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.

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.

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."

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.

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.

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.

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".

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.

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.

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.

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.

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.

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.

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.

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.

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.)

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.

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.

The gabapentin story: "Medical education drives this market"

The quote "Medical education drives this market" is attributed to an author of a Parke -Davis business plan found in a legal exhibit in the proceedings of the United States vs Pfizer, and Parke-Davis. Public documents in this case were reviewed and analyzed by Dr. Michael A. Steinman and his colleagues at the San Francisco Veterans Affairs Medical Center in San Francisco and published in the August 15, 2006 issue of the Annals of Internal Medicine. Federal legal action had been taken against gabapentin manufacturer for promoting off-label uses of the drug.

After a physician or medical student or house officer reads this article she should never view certain "CME" activities in the same way.

An important part of the influence campaign of Parke-Davis (P-D)to promote off-label use of gabapentin was though "thought leaders". These physicians are influential physicians often identified by the affiliation with major academic centers. These department chairs, directors of academic training programs or divisions received payments ranging from $10,000 to about $150,000 between 1993 and 1997 in the forms of honoraria, research grants and educational grants. These folks were often the likely role models for house officers , fellows and medical students. This aspect of the multifaceted efforts of P-D to promote non-FDA approved use of gabapentin is the most troubling to me because of the role well respected physicians played. At some early point,a person could have been simply naive and was duped but at some point most had to be complicit at some level.

There are other aspects detailed by the authors including the use of "medical education" companies hired by P-D to ghost write articles and organize meetings, and supply various CME products which were basically advertisements for off-label use of gabapentin.

The full text version of the Annals article is not available until 6 months after publication on line but an excellent review of the article and commentary about both the article and the accompanying editorial can be found in two posts from August 18,2006 on Health Care Renewal.
In addition to outlining the various tactics (advisory boards, consultant meetings, speakers bureaus, programs funded through unrestricted educational grants), Dr Poses raises valid questions about the multiple corporate positions held by the Annals editorial writer as well an academic appointment and how difficult it would seem to be to fulfill the apparently conflicting fiduciary duties that those various roles demand.

The Annals article and Dr. Poses's posts should be part of medical students courses on evidence based medicine. They need to recognize the borders between research,education and promotion which the authors described as "porous". We can hope they will guard these borders better than some-perhaps too many-of their mentors have done. I am grateful to Dr. Steinman and his associates for their work in plowing through some 8000 pages of publicly available documents to give us a "game plan" for selling a drug to physicians. Hopefully this will be as helpful to physicians as giving the offensive play book to the defensive coordinator of a rival football team.

Yet another analysis of the ALLHAT trial

The idealized world of the medical student as he learns about randomized clinical trials (RCT) is one in which something like this is visualized. Let's do a RCT to find out which is the best way to treat hypertension and then we will have evidence based medicine directing our rational,quality filled medical care.. Well, the ALLHAT trial could be thought of as just such a undertaking so now we should know,right?

With trials of this scope and complexity a large amount of data is generated and rather than a simple black and white answer emerging there are often multiple conclusions all of which do not agree. Such is how this been with ALLHAT. The most recent analysis of this controversial BP trial is from Dr. Frans Leenen from the Ottawa heart Institute.

Here are some of his findings:

Calcium channel blockers(CCBs) were not associated with more coronary artery disease events but were blamed for more episodes of heart failure. Ace inhibitors (ACEi), on the other hand appeared to be more likely to cause stroke,gi bleeding, peripheral artery disease and angina and ( here is a surprise) angio-edema.

Rather than the simple "well that settles it" that was hoped for in ALLHAT, we have arguments and counter-arguments presented,editorials supporting the results and the BP recommendations (JNCVI) largely based on ALLHAT and editorials arguing that the trial was poorly designed and bears no resemblance to the way BP is really treated (i.e. did not compare realistic choices for BP meds) .

We have gone back and forth with CCBs as well. Are they harmful? Are they as good as any other BP treatment ( which is suggested by Leenen's article)? Not only do trial results seem to differ , various analyses in regard to the same trial differ.I doubt if the recent analysis by Leenen will settle much of anything.

Osteopenia-A disease? when do you treat it with medications

Osteoporosis is defined as a decrease in bone mass with pathological changes in the microarchitecture of bone and tendency to fragility fractures. The operational definition is based on the bone mineral density (BMD) measurement and statistical definition is used with osteoporosis said to be present if the BMD is less then 2.5 standard deviations (T score) from the average 25 year old woman's value.For those readings between -1 and -2.5, the term osteopenia is used. By definition 16% of 35 year old women would be osteopenic.

