta-analysis. But remember it is a meta-analysis and often it all turns on which studies you include and which you do not. The authors admit there was much heterogeneity and many of the trials the could have included were judged to be of such poor quality that they were excluded. One can hardly expect the truth to emerge from any type of analysis of trials that were poorly done to begin with so a case can be made for selectivity but... Meta-analyses are so common place now that editorial caveats about their weaknesses are generally no longer mentioned but they should be and my earlier blog on that topic contained a couple of good references.
The editorial paired with the GAIT trial suggested that one might still want to give the following advice: Try the combo of glucosamine sulfate with chondroitin for three months or so and if no better stop the pill. Now maybe it would be to just try the glucosamine sulfate.
Now it looks like there is little or no reason to add chondroitin to glucosamine sulfate even though many of the available preparations combine the two if we are to accept the results of the meta-analysis. But remember it is a meta-analysis and often it all turns on which studies you include and which you do not. The authors admit there was much heterogeneity and many of the trials the could have included were judged to be of such poor quality that they were excluded. One can hardly expect the truth to emerge from any type of analysis of trials that were poorly done to begin with so a case can be made for selectivity but... Meta-analyses are so common place now that editorial caveats about their weaknesses are generally no longer mentioned but they should be and my earlier blog on that topic contained a couple of good references.
The editorial paired with the GAIT trial suggested that one might still want to give the following advice: Try the combo of glucosamine sulfate with chondroitin for three months or so and if no better stop the pill. Now maybe it would be to just try the glucosamine sulfate.
Wednesday, April 11, 2007
Is there anything that statins won't do for us?
From time to time we learn of what seems to be new health benefits from taking statins.
Here is a news item on the most recent good news for the pharma firms that make them.(of course simvastatin,and pravastatin are now generic and the once tongue in cheek suggestion to put statins in the drinking water supply may be more feasible now)
Data presented there seems to show that the risk of death from COPD decreases by a fantastic 83%.Clearly this is much better than the various inhaled medications and seems even better than long term oxygen therapy.
In December 2006 we read that statins markedly decrease the risk of advanced cancer of the prostate and their use is associated with less than 1/2 the risk of fatal or metastatic prostate cancer.
One study indicated that patients with heart failure who take statins reduce their risk of death by 24% if they use statins.
A study from Japan using a cell culture assay system reported that inteferon plus fluvastatin inhibited hepatitis C virus more effectively than did inteferon plus ribaviran.
But all the news is not good.The reported association between low levels of LDL and risk of Parkinson Disease has lead one research group to plan to launch a study to investigate the possible risk of that disease with statin use.
Fro those of us who worry about a devastating world wide epidemic of influenza and inadequate supplies of anti-viral meds, one researcher has suggested that statins may be the answer. Although there is no proof that statins are good treatment for the flu, there is one report that demonstrated by a case-control study that diabetic patients had their risk of pneumonia reduced by 50% with statin use. Still another retrospective study reported a decrease in mortality from community acquired pneumonia (OR 0.36 with a CI 0.14 - .92) in those patients who were taking statins.
There have also been studies that purport to show fewer fractures and decreased risk of dementia in statin user.This multiplicity of benefits has been attributed to the nebulous "pleotrophic" effects of the statin. Another explanation( of course calling something pleotrophic doesn't explain anything)for at least some of these associations is suggested by this publication.
The authors point out that most of these purported,non-cardiac effects were demonstrated in observational studies while the multitude of randomized control trials failed to show them. They suggest that we may be seeing the "healthy user effect". They propose that statin users tend to be folks who exhibit various "healthy" behaviors and may sometimes even belong to a different socio-economic strata.This healthy user effect was one of the proposed reasons behind the dramatic disconnect between observational studies and the randomized trials regarding hormone replacement therapy.
Before we get too giddy with the thought of all the good we are doing with the statins we need to disabuse ourselves of the notion that causal relationships regularly derive from observational studies.
Here is a news item on the most recent good news for the pharma firms that make them.(of course simvastatin,and pravastatin are now generic and the once tongue in cheek suggestion to put statins in the drinking water supply may be more feasible now)
Data presented there seems to show that the risk of death from COPD decreases by a fantastic 83%.Clearly this is much better than the various inhaled medications and seems even better than long term oxygen therapy.
