In the October 26,2006 issue of the New England Journal of Medicine we find a clinical study and an editorial about lung cancer screening using CT which should rekindle the decades old arguments about this topic. ( Survival of Patients with stage I Lung Cancer detected on CT Screening, NEJM 355;17, p. 1763). So high profile are NEJM articles with pickup and amplification by the news media that I will not be surprised when smokers and possibly folks who worked around asbestos and possibly other lung carcinogens will be asking their physicians for chest CTs. A brief review of the current study is found here.
A convincing advocate of the value of imaging screening for early lung cancer has been Dr. Gary M. Strauss. Some of his views can be found here. When we talk about screening we have to talk about the difference between survival rate and mortality rate.The latter is defined as the total number of deaths from the disease in question divided by total number tested. Survival rate is defined as numbers of survivors after some time period divided by total number diagnosed with cancer. If the screening technique were to detect significant numbers of indolent cancers then the survival rate might appear to be improved after the institution of the screening test while the mortality rate might be unchanged. Prostate cancer screening with periodic PSA measurements is sometimes accused of being an example of that. After spending a few decades in the pulmonary disease business I was not impressed with the large number of indolent or clinically insignificant lung cancers.Every pulmonary doctor remembers the occasional case of cured lung cancer that happened to fortunately be detected by a chest xray done for whatever reason. The coin lesions (less than 3 cm by definition) have a much higher cure rate than lung cancers as a whole. All of that leads to the intuitive appeal l (or maybe just hope) that if we could come up with a way to catch lung cancer early the current rather dismal survival rate of lung cancer would improve.
Conventional wisdom contains the nugget that in regard to screening one should use the cause specific mortality as a measure of efficacy not the survival over a given time period.. Strauss has taken the opposite view. More of his thoughts can be found here and here and here.
This brings us to the current study,I-ELCAP aka The International EarlyLung cancer Action Program. It is survival rates that are emphasized in this study (so the issue of lead time bias has to be raised) and the numbers seem impressive. The study is very large with over 31,000 asymptomatic persons at risk of lung cancer being screening with low dose spiral CT and then evaluated with a detailed protocol that utilized followup CTs, PET scans and skinny needle biopsy. They report a "estimated 10-year survival of 88% in the subgroup with clinical stage I lung cancer"
A great deal has happened since the early chest x-ray lung cancer screening projects. We have spiral CT, PET scans and skinny needle biopsies.Perhaps we can now detect lungs cancer early enough (that is small enough?) to remove them while they is still time. Before I reviewed the article I had assumed they were talking about non-small cell cancers (NSCLC) since the small cell variety seems to be another animal entirely. However, no mention is made on survival for each cell type or any indication that they were managed differently and there were 7 small cell cancers detected on the annual screening.Were they resected also? Is it possible that we can actually detect and remove small cell lung cancers that are so early they have not spread? In fact, there are some data indicating long term survival for small cell lung cancers treated with resection.
Thursday, October 26, 2006
Friday, October 20, 2006
"Marketing strategies masquerading as Evidence Based Medicine"
A commentary appears in the October 19,2006 issue of the New England Journal of Medicine regarding allegations about the length to which a drug company will go in influencing patient care by misleading physicians and improperly manipulating the creation of treatment guidelines. The commentary in the Perspective section is entitled " Surviving Sepsis-Practice Guidelines, Marketing Campaigns, and Eli Lilly".The authors are all from the Critical Care Medicine Department at NIH. A summary of their article can be found on the October 19 post on Health Care Renewal.
Xigris (drotrecogin, aka recombinant human activated protein C,rhPAC) is the drug, Lilly is the drug company and the condition for which treatment guidelines were said to be manipulated is sepsis. I have been concerned for some time about the degree to which Big Pharma have used ( and mis- used) the concepts of evidence based medicine to promote various medications but if the commentary accurately reflects reality this example rivals or even exceeds the gabapentin story.
This NEJM article and an earlier article in the Annals of Internal Medicine dealing with gabapentin and the disreputable techniques used to market it ( I posted about it here ) should be mandatory reading for medical students and included in the reading lists of med school courses on EBM and how EBM can be kidnapped and exploited . If the situation is, in fact, as described in the NEJM commentary, egregious is not strong enough an adjective for that type behavior. But "If" is the operative word. For a thoughtful counterpoint to the NEJM commentary to to the Oct 22, 2006 post by Dr. RW. He reminds us that criticism of guidelines or for that matter any treatment should not be based simply on the fact that a drug company may have used various techniues to promote it but should be based on logic and reference to solid evidence and in his analysis of the NEJM article the authors from the NIH fall short in that category.
No one is shocked by the fact that businesses not infrequently promote their goods or services by emphasizing the advantages and minimizing the downside of their products. However, if and when that spin puts patients well being or lives at risk I believe we move past "mere" unethical behavior. There is little room for error in the treatment of sepsis patients and underplaying or ignoring the risk of hemorrhage from activated protein C (Xigris) could well lead to patient fatalities. (The authors assert that the risk of bleeding was not properly noted in the promotional material generated for Xigris). To withhold information about serious side effects from a medication and promote its use by deceptive means included sponsoring guidelines may well move past negligence as well.
There is more .Go to the October 20,2006 post from Health Care Renewal for expression of concern about the role another drug company, Amgen, played in the development of guidelines for uses of Epogen in renal failure.
I do not know if and/or to what degree the experts who authored the two guidelines mentioned above were actually improperly influenced by the drug companies' activities and/or recommended treatments for which the evidence was insufficient but the perception that guidelines might be "usurped ...for commercial purposes" has to make physicians even more skeptical of guidelines in general particularly with such a commentary in a high impact journal. Further, when you consider the uses to which guidelines are put,including quality audits,pay for performance,arguments in legal proceedings it becomes even more important that we know how the sausages are made. And as the NEJM article asserts Xigris does seem to have found its way into performance standards even though I believe it is fair to say that the jury is still out ( or should be) regarding its efficacy and safety.
Xigris (drotrecogin, aka recombinant human activated protein C,rhPAC) is the drug, Lilly is the drug company and the condition for which treatment guidelines were said to be manipulated is sepsis. I have been concerned for some time about the degree to which Big Pharma have used ( and mis- used) the concepts of evidence based medicine to promote various medications but if the commentary accurately reflects reality this example rivals or even exceeds the gabapentin story.
This NEJM article and an earlier article in the Annals of Internal Medicine dealing with gabapentin and the disreputable techniques used to market it ( I posted about it here ) should be mandatory reading for medical students and included in the reading lists of med school courses on EBM and how EBM can be kidnapped and exploited . If the situation is, in fact, as described in the NEJM commentary, egregious is not strong enough an adjective for that type behavior. But "If" is the operative word. For a thoughtful counterpoint to the NEJM commentary to to the Oct 22, 2006 post by Dr. RW. He reminds us that criticism of guidelines or for that matter any treatment should not be based simply on the fact that a drug company may have used various techniues to promote it but should be based on logic and reference to solid evidence and in his analysis of the NEJM article the authors from the NIH fall short in that category.
No one is shocked by the fact that businesses not infrequently promote their goods or services by emphasizing the advantages and minimizing the downside of their products. However, if and when that spin puts patients well being or lives at risk I believe we move past "mere" unethical behavior. There is little room for error in the treatment of sepsis patients and underplaying or ignoring the risk of hemorrhage from activated protein C (Xigris) could well lead to patient fatalities. (The authors assert that the risk of bleeding was not properly noted in the promotional material generated for Xigris). To withhold information about serious side effects from a medication and promote its use by deceptive means included sponsoring guidelines may well move past negligence as well.
There is more .Go to the October 20,2006 post from Health Care Renewal for expression of concern about the role another drug company, Amgen, played in the development of guidelines for uses of Epogen in renal failure.
I do not know if and/or to what degree the experts who authored the two guidelines mentioned above were actually improperly influenced by the drug companies' activities and/or recommended treatments for which the evidence was insufficient but the perception that guidelines might be "usurped ...for commercial purposes" has to make physicians even more skeptical of guidelines in general particularly with such a commentary in a high impact journal. Further, when you consider the uses to which guidelines are put,including quality audits,pay for performance,arguments in legal proceedings it becomes even more important that we know how the sausages are made. And as the NEJM article asserts Xigris does seem to have found its way into performance standards even though I believe it is fair to say that the jury is still out ( or should be) regarding its efficacy and safety.