40% of 65 year old women are osteopenic. Of those who should be offered medication? Currently the medications typically used are the bisphosphonates which have largely replaced estrogen which not too long ago was very popular as it was believed to not only mitigate the aging effects of estrogen decline butcould preserve heart health and lessen the risk of dementia.I considered this question because of a quite a number of women who I would see in the office had been placed on bisphosphonate medications by their gynecologist or family doctor or internist seemingly only because of a BMD score in the osteopenic range.

The Osteoporosis Foundation (NOF) and the American Association of Clinical Endocrinology (AACE) have different recommendations regarding the use of medications. NOF seems to recommend medications for those patients with osteopenia with no risk factors if the T score is below -2 and for those patients with T scores of less than -1.5 if they have one or more risk factors which include low body weight ( less than 127),history or family history of fragility fractures,smoking, estrogen lack or excessive alcohol use ,use of certain medications including steroids. AACE would recommends medication if the T score is less than 1.5 IF the patient has had fracture(s) or if the T score is less than -2.5.( This is the WHO definition of osteoporosis so-strictly speaking- AACE is recommending treatment for osteoporosis not osteopenia and recommends treatment for osteopenia only if there is a history of fractures.)

The consensus answer to the introductory questions is no, all persons said to be osteopenic on the basis of a bone density measurement do not need to receive medications. The opposite answer would seem to mean we should be treating those 16% of normal 25 year old women on the basis of their BMD score. Clinical judgment is required to sort out those patients with osteopenia and other risk factors and clinical features would might benefit from prescription medications.Of course with preventive medication use, you never really know if anything is prevented on not in the individual case only in the aggregate. It may make good sense to suggest a bisphosphonate in a 70 year old women who has one fragility fracture already and tends to be a bit unsteady even in the face on a mildly osteopenic BMD while a younger women with the same score who exercises regularly may not be as good a "candidate". As with all preventive treatments-if that is not an oxymoron-the decision should be one reached by the patient after discussion with the physician. and not a unilateral quasi-judicial decision.BMD is one of the factors to consider but not necessarily the determinative one.

A recent article in the Annals of Internal Medicine is referenced as a source for the statement that bisphosphonates are not longer recommended for osteopenic patients. This is misleading.The Annals article was a computer simulation with numerous assumptions (AKA- a cost effectiveness study) which concluded that therapy with bisphosphonates was not cost effective.But it was a close call and with decreases in drug prices the outcome would be turned around and drugs do have a way of becoming generic and cheaper with time.So folks should not take them now but wait until they are cheaper?As is generic with cost effectiveness articles the authors decide what costs too much not the person using the medications ( i.e. the patient).I realize that often the person using the medication is not the person or financial entity paying for the medications, which ,according to my cynical way of thinking,the reason we have cost effectiveness studies in medicine in the first place.In any event, I am not aware that NOF or AACE have made any changes in their recommendations

bacterial pharnygitis-not just beta-strep

Recent entries on DB's Medical Rants have called attention to a somewhat obscure cause of sore throat, namely a potentially very serious infection with a bacteria with the appropriately ominous name of Fusibacterium necrophorum. I will admit I was not aware of that issue.He discusses this infection in the important context of the "long tail" of diagnostic possibilities.

There is another, arguably a bit more common, cause of bacterial sore throat-infection with Arcanobacterium haemolyticum,formerly known as corynbacterium hemolyticum. This form of bacterial throat infection may be associated with a rash so that confusion with scarlet fever caused by beta-strep is possible. A CDC report indicates it may account for as many as 2.5 % of sore throat cases in young patients,occasionally cause a "membrane" on the throat as in diphtheria and may be penicillin resistant.

Clearly group A , beta-hemolytic streptococcal (GABHS) infection is the most common etiologic bacterial pathogen in pharyngitis but Arcanobacterium infection is easily missed. Not only is it similar to GABHS, a typical throat culture might miss A.Hemolyticum because the usual culture plate used for throat swabs may only show a small area of hemolysis after 24 hours with Arcanobacterium and the report would indicate only no beta strep present.

The e-Medicine article on Arcanobacterium infection suggests that the macrolide family of antibiotics are preferable to penicillin which is the traditional drug of choice for GABHS.

Neisseria gonorrhoeae and corynebacterium diphtheria have to mentioned as well although diphtheria is basically of historical interest only at least in the U.S. As time goes on,I'll bet we will add more bacterial pathogens to the recognized inhabitants of the long tail of etiologic agents of sore throat.