In December 2006 we read that statins markedly decrease the risk of advanced cancer of the prostate and their use is associated with less than 1/2 the risk of fatal or metastatic prostate cancer.
One study indicated that patients with heart failure who take statins reduce their risk of death by 24% if they use statins.
A study from Japan using a cell culture assay system reported that inteferon plus fluvastatin inhibited hepatitis C virus more effectively than did inteferon plus ribaviran.
But all the news is not good.The reported association between low levels of LDL and risk of Parkinson Disease has lead one research group to plan to launch a study to investigate the possible risk of that disease with statin use.
Fro those of us who worry about a devastating world wide epidemic of influenza and inadequate supplies of anti-viral meds, one researcher has suggested that statins may be the answer. Although there is no proof that statins are good treatment for the flu, there is one report that demonstrated by a case-control study that diabetic patients had their risk of pneumonia reduced by 50% with statin use. Still another retrospective study reported a decrease in mortality from community acquired pneumonia (OR 0.36 with a CI 0.14 - .92) in those patients who were taking statins.
There have also been studies that purport to show fewer fractures and decreased risk of dementia in statin user.This multiplicity of benefits has been attributed to the nebulous "pleotrophic" effects of the statin. Another explanation( of course calling something pleotrophic doesn't explain anything)for at least some of these associations is suggested by this publication.
The authors point out that most of these purported,non-cardiac effects were demonstrated in observational studies while the multitude of randomized control trials failed to show them. They suggest that we may be seeing the "healthy user effect". They propose that statin users tend to be folks who exhibit various "healthy" behaviors and may sometimes even belong to a different socio-economic strata.This healthy user effect was one of the proposed reasons behind the dramatic disconnect between observational studies and the randomized trials regarding hormone replacement therapy.
Before we get too giddy with the thought of all the good we are doing with the statins we need to disabuse ourselves of the notion that causal relationships regularly derive from observational studies.
Monday, April 09, 2007
A physician can "expect some bad outcomes" but a patient should expect physician will do the right thing
I have written about the essays of Dr. Lawrence J. Hergott before.His writing has have appeared in the " A piece of my Mind" section of the Journal of the American Medical Association and most are available in full-text form for free.
His "Playing the Moonlight Sonata from Memory-celebrating the Wonders of Our difficult Life"and his other JAMA essays should be part of a handout package of readings for medical students or house officers. He is able to extract experiences from physicians lives and the principles that govern them and put them into words with skill that I envy.
In the "Moonlight Sonata.." piece he candidly writes about a clinical encounter that went very wrong and which although it occurred decades ago still replays itself with"uncomfortable clarity and a surge of briefly incapacitating sadness and guilt" .
He quotes the following advice of a pioneering, invasive cardiologist, Andreas Gruentzig:
"If you are are going to be a physician ,deciding hourly about things that affect the health and lives of patients and their loved ones, expect some bad outcomes. They will occur , no matter how careful or how good you are."
Hergott continues
"We remember forever the suture that tore,the obstetric delivery that went bad...but we quickly forget the decision to order a lung scan that clarifies the diagnosis and saves a life in a subtle case of pulmonary embolism" He is right, we agonize forever over the bad outcome but quickly move past the good decisions that made major favorable differences in our patients lives. The physician who strives to do the right thing for his patients agonizes when things go wrong and he does it not because of momentary incentives.
In another essay entitled Galileo's Grapes Dr. Hergott says the following:
"...in matters of patient care the physician decides and acts alone-and lives alone with the results of those decisions.It is this aspect of medicine that delineates reputation from character. Reputation comes from things we do that others know about.Character emanates mostly from actions taken while no one is looking."
I wonder what accepting pay-for-performance (P4P) payments and playing the P4P game will do to physician's character. The exercise is,at best, accepting a bribe for doing the right thing. ( Again, my gratitude to Dr. Faith Fitzgerald for pointing out the bribe nature of P4P).