Thursday, October 19, 2006
Basis for "Treat to goal" for cholesterol is questioned by Annals Internal Medicine review
A thought provoking-and in a way troubling review- in the October 3, 2006 issue of the Annals of Internal Medicine ( "Lack of Evidence for recommended Low-density Lipoprotein treatment Target: A solvable Problem" by R.A. et al Haywood) was highlighted on October 17,2006 by DB's Medical Rants and by MEDPUNDIT. It questions the evidentiary basis of NCEP's 2004 "treat to goal" set of recommendations. Haywood's article is instructive because of the thoughtful analysis of the data linking cholesterol level and response to statin therapy and outcome and troublesome because it raises doubt about the validity of adherence to the NCEP recommendations of treating to goal. I 'll have to admit that I accepted those targets as a reasonable thing to do leading to at times increasing the statin dose and sometimes adding ezetimibe. In 2004, the NCEP expert panel recommended that physicians treat patients at what they designate at "very high risk" for coronary events to achieve a LDL cholesterol of less than 70 and for those patients judged to be at " high risk" a value of less than 100.
The review's major point is this:
High quality data is lacking to provide basis for the recommendation to titrate lipid lowering therapy to LDL targets or to prove that such therapy is superior to simply prescribing doses of statin drugs used in the clinical trials for patients at high and very high cardiovascular risk.
It should be noted that the authors are quick to point out that they are not saying that there is strong evidence against the current recommendations.
The reply from Dr.Scott Grundy and the NCEP folks likely will be interesting. (I assume they have to reply to this). As thoughtful as this article is you have to wonder how much of an impact it will have.The cardiologists and a number of primary care doctors seemed to have accepted the lower goals rather widely and that concept may be a hard one to get back into the barn. At this point I do not know if we should try to or not.
The review's major point is this:
High quality data is lacking to provide basis for the recommendation to titrate lipid lowering therapy to LDL targets or to prove that such therapy is superior to simply prescribing doses of statin drugs used in the clinical trials for patients at high and very high cardiovascular risk.
It should be noted that the authors are quick to point out that they are not saying that there is strong evidence against the current recommendations.
The reply from Dr.Scott Grundy and the NCEP folks likely will be interesting. (I assume they have to reply to this). As thoughtful as this article is you have to wonder how much of an impact it will have.The cardiologists and a number of primary care doctors seemed to have accepted the lower goals rather widely and that concept may be a hard one to get back into the barn. At this point I do not know if we should try to or not.
Wednesday, October 11, 2006
More bad news regarding second generation antipsychotics.
The October 12, 2006 issue of The New England Journal of Medicine published an article regarding the use of the second generation antipsychotic drugs (SGAs) in the management of aggression and agitation and psychotic behavior in dementia. These drugs are widely used for this application although it is not approved (by the FDA) for that use and in fact there is a "black box" warning regarding increased risk of death in older patients with dementia.
Three drugs were compared with placebo in 421 patients in a multi center study; 1) olanzapine (Zyprexa), 2) risperidone (Risperdal) and 3)quetipine (Seroquel).
This trial differed from the typical efficacy-safety RCT done by drug companies as it looked at a "real clinical life" end point of time of discontinuing the medication because of any reason. The other primary outcome was the number of patients who had a minimal improvement a clinical behavior scale.
The authors concluded that the three drugs were more effective than placebo but the incidence of side effects limited their use. As seems to be more and more the case in clinical trials, there are so many comparisons made and often with rather arcane statistical tools it is difficult to know what to conclude. For example, Zyprexa was significantly better than placebo with the "Cox model" but not when compared with placebo with the "Hockberg adjustment" for multiple comparisons.Apparently this adjustment is an alternative to the Bonferroni technique to decrease the number of "false positives" when multiple comparisons are made. But how do you decide which technique to use-in this case the resultant answers seems 180 degrees apart.
Although the headline news- sound bites about this article may claim these drugs were useless, that characterization seems too simple.They can help control the symptoms of interest but often have to be discontinued because of side effects . Even the authors seems a bit ambivalent in their comments about the results;
"...our findings suggest that there is no large clinical benefit of treatment with atypical antipsychotic medications as compared with placebo."
They also say:
"Although the atypical antipsychotic drugs were more effective than placebo, adverse effects limited their overall effectiveness."
My take on all of this is these drugs may help a bit in the control of agitation and aggression in dementia patients but in a significant number of patients side effects lead to their discontinuation. Certaintly the exuberant enthusiasm driven in no small measure by drug company hype is waning. These drugs are not nearly as good as the efforts to promote them suggested. It would have been interesting and perhaps instructive for Haldol to have been included in the drugs that were compared in this study as for years it has been the stand by drug in difficult situations with dementia patients with aggressive behavior.
Three drugs were compared with placebo in 421 patients in a multi center study; 1) olanzapine (Zyprexa), 2) risperidone (Risperdal) and 3)quetipine (Seroquel).
This trial differed from the typical efficacy-safety RCT done by drug companies as it looked at a "real clinical life" end point of time of discontinuing the medication because of any reason. The other primary outcome was the number of patients who had a minimal improvement a clinical behavior scale.
The authors concluded that the three drugs were more effective than placebo but the incidence of side effects limited their use. As seems to be more and more the case in clinical trials, there are so many comparisons made and often with rather arcane statistical tools it is difficult to know what to conclude. For example, Zyprexa was significantly better than placebo with the "Cox model" but not when compared with placebo with the "Hockberg adjustment" for multiple comparisons.Apparently this adjustment is an alternative to the Bonferroni technique to decrease the number of "false positives" when multiple comparisons are made. But how do you decide which technique to use-in this case the resultant answers seems 180 degrees apart.
Although the headline news- sound bites about this article may claim these drugs were useless, that characterization seems too simple.They can help control the symptoms of interest but often have to be discontinued because of side effects . Even the authors seems a bit ambivalent in their comments about the results;
"...our findings suggest that there is no large clinical benefit of treatment with atypical antipsychotic medications as compared with placebo."
They also say:
"Although the atypical antipsychotic drugs were more effective than placebo, adverse effects limited their overall effectiveness."
My take on all of this is these drugs may help a bit in the control of agitation and aggression in dementia patients but in a significant number of patients side effects lead to their discontinuation. Certaintly the exuberant enthusiasm driven in no small measure by drug company hype is waning. These drugs are not nearly as good as the efforts to promote them suggested. It would have been interesting and perhaps instructive for Haldol to have been included in the drugs that were compared in this study as for years it has been the stand by drug in difficult situations with dementia patients with aggressive behavior.
Sunday, October 08, 2006
Answering services should not make it hard to talk to physician
A recent article in the September/October issue of the Journal of the American Board of Family Practice by David Hildebrandt called attention to an issue with some answering services techniques that serve to prevent patients from contacting their physicians. By simply being asked "Is this an emergency?", many contacts with the physician are eliminated. Patients often call their doctor because they do not know if the issue is serious enough to be considered an emergency or not. This "filtering" technique does not serve the interests of the patient.Procedural barriers limiting contact with doctors cannot be in the physicians' s best interests either.
The survey admittedly was small, only 35 physicians offices were contacted and of those 14 used answering services and 9 of those asked the patients to decide if their call should be fowarded to the doctor. The small sample size precludes robust conclusions about how widespread the practice might be. An larger earlier study by the same lead author involved 91 primary care offices and in 55 the answering services "forced" the patients to decide if it was an emergency requiring a call back from the physician. Clearly ,this is not a good practice but I have encountered worse. I have attempted to contact physicians after hours, and sometimes on Friday afternoon and been unable to contact them at all or anyone providing coverage. The answering machine-not even a human- informs the caller what the office hours are and that if they have an emergency they should go to the nearest emergency room.
Another approach is the nurse telephone triage. While this is better I have some uneasy feeling about this as well. When you get old and cranky you tend to think if things are not done like you did them they are off base. When I was in private practice all calls were referred by the answering service to either the patient's physician or the on call doctor.
Dr. Bruce Bagley,the medical director for quality at the American Academy of Family Physicians, is quoted in the American Medical News story about the article:
"You want the highest level clinical person determining what's an emergency, not a person at an answering service who knows nothing from nothing."
The survey admittedly was small, only 35 physicians offices were contacted and of those 14 used answering services and 9 of those asked the patients to decide if their call should be fowarded to the doctor. The small sample size precludes robust conclusions about how widespread the practice might be. An larger earlier study by the same lead author involved 91 primary care offices and in 55 the answering services "forced" the patients to decide if it was an emergency requiring a call back from the physician. Clearly ,this is not a good practice but I have encountered worse. I have attempted to contact physicians after hours, and sometimes on Friday afternoon and been unable to contact them at all or anyone providing coverage. The answering machine-not even a human- informs the caller what the office hours are and that if they have an emergency they should go to the nearest emergency room.