Practice,practice, practice-will current house officers have time to do that?

What do some cognitive scientists and the folks who teach you how to take a test (Stanley Kaplan et al) have in common? Answer- a belief in the power of practice and challenges just beyond one's level of competence.

The August 6, 2006 Issue of Scientific American has an interesting article by Phillip S. Ross entitled "The Expert Mind".

It discusses studies that have been done regarding master chess players ( who might be considered the Drosophila of the cognitive scientists) and how they approach and solve chess problems. Novices spend more time analyzing various possible moves than masters who quickly narrow the alternatives down apparently without consciously considering all of them.

Are the masters born or made? The author argues that they are made. The entire article should be read to review the evidence he presents.

"Effortful study" and Practice, Practice, practice with exposure to increasingly difficult problems is the key.What seems important is "challenges just beyond one's competence". To a medical student just beginning the clinical years, just about everything is beyond their competence.

It takes time. He quotes one cognitive scientist who believes it takes about ten years to become an expert.In the "old days" a internist who did specialty training did in fact about ten years total
training although some only took nine years.

Before Stanley Kaplan proved otherwise it was believed that the S.A.T. was an aptitude test. He showed one could be coached to improve one' s S.A.T.score and made a career of that. A key to that improvement was practice ( and of course, knowing what type of problems you would face and therefore be able to practice their solution)

I wonder if the current generation of internal medicine house officers will have enough time in their training to practice enough.With my generation's training (graduation in 1965) we had more time.Counting my two years of pulmonary fellowship, it was ten years from the year I entered medical school.Now someone can complete the IM program ( assuming no fellowship) in as little as 7 years from med school entry. In addition, there is less time per week with the current rules limiting time in the hospital and more material placed into the training requirements that takes away from doctor patient time ( e.g. quality training, cultural competency and my favorite "systems based practice").

One of my former partners in a large internal medicine clinic is convinced the level of clinical expertise in regard to general medicine problems is much greater in those docs who have had specialty training than those "general" internists who have had only 3 years post med school training and not just in their specialty but in general IM matters as well. Maybe the three year trainees need more practice.

More on the LABA controversy-a thoughtful analysis from an allergist's perspective

Dr. Stuart Henochowicz, an allergist-internist blogger,recently posted some cogent comments about the use of LABAs in asthma including comments regarding the combo inhalers ( steroids and a LABA).

Asthma patients are often treated by allergists or pulmonary docs or sometimes both and as a pulmonary physician I welcome his thoughts regarding the recent flare up of the concern about the safety of the long acting beta-agonists (LABAs). This exacerbation of concern was triggered mainly by the publication of the poorly done SMART trial and what I believe to be a flawed and overblown meta-analysis in the Annals of Internal Medicine by Salpeter.

Some of his key points are:
LABAs should not be used in asthma without inhaled steroid coverage.
The combo inhalers are very helpful in asthma treatment.
There are data supporting the value of those combination products.

I believe his comments reflect what I sense to be a consensus among physicians who treat asthma on a regular basis, allergists and pulmonary docs. I continue to have concerns that the annals' meta-analysis might cause asthma patients to discontinue their long acting beta agonist-steroid combination inhalers with resultant exacerbation of their asthma.In fact, some medical bloggers have commented that has already happened.

Real medicine's "ill structured problems" versus guideline's well structured ones

I have been thinking lately about the type of medical problems that physicians face. Mathematicians and cognitive scientists talk about well-structured problems and ill-structured problems.

It seems that much of the challenge of patient care falls under the heading of ill-structured problems (ISP). Well structured problems (WSP) are those for which there is a known algorithm.

ISPs have these characteristics:
1.inadequate information form the outset
2.lack of defining guidelines to evaluate the problem
3.mutability of the problem-things changes as you go alone
4.lack of assurance that the problem has been solved

These are complicated problems without a clear cut solution and for which there may not be one right answer. There is no back-of-the-answer to compare with your analysis.

A recent post by Aggravated docsurg gives some great examples of ISPs that a general surgeon faced.Internists have equally demanding cases as well in addition to the simpler, quasi-no brainers.

An ill -structured problem is , by definition, one for which there is no algorithm. Much of the formal education I received in college physics and chemistry and calculus involved the mastery of WSPs of the following type. If a rock drops into a well and the splash is heard 4 seconds later how deep is the well? Physicians do not seem to do much of that type of thinking in their offices.