However, it often may really be accepting a bribe for doing the wrong thing (adhering to a general quality guideline even though that is harmful to a given individual patient.) I recently wrote about that referencing a post from Health Care Renewal.P4P is accepting a bribe for doing something that a guideline or quality indicator says is right with no consideration of the particular facts of the case at hand or the values of the patient.
Dr. Edward Blum has argued that P4P is- at the core- unethical. I agree. For physicians to accept it is to admit and announce that our fiduciary duty to do the right thing for the patient is not enough-we have to be paid extra to do it.We are saying that we will not know and will not do the right thing unless some organization or group tells us what to do and and then gives us a tip for doing it their way. Our efforts to fashion a good reputation,i.e. a profitable one with the insurers, will do the obvious to our character.
Many good arguments have been raised regarding how P4P will have negative consequences in terms of quality and patient outcomes but, in a sense, these arguments , as cogent and reasonable as they may be, may really beg the larger issue. The larger issue is that P4P is unethical and should we be haggling about the technical details of something that is clearly wrong in the first place.
His "Playing the Moonlight Sonata from Memory-celebrating the Wonders of Our difficult Life"and his other JAMA essays should be part of a handout package of readings for medical students or house officers. He is able to extract experiences from physicians lives and the principles that govern them and put them into words with skill that I envy.
In the "Moonlight Sonata.." piece he candidly writes about a clinical encounter that went very wrong and which although it occurred decades ago still replays itself with"uncomfortable clarity and a surge of briefly incapacitating sadness and guilt" .
He quotes the following advice of a pioneering, invasive cardiologist, Andreas Gruentzig:
"If you are are going to be a physician ,deciding hourly about things that affect the health and lives of patients and their loved ones, expect some bad outcomes. They will occur , no matter how careful or how good you are."
Hergott continues
"We remember forever the suture that tore,the obstetric delivery that went bad...but we quickly forget the decision to order a lung scan that clarifies the diagnosis and saves a life in a subtle case of pulmonary embolism" He is right, we agonize forever over the bad outcome but quickly move past the good decisions that made major favorable differences in our patients lives. The physician who strives to do the right thing for his patients agonizes when things go wrong and he does it not because of momentary incentives.
In another essay entitled Galileo's Grapes Dr. Hergott says the following:
"...in matters of patient care the physician decides and acts alone-and lives alone with the results of those decisions.It is this aspect of medicine that delineates reputation from character. Reputation comes from things we do that others know about.Character emanates mostly from actions taken while no one is looking."
I wonder what accepting pay-for-performance (P4P) payments and playing the P4P game will do to physician's character. The exercise is,at best, accepting a bribe for doing the right thing. ( Again, my gratitude to Dr. Faith Fitzgerald for pointing out the bribe nature of P4P).
However, it often may really be accepting a bribe for doing the wrong thing (adhering to a general quality guideline even though that is harmful to a given individual patient.) I recently wrote about that referencing a post from Health Care Renewal.P4P is accepting a bribe for doing something that a guideline or quality indicator says is right with no consideration of the particular facts of the case at hand or the values of the patient.
Dr. Edward Blum has argued that P4P is- at the core- unethical. I agree. For physicians to accept it is to admit and announce that our fiduciary duty to do the right thing for the patient is not enough-we have to be paid extra to do it.We are saying that we will not know and will not do the right thing unless some organization or group tells us what to do and and then gives us a tip for doing it their way. Our efforts to fashion a good reputation,i.e. a profitable one with the insurers, will do the obvious to our character.
Many good arguments have been raised regarding how P4P will have negative consequences in terms of quality and patient outcomes but, in a sense, these arguments , as cogent and reasonable as they may be, may really beg the larger issue. The larger issue is that P4P is unethical and should we be haggling about the technical details of something that is clearly wrong in the first place.
Thursday, April 05, 2007
Individual medical risk assessment-a peculiar, "elusive,ambiguous "process
A committee of the American College of Physicians recently published recommendations for mammogram screening for breast cancer somewhat at odds with the current consensus promulgated by the ACS,ACOG and the USPSTF. They suggested individual risk assessment for women 40-49 rather than the blanket recommendation to get a mammogram every one or two years.Their discussion about individual risk assessment rekindled thoughts about that topic that have been percolating in my brain for some time.