Another approach is the nurse telephone triage. While this is better I have some uneasy feeling about this as well. When you get old and cranky you tend to think if things are not done like you did them they are off base. When I was in private practice all calls were referred by the answering service to either the patient's physician or the on call doctor.
Dr. Bruce Bagley,the medical director for quality at the American Academy of Family Physicians, is quoted in the American Medical News story about the article:
"You want the highest level clinical person determining what's an emergency, not a person at an answering service who knows nothing from nothing."
Friday, October 06, 2006
Is Merck gearing up for "son of Vioxx"?
The editorial commentary by David Graham in the October 4,2006 issue of the Journal of the American Medical Association ("COX-2 Inhibitors,other NSAIDs and cardiovascular Risk,The seduction of Common Sense" vol. 296,no 13 p 1653) is very critical in regard to both Merck and the FDA. If Dr. Graham's analysis is correct Merck is already cooking the books to get a Vioxx like drug approved by the FDA. Admittedly, this is Dr. Graham's analysis of the pre-approval activities of Merck and their version of those activities is likely to differ significantly from his comments and for those we will have to wait a while.
Here is what he said- Merck has announced they will proceed to get approval for etoricoxib,a new COX-2 inhibitor. They will rely , in part, on the results of the MEDAL trial in which etoricoxib was compared with diclofenac and found to demonstrate that the cardiovascular event risk was the same with either medication using a "noninferiority study" design, which according to Graham, is "especially poor" at identifying risk between drugs. Further, the comparator drug was diclofenac which apparently has been associated with an increased risk of c-v events. By inference, he argues etoricoxib must also increase c-v risk.
Graham then says;
"This veiled and misleading ambiguity has much in common with the stratagems used by VIGOR and APPROVe,where the true results were opposite to those claimed and promoted."
There are two articles regarding COX-2 inhibitors in the same issue, one of which demonstrates an increased risk of cardiovascular events with diclofenac.One is a meta-analysis of randomized clinical trials (RCTs) dealing with renal effects and cardiac rhythm problems and the other a systematic analysis of observational studies. It is the latter which provides the following:
The relative risks (RR) of cardiovascular events is elevated with lower and higher doses of celecoxib-1.33 for the 25 mg/day dose and 1.64 for the greater than 25 mg /day dose.
The highest RR reported is with diclofenac at 1.50 while no increased risk is noted with naproxen and ibuprofen but idomethacin's RR is increased at 1.36.(Ref.Cardiovascular Risk and Inhibition of Cyclooxygenase,McGettigen P and Henry,D JAMA vol 296,no 13,p 1633)
The authors make an important comment :
"Typically, in pharmacoepidemiological studies there is reluctance to accept as causal RR estimates much below 2" This is because this type of study is subject to various biases but, predictably, the authors still believe the demonstrated association "are real". (When do authors not believe what they find is true?)
Here is a related quote form David Sackett et al in their second edition of "Evidence Based Medicine" (Churchhill Livingstone reprinted 2001, p.163)
"How Big should relative risk and odds ratios be before we should be impressed by them? ....We might not want to label an odds ratio from a case-control study as impressive unless it is greater than 4...in cohort studies..we might regard a relative risk of greater than 3 as convincing for more serious adverse events"
This systematic analysis utilized data from both case control and cohort studies so somewhere between 3 and 4 might be the threshold for concern according to the Canadian gurus of Evidence based medicine and these were all under 2.
Even though one can argue about causality and relative risk level this issue of JAMA will do little to encourage the use of COX-2 drugs. Graham's suggestion of using naproxen (or ibuprofen) plus a proton pump inhibitor (PPI) as an alternative makes sense and is what I was recommending for the last several years.
Here is what he said- Merck has announced they will proceed to get approval for etoricoxib,a new COX-2 inhibitor. They will rely , in part, on the results of the MEDAL trial in which etoricoxib was compared with diclofenac and found to demonstrate that the cardiovascular event risk was the same with either medication using a "noninferiority study" design, which according to Graham, is "especially poor" at identifying risk between drugs. Further, the comparator drug was diclofenac which apparently has been associated with an increased risk of c-v events. By inference, he argues etoricoxib must also increase c-v risk.
Graham then says;
"This veiled and misleading ambiguity has much in common with the stratagems used by VIGOR and APPROVe,where the true results were opposite to those claimed and promoted."
There are two articles regarding COX-2 inhibitors in the same issue, one of which demonstrates an increased risk of cardiovascular events with diclofenac.One is a meta-analysis of randomized clinical trials (RCTs) dealing with renal effects and cardiac rhythm problems and the other a systematic analysis of observational studies. It is the latter which provides the following:
The relative risks (RR) of cardiovascular events is elevated with lower and higher doses of celecoxib-1.33 for the 25 mg/day dose and 1.64 for the greater than 25 mg /day dose.
The highest RR reported is with diclofenac at 1.50 while no increased risk is noted with naproxen and ibuprofen but idomethacin's RR is increased at 1.36.(Ref.Cardiovascular Risk and Inhibition of Cyclooxygenase,McGettigen P and Henry,D JAMA vol 296,no 13,p 1633)
The authors make an important comment :
"Typically, in pharmacoepidemiological studies there is reluctance to accept as causal RR estimates much below 2" This is because this type of study is subject to various biases but, predictably, the authors still believe the demonstrated association "are real". (When do authors not believe what they find is true?)
Here is a related quote form David Sackett et al in their second edition of "Evidence Based Medicine" (Churchhill Livingstone reprinted 2001, p.163)
"How Big should relative risk and odds ratios be before we should be impressed by them? ....We might not want to label an odds ratio from a case-control study as impressive unless it is greater than 4...in cohort studies..we might regard a relative risk of greater than 3 as convincing for more serious adverse events"
This systematic analysis utilized data from both case control and cohort studies so somewhere between 3 and 4 might be the threshold for concern according to the Canadian gurus of Evidence based medicine and these were all under 2.
Even though one can argue about causality and relative risk level this issue of JAMA will do little to encourage the use of COX-2 drugs. Graham's suggestion of using naproxen (or ibuprofen) plus a proton pump inhibitor (PPI) as an alternative makes sense and is what I was recommending for the last several years.
Thursday, October 05, 2006
Second generation antipsychotics-efficacy versus effectiveness
In the 1960s, the phenothiazines changed the face of psychiatry when chlorpromazine was shown to be effective treatment for schizophrenia. These first generation antipsychotics (FGAs) are associated with major side effects-namely acute extrapyramidal symptoms and tardive dyskinesia. So when the first of the second generation antipsychotics(SGAs),clozapine,was approved by the FDA and it seemed to be less likely to cause these very troublesome side effects another new era in psychiatric therapeutics seemed to be launched. Other SGAs were developed and approved and were widely accepted and generally believed to not only be more efficacious regarding the so-called negative symptoms of schizophrenia but safer and capable of inducing a better quality of life.The evidence that clozapine did in fact produce superior results in symptom reduction in patients resistant to other drugs is convincing: the question seems to be are the other drugs (five have been approved in the last ten years) in the second generation category also superior.
In 2005 and 2006, two clinical trials (CATIE and CUtLASS1) were published which have raised considerable doubt about the alleged superiority of these SGAs. (Thanks to PHARMAGOSSIP for the reference.)
Dr. Jeffery Lieberman from Columbia Psychiatry Department published an excellent commentary on this issue and his article is available on line full text from the AMA site (go to "Newsroom" and then to "Publications" for the comments found in the October 2006 issue of the Archives of General Psychiatry.Also full text free links to the Studies are found in his reference list)
The issue of the relative value of the FGAs and the SGAs is important per se.Dr. Lieberman's comments not only address that but also the broader issue which can be stated as follows:
How can the following happen-A medication is approved by the FDA based on Phase 2 and Phase 3 RCTs, becomes widely accepted largely replacing the older drugs with that application and then following more Scrutiny and analysis is found to not be any better than the drug(s) it replaced?
He suggests two reasons"
1.The traditional efficacy-effectiveness gap. Things do not always work out the same in the helter-skelter world of clinical medicine as they do in the sometimes cherry picked world of randomized clinical trials. The second Gaultian axiom of evidence based medicine is that "Treatments do not work as well in the clinical practice as they do in randomized trials and they cause more problems".(The first axiom is "The basic fact of clinical trials is that everyone does not respond the same to a particular treatment and almost no one has the average effect")
2.Claims of a drug's superiority were "greatly exaggerated". Drug company hype and overt and sometimes covert promotional activities certainly play a role as does (and this is my contribution to that reason) the sincere desire of physicians to be able to have better tools and be better able to treat their patients. In other words, docs yearn for better drugs and sometimes overlook the weakness of the evidence that is presented.