The folks who paint medicine as mostly a series of WSPs solable by algorithms and auditable for quality and reimbursable of the basis of obedience to those guidelines are either ignorant of or choose to ignore the reality of just how complex and ill structured the issues are that physicians face.

Clinical decisions in these ISPs will require all the knowledge, expertise and judgment the physician can bring to bear factoring in the values and wishes of the patient to try and find the particular "clinical truth" for the circumstances at hand. The quality gurus have no generic algorithm for that process.

Why is testing saw palmetto's efficacy different from testing Reiki's

Robert G. Newton in his book "The Truth of Science" (Harvard University Press, Cambridge, Massachusetts, 1997) talks about the Criterion of Coherence.

Newton said that "the most important criterion for ascertaining the truth of a statement is its coherence with a network of assertions that are also regard as true."

In regard to the often made accusation of proponents of unorthodox ideas ( parapsychology,etc) that scientists are inappropriately dismissive of their ideas and are elitists or closed minded he says:

"Researchers justifiably refuse to listen to these claims,to examine them or refute them in detail,because they are incoherent with the rest of our scientific knowledge."

Reiki and distant healing and homeopathy-to name a few-fall outside the boundaries of the coherent web of scientific learning while the possibility that a given herb or root might have some active pharmacological effect and be beneficial does not.In regard to the later there are numerous examples while the former violate too many well accepted and established and coherent scientific principles to seriously expend research time, money and brain power to bother to refute them. Manipulation of an undetectable energy force that is capable of healing any and all diseases,the mastery of which has to be taught by a master should not have to be investigated by a dubious controlled clinical trial.So the difference between testing saw palmetto and Reiki is the difference between testing something that is considered possible in the wide web of scientific knowledge and testing something that is just absurd.

Clinical trials underway to evaluate Reiki

Several clinical trials are being funded by the government to investigate the efficacy of Reiki.
Details can be found in the above link.

Cleveland Clinic received 371,500 for a study involving Reiki and prostate cancer.

My favorite is the 1.8 million study at the University of Michigan studying the effect of Reiki on diabetic patients with numbness in the feet and legs.

This is an interesting endeavor. Since there is no way to test for or measure the transfer of the Reiki energy which purportedly is the basis for the healing, a controlled trial was devised.
One arm will involve treatment administered by a person claiming to have the power to heal by manipulating a undetectable energy force (the "real" Reiki master) and the other arm involves someone who claims to be someone who claims to have the power to heal by manipulating an undetectable energy force (the "fake" Reiki master). Money well spent.

Another NIH sponsored trial is the " Efficacy of distant Healing in Glioblastoma treatment". In this trial "healers"-who come from various schools of distant healing will received a photograph of the patient and will send "mental intentions for healing and well being" for one per day for three days per week. Apparently, here there is no control arm in which fake healers would pretend to send a mental intention.

Dr. Steven Barrett was quoted in a Medscape book review of an IOM report on CAM:

"Methods that are plausible should be tested with well-designed clinical trials. The rest should be discarded"

Can someone explain why the NIH is funding such trials?

Still more about Ketex (telithromycin) and a glimpse into the FDA

The July 19,2006 edition of "Morning Edition" on NPR revealed internal e-mails from the FDA concerning the discussions about the approval-or continuing approval-process for Ketex. Dr. David Graham who will be remembered for his role in the Vioxx issue was quoted as saying ( I paraphrase) -Ketex offers no unique benefits relative to other drugs in its class and other drugs with the same type of hepatotoxicity profile as Ketex were removed from the market by the FDA-such drugs as Rezulin and Trovan.So he is saying that the benefit do not trump the risks.Incidentally, Dr. Graham was actively involved in the recall of those two drugs as well as others.

I've written before about the vigorous promotional effort to sell Ketex as an antibiotic that purportedly offers a mechanism to mitigate the development of microbial resistance.Ghost writers and thought leaders put forth the effort that in part have apparently lead to Ketex developing a respectable market share.

It will be interesting to see if this media-induced transparency will lead the FDA to reconsider its position. There are now 4 fatal liver toxicity cases in the U.S. and the public is being made aware of Dr. Graham's argument for not continuing approval and reminded that a clinical trial that was supposed to demonstrate safety was riddled with fraud and fictional patients.