Risk assessment for various medical conditions has become an everyday part of the activities of primary care physicians. Risk assessment involves the identification of something called risk factors, personal characteristics or test findings that are associated with increased incidence of a given disease. As best I can determine, this term was coined by the researchers in the Framingham study when they spoke of factors that were associated with an increased risk of coronary artery disease. As the "practice model" of internist practices changes from hospital based consultation type to office outpatient more attention is given to preventive medicine which is a world of risk factor identification and risk assessment exercises as well as recitation of various guidelines and targets.
In one of my several medical lives, I spent some time doing executive health exams -or "well baby" checkups on senior executives from several companies. Part of that drill was determining their heart attack risk using the Framingham Risk equation.
Here is an example using the equation from the National Cholesterol Panel's (NCEP) web site.A 67 year old non-smoking man, Mr. Jones,with a history of hypertension under control and systolic blood pressure of 120, with a total cholesterol of 170 and an HDL cholesterol of 75 would have a risk estimate of 9 % according to their risk equation.
This means that if we consider the 10 year health outcomes of 100 men from the Framingham data base with this particular set of characteristics, 9 would have a coronary event. (A so-called hard end point of either a myocardial infarction or coronary death.) Of course, we do not know who the 9 will be until the event occurs and we cannot tell Mr. Jones if he will be one of the nine or not.
What does this" risk "of 9% for Mr Jones mean? Maybe the following mind experiment will shed some light on that. Let's pretend we can clone Mr. Jones and we do so 100 times and consider the question of what will be the outcomes of these 100 Joneses. Will 9% have a coronary artery event or will it be the case that either all will be fine or all will have a coronary event. (My gratitude again to Dr. Goodman and his memorable article in the Annals of Internal Medicine for this line of though that I blogged about here.)
If we believe in medical determinism-clinical outcomes determined by a causal chain of events-we believe that either all will be fine or all will have a heart attack. They will all be fine if they and the original Mr. Jones do not posses the factor(s) that sum up or interact to bring on an event or all will have an event if Mr. Jones had-as will all his clones have-whatever factor(s) known and unknown which determine a coronary artery event. If we believe in a cosmic dice roll then some 9% will have an event and medical science will never know ahead of the event who will because it is simply random.
Another consideration is that while we have placed Mr. Jones in this set of men with these particular features , we could as easily-if we had the data available-place him into a different set or as a member of as many sets as the imagination allows. We could consider him as a member of a set defined by his age, his c-reactive protein value, his performance on a stress test, his calcium score on a heart CT scan and his triglyceride level and if we consider the event rate in a group of men with these features we may well arrive a different value which could be 22%. So what is his risk- 9% or 22% or any of the multitude of other numbers that we could construct in a similar manner.
That type of consideration led the imminent German statistical theorist, Richard Von Mises to say in his book " Probability,Statistics and Truth" that it is only possible to speak of probability in terms of a collective (or in more modern terms -a set or a group) and that to say, for example, that a given person has the probability o.10 of dying in the next year is nonsense. Yet, isn't this is exactly what we do when we we punch in a person's numbers into the Framingham equation and announce to the patient that his risk of a hard cardiac event in the next 10 years is 9%.
Could we not "fine tune" the risk assessment process by having a data base such as the Framingham data base but with more factors added on that seem to correlate with cardiac events, for example c-reactive protein, stress test results etc? It would seem so. However, even though Wang et al did that type of analysis the resultant increase in predictive value was not great and the flurry of letters to the editor with various statistical arguments might leave many of us with our heads spinning.The deterministic view would lead us to try and do this fine tuning to more accurately advise the patient on what to do in spite of the fact there will be residual uncertainty even as we add on other risk factor measurements. But we are still not measuring the individual's risk, we may have made the coarse grain data somewhat more fine, but the risk measurement is a conceptually different entity that the answer we obtain we measure some one's blood sugar or P-R interval.
We are still looking at the incidence or risk of an event in a group of patients sharing a certain set of characteristics as the patient of interest and calling the incidence or risk of that event in the group the individual patient's risk.