There will be much more written about whether FGA or SGA are better or safer and neither Dr. Lieberman nor I claim to have the final word.But if there is a lesson here I think it is that because of the efficacy-effectiveness gap a RCT (or even several RCTs) is/are just the beginning of the process of deciding what to do for a given patient; it is not the determining factor and we often cannot really judge the value of a given treatment until there is enough real world clinical experience to see how it really works.
In 2005 and 2006, two clinical trials (CATIE and CUtLASS1) were published which have raised considerable doubt about the alleged superiority of these SGAs. (Thanks to PHARMAGOSSIP for the reference.)
Dr. Jeffery Lieberman from Columbia Psychiatry Department published an excellent commentary on this issue and his article is available on line full text from the AMA site (go to "Newsroom" and then to "Publications" for the comments found in the October 2006 issue of the Archives of General Psychiatry.Also full text free links to the Studies are found in his reference list)
The issue of the relative value of the FGAs and the SGAs is important per se.Dr. Lieberman's comments not only address that but also the broader issue which can be stated as follows:
How can the following happen-A medication is approved by the FDA based on Phase 2 and Phase 3 RCTs, becomes widely accepted largely replacing the older drugs with that application and then following more Scrutiny and analysis is found to not be any better than the drug(s) it replaced?
He suggests two reasons"
1.The traditional efficacy-effectiveness gap. Things do not always work out the same in the helter-skelter world of clinical medicine as they do in the sometimes cherry picked world of randomized clinical trials. The second Gaultian axiom of evidence based medicine is that "Treatments do not work as well in the clinical practice as they do in randomized trials and they cause more problems".(The first axiom is "The basic fact of clinical trials is that everyone does not respond the same to a particular treatment and almost no one has the average effect")
2.Claims of a drug's superiority were "greatly exaggerated". Drug company hype and overt and sometimes covert promotional activities certainly play a role as does (and this is my contribution to that reason) the sincere desire of physicians to be able to have better tools and be better able to treat their patients. In other words, docs yearn for better drugs and sometimes overlook the weakness of the evidence that is presented.
There will be much more written about whether FGA or SGA are better or safer and neither Dr. Lieberman nor I claim to have the final word.But if there is a lesson here I think it is that because of the efficacy-effectiveness gap a RCT (or even several RCTs) is/are just the beginning of the process of deciding what to do for a given patient; it is not the determining factor and we often cannot really judge the value of a given treatment until there is enough real world clinical experience to see how it really works.
Tuesday, October 03, 2006
The virtual doctor's lounge-the successor to the now defunct real lounge
I written before about the demise of the doctor's lounge in the hospital-the previous site of free coffee, curb stone consultations, physician networking and the sharing of common shared interests and experiences and a chance to vent about whatever. My regular 4 or 5 readers will not be surprised that I blame this on managed care.
In a way, medical blogs have become a surrogate for this experience for physicians many of whom have significantly less face time with other physicians and according to one surgeon blogger even telephone time has become less common as more and more PAs and NPs are delegated the role of calling the consultant.
Today, for example, in this virtual lounge I learned useful information about neuropathic pain from Doctor RW and was reminded by DB about the importance of time in the context of taking it to explain prescription medication to your patients.Memories of 40 years ago were recharged by Dr. Schwab in his comments about the medical drama of a surgeon opening a chest in the emergency room. Medpundit gives me a chuckle when she relates what British soldiers in Iraq think of the British NHS when they claim they would rather get shot in the head and get to go to a great US military hospital or receive a less serious wound and end up in the NHS. As usual the pulmonary docs at their site present fascinating cases.
The medical web does provide some of what we had at the lounge (we can certainty vent 24-7) and in some ways much more in terms of connectivity with information but I think how great it would be if had both.Sitting down over coffee and discussing a difficult case with a respected colleague is something many of us miss.
In a way, medical blogs have become a surrogate for this experience for physicians many of whom have significantly less face time with other physicians and according to one surgeon blogger even telephone time has become less common as more and more PAs and NPs are delegated the role of calling the consultant.
Today, for example, in this virtual lounge I learned useful information about neuropathic pain from Doctor RW and was reminded by DB about the importance of time in the context of taking it to explain prescription medication to your patients.Memories of 40 years ago were recharged by Dr. Schwab in his comments about the medical drama of a surgeon opening a chest in the emergency room. Medpundit gives me a chuckle when she relates what British soldiers in Iraq think of the British NHS when they claim they would rather get shot in the head and get to go to a great US military hospital or receive a less serious wound and end up in the NHS. As usual the pulmonary docs at their site present fascinating cases.
The medical web does provide some of what we had at the lounge (we can certainty vent 24-7) and in some ways much more in terms of connectivity with information but I think how great it would be if had both.Sitting down over coffee and discussing a difficult case with a respected colleague is something many of us miss.
Friday, September 29, 2006
Price controls for physician services, the results are predictable
In the September 28, 2006 edition of DB's Medical Rants we find a great quote from Scapel entitled "Are all physicians equal?"
In one of the subsequent letters to Scapel we are correctly told that in the health care "market" prices are determined by a fairly small number of payers, e.g. CMS and the major insurers who follow CMS lead. In regard to physician's fees, there is -for the most part- price controls.Since insurers tend to duplicate CMS's fee structures we have in effect government price controls on physician fees.
(I realize there are a small minority of physicians who operate outside of this control system, for example some dermatologists who do mainly cosmetic work and the concierge practices)
I wrote about this issue before when I suggested an important addition to the medical school curriculum, namely a primer on basic real world economics.What happens when there are price controls is well recognized and repeatedly has been explained in great clarity by economists such as Thomas Sowell.Here are some of his comments on that subject.
Four things tend to happen when there are price controls:
1.Demand increases,there is increased use of the service or product (A recent example-see how long it takes to get in for a colonoscopy since Medicare began covering screening exams)
2.Supply decreases and shortages develop(with price controls in place, suppliers do not rush into that market and we are seeing that in the area of primary care, where fees are set the lowest, fewer medical graduates are opting for primary care specialties)
3.Quality decreases.(providers have little reason to try and differentiate themselves on the basis of quality because of 1 and 2 they have no need for new customers.They may try and make up for lower unit prices by increasing their volume of business, spending less time with each customer, etc.)
4.Black markets tend to develop.This apparently has not happened yet here but has in rigidly socialized countries.
To quote Sowell (from Applied Economics,Thinking Beyond Stage One,2004,Basic Books, p.93)
"All of these things have been found when the prices of medical care have been controlled-and all are particularly harmful in matters involving, pain ,disability and death".
In one of the subsequent letters to Scapel we are correctly told that in the health care "market" prices are determined by a fairly small number of payers, e.g. CMS and the major insurers who follow CMS lead. In regard to physician's fees, there is -for the most part- price controls.Since insurers tend to duplicate CMS's fee structures we have in effect government price controls on physician fees.
(I realize there are a small minority of physicians who operate outside of this control system, for example some dermatologists who do mainly cosmetic work and the concierge practices)
I wrote about this issue before when I suggested an important addition to the medical school curriculum, namely a primer on basic real world economics.What happens when there are price controls is well recognized and repeatedly has been explained in great clarity by economists such as Thomas Sowell.Here are some of his comments on that subject.
Four things tend to happen when there are price controls:
1.Demand increases,there is increased use of the service or product (A recent example-see how long it takes to get in for a colonoscopy since Medicare began covering screening exams)
2.Supply decreases and shortages develop(with price controls in place, suppliers do not rush into that market and we are seeing that in the area of primary care, where fees are set the lowest, fewer medical graduates are opting for primary care specialties)
3.Quality decreases.(providers have little reason to try and differentiate themselves on the basis of quality because of 1 and 2 they have no need for new customers.They may try and make up for lower unit prices by increasing their volume of business, spending less time with each customer, etc.)
4.Black markets tend to develop.This apparently has not happened yet here but has in rigidly socialized countries.
To quote Sowell (from Applied Economics,Thinking Beyond Stage One,2004,Basic Books, p.93)
"All of these things have been found when the prices of medical care have been controlled-and all are particularly harmful in matters involving, pain ,disability and death".
Tuesday, September 19, 2006
The DREAM study, Are we preventing or just delaying diabetes?