Medicare D patients now enjoying the "Hole" while Pharma companies enjoying the profits

One of the interesting features of Medicare Part D is the so called dough-nut hole, the time when the savings go away and the patients pay for the entire cost of meds until another threshold of medicine cost is reached and Medicare kicks in again covering most of the cost. The profit boost to pharmaceutical companies comes from the fact that previously those so called dual-eligible patients ( those who were eligible for both Medicade and Medicare) are now receiving their drugs solely from the Part D program. Under the states' administration of the medicaid program they were able to and did negotiate lower prices on the drugs paid for under that program but the federal government is not allowed to do that under the rules of part D. This is all explained with numbers in a recent NYT article on the subject.

This windfall is, of course, occuring while CMS has enacted more cuts in professional fees for medical services performed for Medicare recepients.Pay less to the docs ,more to the drug companies, can you guess who really knows how to lobby.

NEJM article -time to event analysis and still more on the Vioxx matter

In the July 13, 2006 issue of NEJM, S.W. Lagakos, a statistical consultant for the journal, writes about time-to-event analysis for long term treatments in the context of the APPROVe trial. This was the trial to see if Vioxx could prevent the recurrence of colon polyps and which demonstrated an increased risk of cardiovascular events in the treated group and which in all likelihood both Merck the NEJM wishes never happened.

The article is found in the perspective section and labeled "statistics and medicine".Dr. Lagakos discussed some of the issues involved in a time-to-event analysis such as the appropriate period of follow-up and the assumptions of the proportional hazards technique and the log rank test and monotonicity.If the purpose of this article was to inform readers so that they could read studies with these tests in an at least semi-informed manner,I am not sure he succeeded. I read it twice and still do not have a good sense of the statistical issues.However,I doubt a didactic motivation was operative.

He does make it clear that-in his opinion-that one cannot conclude that rofecoxib poses no increased cardio-vascular risk in less than 18 months. This 18 month threshold has become an issue in some of the many law suits pending in the courts.

The throngs of plaintiff attorneys involved in Vioxx cases could not be more pleased.The NEJM seems to be still trying to compensate for publishing the APPROVe trial in the first place.

Does value=quality/cost ?Is it immoral not to measure value?

I suspect we will be hearing more and more about paying for "quality" since the recess appointment of Dr. Donald Berwick to be the head of CMS. His views on central planning of medical care are the subject of much discussion. The following is a lightly re-edited version of a commentary I wrote several years ago on "measuring" quality and value.

Dr. RobertWachter, Professor of Medicine at UCSF , tells us that "value=quality/cost" and we have a moral obligation to "solve" equations for various clinical services. I reference his comments in the ACP observer as he replies to a letter to the editor commenting on the interview he gave discussing the overseas out-sourcing of medical services.(ACP Observer,July/August/2006 pg4) Dr. Wachter says in part:

Health care will be judged by its value: i.e.quality/cost...It is immoral not to seek ways to provide high quality care at more affordable costs"

It seems to me that this "equation" presupposes an intrinsic theory of value in which value is considered to be something that can be objectively measured and is an intrinsic property of a good or service much like the specific gravity of a liquid or the density of a compound.

Since the Austrian School of economics popularized the subjective theory of value most mainstream economists reject the intrinsic value theory.

The same service may be more or less valued by a given person as her circumstances and desires change. No two individuals need value the same thing to the same degree though they may.Value to most economists is not an intrinsic measurable number but rather value is subjective and is in "the eye of the beholder". Thomas Sowell ( pg 51,Knowledge and Decisions,Basic Books, 1966) puts it this way:

"Value being ultimately subjective, it varies not only from person to person but from time to time with the same person, and varies according to how much of the given good he already has."

Advocates of the subjective value theory would argue that to define value with the above equation is to erroneously claim that value (or in this case "quality" which along with "cost" determines "value") is an objectively measured entity. Are the medical quality experts( as best I can tell this is a self proclaimed designation) who are able to or claim to be able devise means to measure quality merely substituting their preferences-dressed up as objective measurements-for the value judgments of others?

Wachter continues saying:

"Patients, payers and policy makers now expect us to tap into actual clinical data to assess a physician's quality of care.I suspect once we truly figure out how to do that..."

I take this to mean that exactly how to measure the quality of care has not yet been "figured out". Somehow, I think that compliance with guidelines and adherence to protocols will play a big role in this-it has so far- and I doubt if patients will be asked what it is they value. I agree that payers and policy makers want quality data to use as a cost containment tool, the gatekeeper concept now largely abandoned, but patients want a physician who will spend time with them,care about their problem and be more interested in doing what the doc and patients agree on as the right course for that person and not adherence to some guideline that the patient has probably never heard of and does not take the particulars of his situation into account.