Probability theory is obviously a sine qua non of medical science and the evidence we use but we when we speak of a patient's probability or risk of developing a given disease as opposed the risk or attack rate of disease in a group we realize how-in Goodman's words- "ambiguous and elusive" that concept is.
So, it is with less that bubbling-over enthusiasm that I react to the ACP recommendation for individual risk assessment in regard to recommendations for mammogram screening, particularly when the risk equations based on the Gail Model seem to be little better than a coin flip according to their own review.
The ACP guidelines say :
"...the Gail model accurately predicts the number of cases of breast cancer that will develop in a given population but is much less accurate in determining which individual women will develop breast cancer"
My contention is that that the panel misunderstands the conceptual difference between the group prediction and the individual patient prediction.It is not just a matter of being "more accurate" in the former case, it is that in the individual case, the meaning of the term "risk" is unclear and that the activity only really makes sense in the case of the population. Goodman's article explains how at one time "chance" and "probability" were different concepts, the former referencing random events and the latter term used to denote a degree of belief applied to situations believe to be unique as in the expression of an opinion as to whether a claim was consistent with the supporting evidence.
When we see Mrs.Jones in the office, it is the case that she will or will not develop breast cancer over her lifetime. It may be that we are fooling ourselves as much as Mrs. Jones when we tell her what her "risk" is.
Risk assessment for various medical conditions has become an everyday part of the activities of primary care physicians. Risk assessment involves the identification of something called risk factors, personal characteristics or test findings that are associated with increased incidence of a given disease. As best I can determine, this term was coined by the researchers in the Framingham study when they spoke of factors that were associated with an increased risk of coronary artery disease. As the "practice model" of internist practices changes from hospital based consultation type to office outpatient more attention is given to preventive medicine which is a world of risk factor identification and risk assessment exercises as well as recitation of various guidelines and targets.
In one of my several medical lives, I spent some time doing executive health exams -or "well baby" checkups on senior executives from several companies. Part of that drill was determining their heart attack risk using the Framingham Risk equation.
Here is an example using the equation from the National Cholesterol Panel's (NCEP) web site.A 67 year old non-smoking man, Mr. Jones,with a history of hypertension under control and systolic blood pressure of 120, with a total cholesterol of 170 and an HDL cholesterol of 75 would have a risk estimate of 9 % according to their risk equation.
This means that if we consider the 10 year health outcomes of 100 men from the Framingham data base with this particular set of characteristics, 9 would have a coronary event. (A so-called hard end point of either a myocardial infarction or coronary death.) Of course, we do not know who the 9 will be until the event occurs and we cannot tell Mr. Jones if he will be one of the nine or not.
What does this" risk "of 9% for Mr Jones mean? Maybe the following mind experiment will shed some light on that. Let's pretend we can clone Mr. Jones and we do so 100 times and consider the question of what will be the outcomes of these 100 Joneses. Will 9% have a coronary artery event or will it be the case that either all will be fine or all will have a coronary event. (My gratitude again to Dr. Goodman and his memorable article in the Annals of Internal Medicine for this line of though that I blogged about here.)
If we believe in medical determinism-clinical outcomes determined by a causal chain of events-we believe that either all will be fine or all will have a heart attack. They will all be fine if they and the original Mr. Jones do not posses the factor(s) that sum up or interact to bring on an event or all will have an event if Mr. Jones had-as will all his clones have-whatever factor(s) known and unknown which determine a coronary artery event. If we believe in a cosmic dice roll then some 9% will have an event and medical science will never know ahead of the event who will because it is simply random.
Another consideration is that while we have placed Mr. Jones in this set of men with these particular features , we could as easily-if we had the data available-place him into a different set or as a member of as many sets as the imagination allows. We could consider him as a member of a set defined by his age, his c-reactive protein value, his performance on a stress test, his calcium score on a heart CT scan and his triglyceride level and if we consider the event rate in a group of men with these features we may well arrive a different value which could be 22%. So what is his risk- 9% or 22% or any of the multitude of other numbers that we could construct in a similar manner.