The results of the DREAM study have published in the NEJM (ramipril arm) and the Lancet ( rosiglitizone arm) . This trial will get a lot of press and in the eyes of cynical old docs like me a lot of spin. Fortunately, the eagle eyed and clear thinking world of medical bloging will have offer anti-spin or at the least an opinion a bit different from the pharm company's press releases ( see here and here ) and the repetition of some of it by main stream media .
DREAM was large randomized clinical trial involving patients with the label pre-diabetes ( impaired fasting glusoce and/or glucose intolerance) and the aim was to see if a TZD (thiazolidenedione) and/or an ace inhibitor would prevent the progression of pre diabetes to diabetes. The rosi group received daily rosiglitizone for 3 years plus education regarding diet and exercise and 11.6 % progressed to diabetes in 3 years versus 26% of the placebo group.In the rosi group 0.5% developed heart failure versus 0.1% in the placebo group.The ramipril trial was negative in the sense of no effect on the development of diabetes.
Here is how the study's authors framed things in the final paragraph of their discussion section-paraphrased- If you treat 1000 patients for three years with rosiglitizone, 144 cases of diabetes will be prevented and 5 will develop heart failure.
The problem I have with that is the use of the word "prevented". I take prevent to mean you will not develop a condition. In this situation I believe you are simply delaying what seems to be almost always the case in type 2 diabetes-and by extension pre-diabetes- progressive worsening of the glucose control. Here prevention seems to mean to "prevent" diabetes for three years. The data is just not sufficient to make the statement that diabetes has been prevented.To be able to say that you would need a really long follow up.
It is well known that TZDs can improve blood sugar control in diabetes and it is no surprise it could do the same in patients with early diabetes -or pre-diabetes-and it is also well known that they may cause fluid retention and heart failure. so I see nothing really new here except what I think is exaggerated talk about prevention.
The comments made after the Diabetes Prevention Trial( o.k., they called it prevention)were much more appropriately circumspect. That trial compared exercise plus diet, metformin and a control group all with glucose intolerance and over a 3 year period 29% of the control group , 22% of the metformin group and 14% of the exercise/diet group developed diabetes."We simply don't know how long beyond the 3 year period diabetes can be delayed " was the comment made by one of the study's authors. This is a study whose results I frequently discussed with overweight patient with borderline blood sugars in the hope of encouraging life style changes but I did not promise diabetes would be prevented.
DREAM was large randomized clinical trial involving patients with the label pre-diabetes ( impaired fasting glusoce and/or glucose intolerance) and the aim was to see if a TZD (thiazolidenedione) and/or an ace inhibitor would prevent the progression of pre diabetes to diabetes. The rosi group received daily rosiglitizone for 3 years plus education regarding diet and exercise and 11.6 % progressed to diabetes in 3 years versus 26% of the placebo group.In the rosi group 0.5% developed heart failure versus 0.1% in the placebo group.The ramipril trial was negative in the sense of no effect on the development of diabetes.
Here is how the study's authors framed things in the final paragraph of their discussion section-paraphrased- If you treat 1000 patients for three years with rosiglitizone, 144 cases of diabetes will be prevented and 5 will develop heart failure.
The problem I have with that is the use of the word "prevented". I take prevent to mean you will not develop a condition. In this situation I believe you are simply delaying what seems to be almost always the case in type 2 diabetes-and by extension pre-diabetes- progressive worsening of the glucose control. Here prevention seems to mean to "prevent" diabetes for three years. The data is just not sufficient to make the statement that diabetes has been prevented.To be able to say that you would need a really long follow up.
It is well known that TZDs can improve blood sugar control in diabetes and it is no surprise it could do the same in patients with early diabetes -or pre-diabetes-and it is also well known that they may cause fluid retention and heart failure. so I see nothing really new here except what I think is exaggerated talk about prevention.
The comments made after the Diabetes Prevention Trial( o.k., they called it prevention)were much more appropriately circumspect. That trial compared exercise plus diet, metformin and a control group all with glucose intolerance and over a 3 year period 29% of the control group , 22% of the metformin group and 14% of the exercise/diet group developed diabetes."We simply don't know how long beyond the 3 year period diabetes can be delayed " was the comment made by one of the study's authors. This is a study whose results I frequently discussed with overweight patient with borderline blood sugars in the hope of encouraging life style changes but I did not promise diabetes would be prevented.
Monday, September 18, 2006
NIH report on use of multi-vitamins-we just don't know
The September 5, 2006 issue of the Annals of Internal Medicine reports on a NIH Conference on the use of multivitamins/mineral supplements (MVMs) and chronic disease prevention.
Their conclusion:
...the present evidence is insufficient to recommend either for or against the use of MVMs by the American public to prevent chronic disease."
A major reason for the panel's inability to make a firm recommendation is the lack of randomized clinical trials.However, the panel interestingly also states that "multivitamin trials are unlikely to lead to generalizable knowledge".
This is because a distinction between the effects of the individual components is unlikely to be made for several reasons including 1)the placebo group is likely to take vitamins anyway, 2)a very large sample size would be required making funding and execution of the trial problematic and 3)results would be likely outdated as the composition of the commonly used MVMs tend to change. Further, there is reason to believe that some subgroups may benefit from a given component while another subgroup might be harmed.
So what are we hearing? We cannot say if MVMs should be taken by everyone to prevent chronic disease or cancer because of the lack of RCTs and it is unlikely that even if we could the related RCTs they probably would not answer the question anyway. Should we withhold judgment if there is no randomized trial directly addressing the issue? Are we unnecessarily limiting ourselves by punting every question if RCTs are not available? That does appear to be the modus operandi of the public health community and yet in that context there is justification for withholding judgment until the evidence is quite strong. To make policy decisions sound evidence is required. Individual physicians have to often make decisions with the data they have not the evidence they wished they had. Of course, physicians do not have to tell everyone what to do , just the patient on the other side of the desk.
Their conclusion:
...the present evidence is insufficient to recommend either for or against the use of MVMs by the American public to prevent chronic disease."
A major reason for the panel's inability to make a firm recommendation is the lack of randomized clinical trials.However, the panel interestingly also states that "multivitamin trials are unlikely to lead to generalizable knowledge".
This is because a distinction between the effects of the individual components is unlikely to be made for several reasons including 1)the placebo group is likely to take vitamins anyway, 2)a very large sample size would be required making funding and execution of the trial problematic and 3)results would be likely outdated as the composition of the commonly used MVMs tend to change. Further, there is reason to believe that some subgroups may benefit from a given component while another subgroup might be harmed.
So what are we hearing? We cannot say if MVMs should be taken by everyone to prevent chronic disease or cancer because of the lack of RCTs and it is unlikely that even if we could the related RCTs they probably would not answer the question anyway. Should we withhold judgment if there is no randomized trial directly addressing the issue? Are we unnecessarily limiting ourselves by punting every question if RCTs are not available? That does appear to be the modus operandi of the public health community and yet in that context there is justification for withholding judgment until the evidence is quite strong. To make policy decisions sound evidence is required. Individual physicians have to often make decisions with the data they have not the evidence they wished they had. Of course, physicians do not have to tell everyone what to do , just the patient on the other side of the desk.
Saturday, September 16, 2006
From the Annals of Internal Medicine:Oscar winners live longer-no,wait, maybe they don't
The September 2006 issue of the Annals of Internal Medicine published an article (Do Oscar Winners Live Longer than less Successful Peers? A reanalysis of the evidence.Sylvestre,Huszti,and Hanley.Annals Internal Medicine,vol.145, no. 5, p. 361) that contradicted an earlier Annals'article that claimed Oscar winners live longer than their fellow actors.The abstract is available online. Why does a respected medical journal bother itself with this issue anyway?
Subscription is required for the full text of the article and also for the important letter from two of the Annals editors, Steven Goodman, an epidemiologist whose work I have found very impressive and useful and Harold Sox the editor. The original paper was published 5 years ago and found-by one analysis-a 3.9 year increase in life expectancy in Oscar winners. Here the operative words appear to be "by one analysis". The results vary significantly based on the type of analysis used and the epidemiologists-statisticians are not in agreement on how to analyse the data.
The issue here, as explained by Goodman and Sox is "when to start the clock" in a situation wherein there is a sudden change in risk due some event. Such events could include starting a treatment and in that instance there would be considerable medical interest, certaintly more than Oscar winner' longevity. Starting the clock at the wrong time can trigger something called "the immortal time bias" ( also known as "time zero" problem) something I have posted about before in the context of COPD treatment.