I believe "quality" which is now the main rhetorical tool of the cost-containment movement has become a classic bait-and-switch term. Everyone, docs and patients alike,would naturally say we want to give/receive good care or "quality" care. But the quality guidelines so often turn out to be what some self-appointed quality guru, committee or task force says is an quality indicator and are often no more than simplistic, easy-to-count, check-off list items, some of which may have counterproductive or harmful effects.

I have no doubt there are many well-intentioned physicians working hard to improve medical care- if you will improve quality- but much of the quality movement and arguably its major motive force is to contain costs.


The movement to contain costs is the result of so much of medical care being paid for with other people's money. We are not instructed about the moral imperative of providing high quality legal services, or haircuts or home repairs at more affordable costs because the people who use these services pay for them themselves.

Some may rejoice in the passage of Obama care as a golden opportunity to improve the quality of medical care while the more cynical think of the legislation with unparalleled power placed in the hands of various governmental agencies as the mother of all opportunities for what economists call rent seeking in which various interested parties ( now known a stake holders) seek special privilege.

Still more on LABAs, asthma and the Annals meta-analysis

I was eagerly awaiting the replies to the recent Salpeter meta-analysis (MA) posted about here.

I suspect the rapid responses are available only by subscription, so here are some of the critical comments paraphrased:

1.The MA was basically a warm over of the SMART trial since about 3/4 of the data in the MA was derived from SMART and apparently all of the mortality data. I have commented before on the inadequacies of the SMART trial and how it may well be a poster child for how not to do a large RCT.

2.Since SMART was not able to answer the big question (i.e does the use of inhaled corticosteroids (ICS) protect from any putative harm derived from the LABAs),neither can a MA based largely on SMART. There was a one sentence summary in the analysis section that purported to show that ICS were not protective but no tabular data was presented and a conclusion that important should have been explicated further.

3.Salpeter's recommendation of inhaled anti-cholinergics to replace LABAs in asthma treatment was ill-advised as there are no clinical trial data showing its efficacy and safety in asthma treatment (as opposed to COPD treatment).

4.Concern was expressed that patients would be stopping their LABAs on their own based on the lay press's reporting of this article.One group of letter writers said exactly that had happened with the resultant exacerbation of patients symptoms.

5.Salpeter's comment that 4,000 of the 5,000 U.S.Asthma deaths per years could be blamed on LABAs was criticized by several letters.Two writers commented that the CDC data indicate that in 1996 asthma deaths were about 5,600 and by 2,003 ( the last year for which data is available) it had decreased to about 4,800. Salmeterol was introduced in the U.S. in 1994. Although this data does not at all prove salmeterol introduction decreased asthma deaths it is consistent with that interpretation and does not support the opposite conclusion. But, in any event the comment that 80% of asthma deaths are due to LABA is unwarranted hyperbole at best.Another letter supplied British data also showing a decrease in asthma deaths in the era following the intoduction of a LABA.

Just as the controversy over the Salpeter article grows, even more disagreement is likely to be generated by a recent article by the Salpeter father and daughter combo concluding that LABAs and short acting beta-agonists also increase the mortality in patients with COPD.

FDA gives continuing approval to Ketex-fatal liver disease notwithstanding

The FDA, after reviewing the fatal cases of liver disease associated with use of telithromycin( Ketex) decided to continue to allow its use. It is approved for mild to moderately severe respiratory infections including community acquired pneumonia,bacterial sinusitis and exacerbations of chronic obstructive lung disease.

It has been promoted heavily by the manufacturer and uses as a promotional hook the purported theoretical arguments that it is less prone to induce bacterial resistance.It range of activity seems about the same as Biaxin and Zithromax and a side effect profile in the same general range as these two well established and safe drugs with the exception of the fatal liver disease complication

Earlier I had blogged about allegations of possible fraud ( fabrication of data) in some of the treatment trials involving Ketex, quoting Health Care Renewal and the Wall street Journal.
The drug was approved by the FDA in April 2004 and has been advertised heavily and promoted by "thought leaders" in various CME and pseudo-CME forums.Most recently, a RCT using Ketex in asthma patients showed some indications of improvement. In June 2006, Sanofi-Aventis suspended enrollment in pediatric studies that were using Ketex for respiratory infections. With the reported liver disease cases, I doubt we will see many doctors recommending telithromycin to "improve" asthma or to treat children.