That type of consideration led the imminent German statistical theorist, Richard Von Mises to say in his book " Probability,Statistics and Truth" that it is only possible to speak of probability in terms of a collective (or in more modern terms -a set or a group) and that to say, for example, that a given person has the probability o.10 of dying in the next year is nonsense. Yet, isn't this is exactly what we do when we we punch in a person's numbers into the Framingham equation and announce to the patient that his risk of a hard cardiac event in the next 10 years is 9%.
Could we not "fine tune" the risk assessment process by having a data base such as the Framingham data base but with more factors added on that seem to correlate with cardiac events, for example c-reactive protein, stress test results etc? It would seem so. However, even though Wang et al did that type of analysis the resultant increase in predictive value was not great and the flurry of letters to the editor with various statistical arguments might leave many of us with our heads spinning.The deterministic view would lead us to try and do this fine tuning to more accurately advise the patient on what to do in spite of the fact there will be residual uncertainty even as we add on other risk factor measurements. But we are still not measuring the individual's risk, we may have made the coarse grain data somewhat more fine, but the risk measurement is a conceptually different entity that the answer we obtain we measure some one's blood sugar or P-R interval.
We are still looking at the incidence or risk of an event in a group of patients sharing a certain set of characteristics as the patient of interest and calling the incidence or risk of that event in the group the individual patient's risk.
Probability theory is obviously a sine qua non of medical science and the evidence we use but we when we speak of a patient's probability or risk of developing a given disease as opposed the risk or attack rate of disease in a group we realize how-in Goodman's words- "ambiguous and elusive" that concept is.
So, it is with less that bubbling-over enthusiasm that I react to the ACP recommendation for individual risk assessment in regard to recommendations for mammogram screening, particularly when the risk equations based on the Gail Model seem to be little better than a coin flip according to their own review.
The ACP guidelines say :
"...the Gail model accurately predicts the number of cases of breast cancer that will develop in a given population but is much less accurate in determining which individual women will develop breast cancer"
My contention is that that the panel misunderstands the conceptual difference between the group prediction and the individual patient prediction.It is not just a matter of being "more accurate" in the former case, it is that in the individual case, the meaning of the term "risk" is unclear and that the activity only really makes sense in the case of the population. Goodman's article explains how at one time "chance" and "probability" were different concepts, the former referencing random events and the latter term used to denote a degree of belief applied to situations believe to be unique as in the expression of an opinion as to whether a claim was consistent with the supporting evidence.
When we see Mrs.Jones in the office, it is the case that she will or will not develop breast cancer over her lifetime. It may be that we are fooling ourselves as much as Mrs. Jones when we tell her what her "risk" is.
Wednesday, April 04, 2007
"The more things change"- "debate" on mammograms for age 40-49
Med Page Today gives a good summary of the some of the issues re-raised by recent recommendations of the American College of Physicians (ACP) regarding mammograms for women aged 40-49.
The ACP recommendations are contrary to those of the American Cancer Society, the American College of Obstetrics and Gynecology and even the USPSTF,an organization not known to be the first one to recommend anything.
The ACP committee seems to be saying rather than making a blanket recommendation for all women 40-49 to get annual or every other year mammogram that the woman should discuss the benefits and risks her physician. They suggest that the woman's individual risk be determined. They argue that the benefits-they seem to admit there are mortality benefits-are less than for older women and the risks ( mainly of false positives) are greater in the younger women and therefore a blanket recommendation is not appropriate.The ACP committee seems to have considerable faith in this individual risk assessment process even though there is no evidence that that approach is -in any way-superior to the blanket recommendation approach.
In my experience, in men with false positive PSA values and in women with suspicious findings on a mammogram that subsequently are demonstrated to be a false positive, the response almost always seems to be "thank goodness it wasn't cancer". Further, those folks almost always continue with their periodic screening.
I suspect that the ACP article will not change the practice of many primary care doctors for at least some of the following reasons:
The consensus of recommendation-making organizations is for routine screening.
Assessment of individual risk is very inexact and limited-most women with breast cancer do not have one of the traditional risk factors. Actually, I think it is worse than that and I have blogged about that issue before.