One study demonstrated that inhaled corticosteroids (ICS) treatment increased survival in COPD but another analysis indicated that the survival advantage was not real but an example of the immortal time bias although the original authors denied that was the case. Just as in the Oscar winner longevity controversy there was disagreement if there was or was not a bias in the ICS data due to disagreements about the clock starting issue.
The Annals editorialists state their explanatory comments are published largely because "the analytic methods at issue apply to many health care research questions ."Apparently the statistical issue of how to handle the zero time issue is not settled as Goodman and Sox invite other members of the statistical fraternity to "take up the challenge of determining the most appropriate way to measure the effect of winning an Oscar and the statistical uncertainty around the results." Of course, their concern is not really with Oscar winners's longevity but with the application of these techniques to more therapeutically relevant medical studies.
How to analyze the evidence in evidence based medicine is still to a large degree a work in progress.
Subscription is required for the full text of the article and also for the important letter from two of the Annals editors, Steven Goodman, an epidemiologist whose work I have found very impressive and useful and Harold Sox the editor. The original paper was published 5 years ago and found-by one analysis-a 3.9 year increase in life expectancy in Oscar winners. Here the operative words appear to be "by one analysis". The results vary significantly based on the type of analysis used and the epidemiologists-statisticians are not in agreement on how to analyse the data.
The issue here, as explained by Goodman and Sox is "when to start the clock" in a situation wherein there is a sudden change in risk due some event. Such events could include starting a treatment and in that instance there would be considerable medical interest, certaintly more than Oscar winner' longevity. Starting the clock at the wrong time can trigger something called "the immortal time bias" ( also known as "time zero" problem) something I have posted about before in the context of COPD treatment.
One study demonstrated that inhaled corticosteroids (ICS) treatment increased survival in COPD but another analysis indicated that the survival advantage was not real but an example of the immortal time bias although the original authors denied that was the case. Just as in the Oscar winner longevity controversy there was disagreement if there was or was not a bias in the ICS data due to disagreements about the clock starting issue.
The Annals editorialists state their explanatory comments are published largely because "the analytic methods at issue apply to many health care research questions ."Apparently the statistical issue of how to handle the zero time issue is not settled as Goodman and Sox invite other members of the statistical fraternity to "take up the challenge of determining the most appropriate way to measure the effect of winning an Oscar and the statistical uncertainty around the results." Of course, their concern is not really with Oscar winners's longevity but with the application of these techniques to more therapeutically relevant medical studies.
How to analyze the evidence in evidence based medicine is still to a large degree a work in progress.
Thursday, September 14, 2006
No pens or mugs allowed from Big Pharma at Stanford
It has not gone unnoticed (whatever does) by the medical blogger world the irony or hypocrisy of Stanford's Medical School prohibiting the receipt of drug companies' pens and mugs (which are recognized to contain tiny and incredibly powerful mind-control devices) but continuing to allow faculty to be involved in numerous financial arrangements with drug and other medically related business entities. Free lunches and drug samples are also prohibited in their new policy but apparently faculty members can sit on boards of directors of drug and other medical businesses.
Multiple examples of the multiple conflicts of interests at Stanford was highlighted by Health Care Renewal 's Sept 14,2008 posting. No mention is made in the Stanford game plan to do away with the lucrative arrangements between faculty members Big Pharma and other medically related commercial enterprises. Standford's Dean Pizzo's video explaining the new policy can be found on their web site.
Multiple examples of the multiple conflicts of interests at Stanford was highlighted by Health Care Renewal 's Sept 14,2008 posting. No mention is made in the Stanford game plan to do away with the lucrative arrangements between faculty members Big Pharma and other medically related commercial enterprises. Standford's Dean Pizzo's video explaining the new policy can be found on their web site.
Sunday, September 10, 2006
FDA offers recipe for proper mixing of aspirin and ibuprofen
Aspirin is widely used to decrease the risk of heart attacks. It is an essential part of secondary prophylaxis and typically is recommended to persons who have not had a cardiac event but who have an increased risk of developing coronary artery disease. The American Heart Association recommends prophylactic aspirin for those who have a ten year heart attack risk of 10% or greater and the usually-much-more conservative U.S Preventive Services Task Force recommends aspirin for those who have a five year risk of 3 % or higher.
Ibuprofen is widely used for a variety of aches and pains and its use is prevalent in the same age group who usually qualify for aspirin prophylaxis. However, there is evidence that ibuprofen may interfere with the beneficial effect that aspirin has on blood platelets. It is thought that ibuprofen and perhaps other NSAIDs interfere with aspirin gaining access to the molecular site on which it acts to inhibit platelet aggregation which is the putative mechanism involving in aspirin's success in decreasing coronary events.( Ibuprofen and aspirin are thought to chemically link up to sites in close proximity so that ibuprofen's presence may "crowd out" aspirin)
The FDA has recently published a paper explaining what is known about the asa-ibuprofen interaction issue and what practically can be done to enjoy whatever cardioprotective effect aspirin has and still be able to take ibuprofen for various pains. It is well worth reading and perhaps having copies handy to give patients.
Basically the advice is this:
Wait at least 1/2 hour after taking immediate release aspirin before taking ibuprofen. Wait 8 hours after taking 400 mg. of ibuprofen before taking aspirin.
The above advice does not apply to the popular enteric coated aspirin (ECASA) whose absorption is slower and 1/2 hour may not be long enough for aspirin to complete its inhibition of cyclooxygenase.The FDA did not believe there was adequate evidence to make specific recommendations regarding other NSAIDs-other than a general cautionary note. However, one recent article provided some data indicating a similar problem with the combination of aspirin and naproxen.
Ibuprofen is widely used for a variety of aches and pains and its use is prevalent in the same age group who usually qualify for aspirin prophylaxis. However, there is evidence that ibuprofen may interfere with the beneficial effect that aspirin has on blood platelets. It is thought that ibuprofen and perhaps other NSAIDs interfere with aspirin gaining access to the molecular site on which it acts to inhibit platelet aggregation which is the putative mechanism involving in aspirin's success in decreasing coronary events.( Ibuprofen and aspirin are thought to chemically link up to sites in close proximity so that ibuprofen's presence may "crowd out" aspirin)
The FDA has recently published a paper explaining what is known about the asa-ibuprofen interaction issue and what practically can be done to enjoy whatever cardioprotective effect aspirin has and still be able to take ibuprofen for various pains. It is well worth reading and perhaps having copies handy to give patients.
Basically the advice is this:
Wait at least 1/2 hour after taking immediate release aspirin before taking ibuprofen. Wait 8 hours after taking 400 mg. of ibuprofen before taking aspirin.
The above advice does not apply to the popular enteric coated aspirin (ECASA) whose absorption is slower and 1/2 hour may not be long enough for aspirin to complete its inhibition of cyclooxygenase.The FDA did not believe there was adequate evidence to make specific recommendations regarding other NSAIDs-other than a general cautionary note. However, one recent article provided some data indicating a similar problem with the combination of aspirin and naproxen.
Friday, September 08, 2006
Should the single digital FOBT be abandoned?
For years physicians in the office setting have included a digital rectal exam and then tested stool captured by the gloved finger for occult blood.
A recent study published in the Annals of Internal Medicine compared the results of the single digital FOBT ( fecal occult blood test) with the take home FOBT kit which involves the patient testing 6 samples of stool at home presumably after following the dietary guidelines indicated in the literature found with the kit. 6 samples should be better than 1 in terms of sensitivity which is exactly what the researchers found in 2655 patients who also underwent screening colonoscopy.
The single FOBT test did badly, with a sensitivity of only 4.9% in detecting "advanced neoplasia" which was defined as tubular adenomas larger than 10 mm., adenomas with villous patterns, high grade dysplasia or invasive cancer. The six test kit did better with a sensitivity of 23.9%.
Specificities for the two tests were in the 90% plus range. The authors concluded that the single finger FOBT is a poor screening test and clearly it is not enough to do if the intent is screening for colon cancer or polyps. I would add that the six-sample method is certainly not a substitute for colonoscopy either.
A recent study published in the Annals of Internal Medicine compared the results of the single digital FOBT ( fecal occult blood test) with the take home FOBT kit which involves the patient testing 6 samples of stool at home presumably after following the dietary guidelines indicated in the literature found with the kit. 6 samples should be better than 1 in terms of sensitivity which is exactly what the researchers found in 2655 patients who also underwent screening colonoscopy.
The single FOBT test did badly, with a sensitivity of only 4.9% in detecting "advanced neoplasia" which was defined as tubular adenomas larger than 10 mm., adenomas with villous patterns, high grade dysplasia or invasive cancer. The six test kit did better with a sensitivity of 23.9%.