Both the manufacturer and some ID specialists appropriately concerned about the antibiotic resistance issue had high hopes for Ketex. It seemed to offer good defenses against the mechanisms by which bacteria were developing resistance to the macrolides. But I can see no indication for a drug that in the individual patient offers nothing that a macrolide does not offer and runs the risk of serious liver toxicity.There are too many other good antibiotics to use in respiratory tract infections to risk fatal liver disease.

Retired Doc's suggestion for med school curriculum Part 13

Had I been aware of the degree to which CAM (complementary and alternative medicine) has been accepted, taught,and practiced in at least some medical schools, I would have made this suggestion as Part 1 of the suggested curriculum series. Logically it should be Part 1 because to learn the science and art of medicine,which is supposed to be what medical schools teach, one should be able to know how to distinguish between science and pseudo-science.

I would have thought that college graduates entering med school would know well the distinction between the two and I suspect most do on entry. However, after learning their med school has a CAM clinic, CAM instructors and practitioners and that the NIH funds CAM research and that the FDA uses less stringent standards of evidence in evaluating alternative therapies,their understanding of the distinction may become blurred.

To mitigate that potential blurring, here is some material (not intended to be comprehensive) to include in the "what is science, anyway?" lecture.

The discussion might well begin with Einstein's comment regarding the development of western science which he said to be based on two things' The invention of the formal logic system by the Greeks and the discovery of the possibility of finding causal relationship by systematic experiments.

A discussion of Karl Popper's treatment of the problem of "demarcation" should be included. To Popper this was the basic issue of what is the difference between science and psuedo-science.
He said:

"...the criterion of the scientific status of a theory is its falsifiability,or refutability, or testability."

If a theory cannot be stated in such a way as to allow for its refutation, it is not science.

Edward O.Wilson is his book ,"Consilience, the Unity of Knowledge" says this about the difference between science and pseudo-science;

Science... is the organized systematic enterprise that gathers knowledge about the world and condenses the knowledge into testable laws and principles.

Wilson's diagnostic features of science are ( I paraphrase a bit)

1.repeatability
2.economy-abstract the information into its simplest form
3.mensuration-measure it
4.heuristics-the best science stimulates further discovery
5.consilience about which Dr. Wilson says that the explanation most likely to survive are those that can :

"be connected and proven consistent with one another."

Mention needs to made of the importance of reductionism wherein that which is thought relevant to the problem at hand is walled off and for the time being the rest ignored.This is a major difference between western scientific thinking and eastern holistic thought which is prevalent in the fables of some forms of alternative medicine. The few folks who read this on their computers can do so because of the accomplishments of western scientific thought and not the efforts of those who believe that everything is related to everything and the methods of western scientific thought are no more valid than say the undetectable "lifeforces" of reiki.

I became more convinced that a lecture or lectures on what is science and how well it has worked needs to be part of the curriculum when I read this June 18, 2006 posting by Dr. RW on the activities of the SAMA.Based on their statements they seem to believe that it is not clear what "type of science" is needed to evaluate CAM.It is hard to believe that medical educators have failed so badly .

The above suggestions are not intended to be all inclusive but the main point is that the powers that be in medical education need to make sure that their students know the difference between science and pseudo-science, teach them about the former and stop promoting the latter.

AMA recommends mandatory medical insurance-Is this "boil the oceans redux?

The AMA passed a policy resolution supporting mandatory medical insurance for those persons and families that can afford it and subsidies for those who can't.

Here is how I understand how the AMA perceives the issue.

The problem is too many people do not have health insurance.
Therefore, those individuals and families who can afford the insurance will be forced to purchase it. There should be subsidies for those who cannot afford it.

Who will decide if a family can afford it? The government will. Who better to decide how one should spend their money than the government.

Where will the subsidies come from? The government. Where will they get the money? From the individuals and families who can afford health insurance. The government gets all its money from the people who make money. One of the AMA's arguments for this proposal is that "cost shifting" has become a problem and the system has no more elasticity to allow for further shifting as if this proposal is not cost shifting itself.

How will the folks be forced to buy insurance. Well although AMA left many details to be worked out they favor the enforcement to be carried out by the tax structure. I think this means the IRS. I guess IRS does not have enough to do already.

Predictably, the libertarian CATO Institute opposes the mandated medical insurance proposal, both on practical and philosophical grounds.Michael Tanner, in Cato's policy analysis number 565, points out the difficulties in implementing such a program. He analyzes how relatively ineffective mandatory auto insurance has been with the uninsured rates in states with mandatory insurance being little different from those states without such laws.He writes in detail about the problems associated with various possible enforcement techniques.