Discussions about risk is never easy and with the limited time physicians now have with each patient the logistics virtually prohibit a meaningful exchange,at least outside of a retainer practice.
The big elephant in the exam room is the issue of malpractice.Missed diagnosis of breast cancer is a major cause of malpractice suits. Who wants to be guilty of discouraging a mammogram ? "Doctor, were you not aware of the American Cancer Society's guidelines?"
It is interesting that everyone (ACP committee and all of the above mentioned groups) believe that for women fifty and over the data firmly indicate that the benefits of screening annually out weighs the risk. ACP and others have argued that the data for women 40-49 indicates a smaller mortality benefit and a greater risk so an individual risk assessment makes sense for the over 40 under 50 group. So a woman at fifty enters into a time when the doubt vanishes? The age grouping is arbitrary,statisticians could have as easily analyzed data in the age groups 44-53, 54-63 etc. There is no biological basis for believing that somehow things change at fifty. Risk assessment for a 54 year old woman without any of the generally recognized risk factors is just as imprecise and obscure as it is for a 46 year old woman. One has to weigh by some mysterious calculus the likelihood of cancer being detected by the test and cured by early treatment against the likelihood of having a false positive test leading to some measurable degree of anxiety and angst plus some unknown risk of detecting a type or subtype of breast cancer that didn't need to be treated anyway( if there is in fact such a thing). Try doing that in a 15 minute visit already filled with other important issues to discuss.
The ACP recommendations are contrary to those of the American Cancer Society, the American College of Obstetrics and Gynecology and even the USPSTF,an organization not known to be the first one to recommend anything.
The ACP committee seems to be saying rather than making a blanket recommendation for all women 40-49 to get annual or every other year mammogram that the woman should discuss the benefits and risks her physician. They suggest that the woman's individual risk be determined. They argue that the benefits-they seem to admit there are mortality benefits-are less than for older women and the risks ( mainly of false positives) are greater in the younger women and therefore a blanket recommendation is not appropriate.The ACP committee seems to have considerable faith in this individual risk assessment process even though there is no evidence that that approach is -in any way-superior to the blanket recommendation approach.
In my experience, in men with false positive PSA values and in women with suspicious findings on a mammogram that subsequently are demonstrated to be a false positive, the response almost always seems to be "thank goodness it wasn't cancer". Further, those folks almost always continue with their periodic screening.
I suspect that the ACP article will not change the practice of many primary care doctors for at least some of the following reasons:
The consensus of recommendation-making organizations is for routine screening.
Assessment of individual risk is very inexact and limited-most women with breast cancer do not have one of the traditional risk factors. Actually, I think it is worse than that and I have blogged about that issue before.
Discussions about risk is never easy and with the limited time physicians now have with each patient the logistics virtually prohibit a meaningful exchange,at least outside of a retainer practice.
The big elephant in the exam room is the issue of malpractice.Missed diagnosis of breast cancer is a major cause of malpractice suits. Who wants to be guilty of discouraging a mammogram ? "Doctor, were you not aware of the American Cancer Society's guidelines?"
It is interesting that everyone (ACP committee and all of the above mentioned groups) believe that for women fifty and over the data firmly indicate that the benefits of screening annually out weighs the risk. ACP and others have argued that the data for women 40-49 indicates a smaller mortality benefit and a greater risk so an individual risk assessment makes sense for the over 40 under 50 group. So a woman at fifty enters into a time when the doubt vanishes? The age grouping is arbitrary,statisticians could have as easily analyzed data in the age groups 44-53, 54-63 etc. There is no biological basis for believing that somehow things change at fifty. Risk assessment for a 54 year old woman without any of the generally recognized risk factors is just as imprecise and obscure as it is for a 46 year old woman. One has to weigh by some mysterious calculus the likelihood of cancer being detected by the test and cured by early treatment against the likelihood of having a false positive test leading to some measurable degree of anxiety and angst plus some unknown risk of detecting a type or subtype of breast cancer that didn't need to be treated anyway( if there is in fact such a thing). Try doing that in a 15 minute visit already filled with other important issues to discuss.
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