Specificities for the two tests were in the 90% plus range. The authors concluded that the single finger FOBT is a poor screening test and clearly it is not enough to do if the intent is screening for colon cancer or polyps. I would add that the six-sample method is certainly not a substitute for colonoscopy either.
Wednesday, September 06, 2006
More on Quality Improvement Organizations"-another study fails to clearly show they work
I have written before the Quality Improvement Organizations (QICs) .The Sept 5, issue of the Annals of Internal Medicine published another study that was unable to clearly demonstrate that their efforts to improve quality in fact improves quality. The accompanying editorial noted that although the study tended to show some rather small improvements in the group that received a quality improvement "intervention", other factors not adequately controlled for could also have been responsible study design and analysis left much to desire. The editorialist quotes a 2006 publication for the Institute of Medicine that noted of 33 recent studies investigating QICs efficacy 9 show positive results, 16 yielded ambiguous results and 8 either found no impact or a negative impact .
Allthough the QIC website proclaims the organization strives to "make sure patients get the right care at the right time" studies-including their own such as this one from the Annals- seem unable to unambiguously demonstrate that what they do improve quality and even when some indication of quality improves (and in the interest of fairness it should be noted that a number of indicators did show improvement) after intervention the studies are so poorly designed they cannot attribute the results to their efforts.
I can't decide if their statement "make sure patients get the right care at the right time" is born of extreme naivete or typical governmental bureaucratic hubris but I think that any physician who has been in practice for more than five minutes would never promise anything so grandiose and impossible to deliver.The QICs seem unable to do something much simpler,namely to show that their interventions actually do what they purport to do but do not loose faith, the authors promise us more and better designed studies.
Allthough the QIC website proclaims the organization strives to "make sure patients get the right care at the right time" studies-including their own such as this one from the Annals- seem unable to unambiguously demonstrate that what they do improve quality and even when some indication of quality improves (and in the interest of fairness it should be noted that a number of indicators did show improvement) after intervention the studies are so poorly designed they cannot attribute the results to their efforts.
I can't decide if their statement "make sure patients get the right care at the right time" is born of extreme naivete or typical governmental bureaucratic hubris but I think that any physician who has been in practice for more than five minutes would never promise anything so grandiose and impossible to deliver.The QICs seem unable to do something much simpler,namely to show that their interventions actually do what they purport to do but do not loose faith, the authors promise us more and better designed studies.
Tuesday, September 05, 2006
Trial underway to test use of steroids in severe pneumonia
In the August 14,2006 issue of Internal Medicine News we learn of reports that corticosteroids may reduce the morbidity and mortality of severe bacterial pneumonia.
Dr. Antoni Torres from the University of Barcelona apparently become interested in the potential value of steroids in this application from his observational study of 1,424 hospitalized patients in which one of the independent protective risk factors was COPD. This seems counterintuitive but he reasoned that perhaps it was the use of steroids (which is routine in exacerbations of COPD) that was protective.
The news article reported that a small RCT (46 patients) showed a reduction in mortality in the group receiving 200 mg of hydrocortisome IV followed by 7 days of a lower dose(Am J. Respir.Crit.Care.2005,171:242-8). I could not find that reference on PUBMED but here Dr. Torres discusses the issue.
Another larger RCT is currently in progress in Italy. Patients will be those with community acquired pneumonia who have a high mortality risk and a C-reactive-protein above 15. The thought here seems to be that in severe pneumonia -as flagged by the CRP value-there is an important element of systemic inflammatory response which might be mitigated by the steroids.
The value of steroids in sepsis has been difficult to ascertain as indicated in this 2004 Annals of Internal Medicine summary of a recent meta-analysis. I suspect the value of steroids may be a bit hard to sort out in pneumonia as well. RCTs in seriously ill patients who are heterogeneous in multiple aspects offer quite a challenge and finding the right dose-if there is one-may be difficult as suggested by the results of the sepsis treatment meta-analysis in which it appeared that "high-dose" was harmful and "low dose" helpful.
Dr. Antoni Torres from the University of Barcelona apparently become interested in the potential value of steroids in this application from his observational study of 1,424 hospitalized patients in which one of the independent protective risk factors was COPD. This seems counterintuitive but he reasoned that perhaps it was the use of steroids (which is routine in exacerbations of COPD) that was protective.
The news article reported that a small RCT (46 patients) showed a reduction in mortality in the group receiving 200 mg of hydrocortisome IV followed by 7 days of a lower dose(Am J. Respir.Crit.Care.2005,171:242-8). I could not find that reference on PUBMED but here Dr. Torres discusses the issue.
Another larger RCT is currently in progress in Italy. Patients will be those with community acquired pneumonia who have a high mortality risk and a C-reactive-protein above 15. The thought here seems to be that in severe pneumonia -as flagged by the CRP value-there is an important element of systemic inflammatory response which might be mitigated by the steroids.
The value of steroids in sepsis has been difficult to ascertain as indicated in this 2004 Annals of Internal Medicine summary of a recent meta-analysis. I suspect the value of steroids may be a bit hard to sort out in pneumonia as well. RCTs in seriously ill patients who are heterogeneous in multiple aspects offer quite a challenge and finding the right dose-if there is one-may be difficult as suggested by the results of the sepsis treatment meta-analysis in which it appeared that "high-dose" was harmful and "low dose" helpful.
Wednesday, August 30, 2006
Is interval training better for metabolic syndrome?
Physicians routinely recommend exercise for patients with the metabolic syndrome-typically walking.Exercise is a generally accepted strategy to loose weight and improve lipids and glucose tolerance.
Interval training (IT) has been popular with runners for years. The famous distance runner Emile Zatopek popularized it in the 1950's. IT involves alternating high speed or high intensity exercise periods with rest or low energy output periods, e.g. sprinting for 100 yards followed by jogging or walking for 100 yards.There is a "loading" period and a "recovery period".In the recovery period there is at least partial regeneration of adenosine triphosphate and creatine phosphate and decrease in lactate and hydrogen ions.IT is contrasted with constant loading exercise (CLE) or continuous exercise at more or less the same pace or energy output level. Muscle strength and endurance have been shown to increase with interval training while CLE mainly improves endurance.
Recently, Dr. Anna Tjonna and associates from Norway published the results of a small study that indicated that interval training was better than traditional exercise ( i.e prolonged exercise at a lower energy output aka continuous exercise) in terms of improvement in HDL cholesterol and blood sugar in patients with the metabolic syndrome. The IT group exercised at 90-95% of maximum heart rate for 4 minutes followed by a 3 minute rest. They did 4 sets three times a week. The comparison group exercised at 70% of max heart rate for 40 minutes three times a week.
There is a understandable reluctance to encourage sedentary, overweight middle and older aged patients to exercise at that high a level of exercise because of a perceived greater risk of cardiac events and the likelihood of greater musculo-skeletal injuries.We almost always tell patients to begin with a walking program and go from there. "Going from there" often involves someone jogging for a short distance and then walking and then jogging again, which is basically a mild form of interval training. But it is not clear how much exercise or what level of energy output is required to actually change the metabolic parameters of the metabolic syndrome.In fact, the literature on the effect of running on HDL is a bit murky as well. There is some evidence that a higher level of exercise is required to significantly elevate a low HDL than occurs with the usual middle aged metabolic syndrome patient as they try to
"get healthier" with a walking program.Patients with elevated triglycerides usually enjoy a greater increase in HDL with exercise as a result of the fall in triglyceride levels.
I am not going to send a 55 year old man with a BMI of 31 and metabolic syndrome over to the high school track to do wind sprints but the notion of interval training is getting more attention from exercise physiologists and rehab professionals. Deep water running (running in place with a flotation vest in a swimming pool) has been a technique to keep injured athletes fit while they heal and has been applied to older patients to increase their level of cardiovascular fitness and appears to be a relatively low injury risk type exercise.For example,deep water running seemed safe and effective in increasing fitness levels in older women in this study from Sweden. IT has been shown to be feasible and effective in increasing fitness in patients with chronic obstructive lung disease and has been shown to increase anaerobic capacity as well as aerobic in cardiac rehab patients while continuous type training only increased the later.