On a philosophical level they echo AMA delegate, Dr. David McKalip who said " What you're doing here today will results in a single payer system"

Cato puts it this way:
An individual mandate crosses an important line: accepting the principle that it is the government's responsibility to ensure that every American has health insurance. In doing so, it opens the door to widespread regulation of the health care industry and political interference in personal health care decisions. The result will be a slow but steady spiral downward toward a government-run national health care system.

Does the AMA resolution confuse " Wouldn't it be nice if..?" with "Lets pass a law making it happen"?

When Will Rogers was asked how to implement his suggestion regarding the German U-Boat problem by boiling the oceans, he replied that he would leave that up to the detail men and that he was a policy man.Some of us feel uneasy encouraging the government to work out the details of our health care policy but it seems now the AMA does not.

NEJM Health Policy report-employee sponsored medical insurance

Since employer-sponsored medical insurance is the cornerstone of health care in the U.S. physicians will be well advised to be aware of-at least- the basics of the history of that phenomenon. A non-exhaustive primer can be found in the July 6,2006 issue of NEJM written by David Blumenthal.("Employer-Sponsored Health Insurance in the United States-Origins and Implications"NEJM 355:1,p.82)

We are told that it may have been the opposition from the then apparently much more powerful AMA and possibly Roosevelt's friendship with his in-law Dr. Harvey Cushing that led to the omission of national health insurance from the Social Security law.

The relationship of the price and wage controls from WW II and the rise of employee hospitalization insurance ( people apparently went to the hospital back then when they were sick) is discussed, along with the ruling that such benefits should be considered part of the wage package and therefore part of union contract negotiations. Tax code provisions made employer medical insurance plans beneficial to employee and employers.

One example of [presumably] unintended consequences is the effect of the 1974 passage of ERISA leading to many large employers becoming self insured and thereby being largely exempted from state regulation of the coverage and small employers facing higher costs to provide insurance.

Much less well know is the 1990 ruling by the Financial Accounting Standards Board (FASB),which is the group that sets the rules for the accounting industry.By ruling that companies who covered health care of retirees had to carry those future liabilities on their balance sheets , the assets of many companies were reduced, stock values fell and as a result a number of firms stopped the practice of offering such coverage.

Another useful overview of how we got to where we are now can be found at the University of Nebraska web site in their video library of grand rounds in which Dr. Lynell Klassen discusses " The Practice of Medicine in 2011".

For a reader who has the time and energy to dive deeper into this issue, Paul Starr's book "The Social Transformation of American Medicine" is still in print and appears to be an obligatory reference for any review of the subject.

Australian authors berate academic medicine for not calling the absurd "absurd"

A 2005 Medical Journal of Australia article pulls no punches as it decries the rise of CAM (complementary and alternative medicine) in academia.

The authors,Wallace Simpson and Kimball Atwood iv,discuss how something as absurd as much of CAM has gained an alarming degree of respectability in medical schools. They speak of :

"The guardians that usually keep the institution of medicine from reeling off into irrationality are social contracts built into medical science and ethical behavior. The academic community guards the contractual borders of science, while laws and regulations encode our ethical system. For the Absurd to have advanced, there must have been some breakdown of these social guardians."

So, why did the medical academics (collectively) fail in this role?

The authors suggest that the rise of Postmodernism is a factor. I cannot help but think that the availability of federal and foundation research money to " investigate"- or more commonly promote-CAM has to also be a major factor. Why else would medical schools sponsor CAM clinics and conferences?

For whatever reasons, it seems that medical schools ( many of them ) have lost their way. It used to be about teaching the science and art of medicine not the science, pseudoscience and art of medicine. What is the compromise between science and pseudo science? There is none.

Does Complicity theory explain aspects of the COXIB matter?

Paul Dieppe of the University of Bristol attempts to explain aspects of the VIOXX matter using complicity theory. His article is interesting reading and thanks to Pharmagossip for the link.

I think deciphering why things happen is a bit like interpreting poems to discern what did the author really mean. It is an interesting exercise and often we seem to feel better when we "know" why things happen but in the end is it anything more than speculation?

Dieppe says in part:

"Complicity works like that. All those with a vested interest in an enterprise get sucked into the rhetoric associated with it, and they soon ' believe' in everything that is going on within that enterprise. If personal financial gain is involved, corruption may also occur."

How much they believe and how much "they go along to get along" is hard to determine but it is clear that people in groups do things they would never do on their own.