The single study quoted above is not going to change physicians' exercise prescriptions but maybe there is something metabolically desirable (perhaps a greater increase in the GLUT4 glucose transporter protein or something like that) about the interval training. If so and further data confirm the study from Norway,deep water running may become a way to "treat metabolic syndrome" by providing a safe way to do intervals. ( Disclosure: I became an avid advocate of aquatic exercising 2 years ago.While I was recovering from a subcortical trabecular fracture of the femur aqua-jogging kept me reasonably fit until I could go back to running and was good mental therapy for me and those around me who had to deal with someone who for the first time in 30 years was not running regularly.)
Interval training (IT) has been popular with runners for years. The famous distance runner Emile Zatopek popularized it in the 1950's. IT involves alternating high speed or high intensity exercise periods with rest or low energy output periods, e.g. sprinting for 100 yards followed by jogging or walking for 100 yards.There is a "loading" period and a "recovery period".In the recovery period there is at least partial regeneration of adenosine triphosphate and creatine phosphate and decrease in lactate and hydrogen ions.IT is contrasted with constant loading exercise (CLE) or continuous exercise at more or less the same pace or energy output level. Muscle strength and endurance have been shown to increase with interval training while CLE mainly improves endurance.
Recently, Dr. Anna Tjonna and associates from Norway published the results of a small study that indicated that interval training was better than traditional exercise ( i.e prolonged exercise at a lower energy output aka continuous exercise) in terms of improvement in HDL cholesterol and blood sugar in patients with the metabolic syndrome. The IT group exercised at 90-95% of maximum heart rate for 4 minutes followed by a 3 minute rest. They did 4 sets three times a week. The comparison group exercised at 70% of max heart rate for 40 minutes three times a week.
There is a understandable reluctance to encourage sedentary, overweight middle and older aged patients to exercise at that high a level of exercise because of a perceived greater risk of cardiac events and the likelihood of greater musculo-skeletal injuries.We almost always tell patients to begin with a walking program and go from there. "Going from there" often involves someone jogging for a short distance and then walking and then jogging again, which is basically a mild form of interval training. But it is not clear how much exercise or what level of energy output is required to actually change the metabolic parameters of the metabolic syndrome.In fact, the literature on the effect of running on HDL is a bit murky as well. There is some evidence that a higher level of exercise is required to significantly elevate a low HDL than occurs with the usual middle aged metabolic syndrome patient as they try to
"get healthier" with a walking program.Patients with elevated triglycerides usually enjoy a greater increase in HDL with exercise as a result of the fall in triglyceride levels.
I am not going to send a 55 year old man with a BMI of 31 and metabolic syndrome over to the high school track to do wind sprints but the notion of interval training is getting more attention from exercise physiologists and rehab professionals. Deep water running (running in place with a flotation vest in a swimming pool) has been a technique to keep injured athletes fit while they heal and has been applied to older patients to increase their level of cardiovascular fitness and appears to be a relatively low injury risk type exercise.For example,deep water running seemed safe and effective in increasing fitness levels in older women in this study from Sweden. IT has been shown to be feasible and effective in increasing fitness in patients with chronic obstructive lung disease and has been shown to increase anaerobic capacity as well as aerobic in cardiac rehab patients while continuous type training only increased the later.
The single study quoted above is not going to change physicians' exercise prescriptions but maybe there is something metabolically desirable (perhaps a greater increase in the GLUT4 glucose transporter protein or something like that) about the interval training. If so and further data confirm the study from Norway,deep water running may become a way to "treat metabolic syndrome" by providing a safe way to do intervals. ( Disclosure: I became an avid advocate of aquatic exercising 2 years ago.While I was recovering from a subcortical trabecular fracture of the femur aqua-jogging kept me reasonably fit until I could go back to running and was good mental therapy for me and those around me who had to deal with someone who for the first time in 30 years was not running regularly.)
Monday, August 28, 2006
Houston V.A. physicians examine P4P data and find evidence of gaming and treating the chart
The possibility that health care providers (HCP) might try to game the system and treat the chart when offered or forced to play the P4P game is well recognized and quite consistent with basic human nature.
Researchers from the Houston Veteran's Administration Hospital have published an article indicating that behavior of that type does in fact occur. Dr. Laura S. Peterson and her associates write in the August 15 2006 issue of the Annals of Internal Medicine.
They reviewed 16 articles and in 4 studies they found evidence of unintended effects-adverse selection and gaming or treating the chart to achieve financially rewarded goals. Importantly, for those of us who believe this entire P4P movement is motivated by a desire to save money, they found no evidence that these efforts are cost effective. Of course, lack of evidence does not necessarily mean evidence that they are not cost effective but the third party payers and CMS may at some point pull back if they are continue to be unable to show they there are cost savings to the payers. I hope so.
Researchers from the Houston Veteran's Administration Hospital have published an article indicating that behavior of that type does in fact occur. Dr. Laura S. Peterson and her associates write in the August 15 2006 issue of the Annals of Internal Medicine.
They reviewed 16 articles and in 4 studies they found evidence of unintended effects-adverse selection and gaming or treating the chart to achieve financially rewarded goals. Importantly, for those of us who believe this entire P4P movement is motivated by a desire to save money, they found no evidence that these efforts are cost effective. Of course, lack of evidence does not necessarily mean evidence that they are not cost effective but the third party payers and CMS may at some point pull back if they are continue to be unable to show they there are cost savings to the payers. I hope so.
Sunday, August 27, 2006
heuristics and statistics-we need and use both in medicine
In spite of at least one terrible publication to the contrary-the criticism of which is reviewed here- there can be little doubt that experienced clinicians perform better than do novices. Experience and practice really no matter.During the five to ten years it seems to take for a recent medical graduate to become at least a low level expert basically no time is spent on courses on medical decision making.
Does the experienced clinician talk about or think about likelihood ratios or prior probabilities? Does he explicitly use equations to determine positive predictive values etc? Not the ones I have been associated with. What the experienced docs seem to deal in mainly are heuristics. These are rules of thumb,short cuts, and simple judgments that operate in many of the decisions that physicians make.
Dr. Pat Croskerry published an interesting article in the Canadian Journal anesthesiology ( vol. 52:6 p.r1) in which he discusses decision making. He does this from the viewpoint of anesthesiology but it has broad application to medical decision making in general.
His major point is that physicians make many decisions through the mechanisms of heuristics and while they often are effective there are cognitive impediments that limit their usefulness. We need to be aware of those mental tendencies so that we can compensate for them .One example, about which I have written earlier, is "premature closure"., i.e. making a diagnosis and then shutting out consideration that it could be incorrect even as evidence to the contrary accumulates. He mentions many other cognitive tendencies which he refers to as "cognitive dispositions to respond" (CDRs) rather then the earlier tendency to label them as biases or fallacies.Some have intriguing names such as "playing the odds", "Sutton's Slip" and "ego bias". I have not had time yet to research what those terms refer to but some of them may be the topic of a later posting.
His position is that doctors do not typically think in a formalized, statistical manner using formulas which dispassionately weigh the evidence and we should recognize that fact of life and learn about and make efforts to control the CDRs in order to better harness our use of heuristics.
Statistical analysis is an essential element in clinical research but many of the decisions we make in the heat of the clinical battles that take place every day rely on mental processes that seem to have little to do with statistics.
Does the experienced clinician talk about or think about likelihood ratios or prior probabilities? Does he explicitly use equations to determine positive predictive values etc? Not the ones I have been associated with. What the experienced docs seem to deal in mainly are heuristics. These are rules of thumb,short cuts, and simple judgments that operate in many of the decisions that physicians make.
Dr. Pat Croskerry published an interesting article in the Canadian Journal anesthesiology ( vol. 52:6 p.r1) in which he discusses decision making. He does this from the viewpoint of anesthesiology but it has broad application to medical decision making in general.
His major point is that physicians make many decisions through the mechanisms of heuristics and while they often are effective there are cognitive impediments that limit their usefulness. We need to be aware of those mental tendencies so that we can compensate for them .One example, about which I have written earlier, is "premature closure"., i.e. making a diagnosis and then shutting out consideration that it could be incorrect even as evidence to the contrary accumulates. He mentions many other cognitive tendencies which he refers to as "cognitive dispositions to respond" (CDRs) rather then the earlier tendency to label them as biases or fallacies.Some have intriguing names such as "playing the odds", "Sutton's Slip" and "ego bias". I have not had time yet to research what those terms refer to but some of them may be the topic of a later posting.
His position is that doctors do not typically think in a formalized, statistical manner using formulas which dispassionately weigh the evidence and we should recognize that fact of life and learn about and make efforts to control the CDRs in order to better harness our use of heuristics.
Statistical analysis is an essential element in clinical research but many of the decisions we make in the heat of the clinical battles that take place every day rely on mental processes that seem to have little to do with statistics.
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