The Limits of Risk Factor Epidemiology

First a great quote, from Michale Thun, VP of Epidemiology and Surveillance Research at the American Cancer society:

With epidemiology you can tell a little thing from a big thing.What's very hard to do is to tell a little thing from nothing at all.

Gary Taubes in his widely cited article,"Epidemiology Faces Its Limits",Science, Vol 269,p. 164,July 1995, followed that quote with this comment:

...journals today are full of studies suggesting that a little risk is not nothing at all.

There is no basic law of science or statistics or epidemiology or metaphysics which will define how large a relative risk or a odds ratio has to be before physicians and patients need be concerned. Here we are talking about the interpretation or weighing of the evidence that accrues in the quest for evidence on which to base medicine.

Committees that author guidelines typically outline for the reader what their evidentiary hierarchy will be, usually randomized clinical trials at the top etc. But what are the rules for judging individual studies particularly the observational ones, e.g. case control studies and cohort studies.How big should a RR (or ORs for case-control studies) be before they consider that study worthy of adding to the pile of evidence worth of consideration ?

To get a sense of what the professionals do in that regard we could survey experts and see rules of thumb they use in knowing when to consider an observational study worthy of worrying about or suitable for publication. What we learn is that it may not be just the size of the RR but the overall context.

Robert Temple of the FDA is quoted by Taubes as saying:

My basic rule is if the relative risk isn't at least 3 or 4, forget it.

However, Dr. John Bailar,from McGill,believes there is no magic dividing line.

If it's a 1.5 relative risk and it's only one study and even a very good one, you scratch your chin and say maybe.

It is not size of the RR alone ( but we have to agree at some point low is too low say 1.03 relative risk) but the results of other studies addressing the same issue and concerns about scientific in general and in specific biological plausibility have to be factored in. Even though the size of the RR or OR ( odds ratio) is not necessarily determinative it is easy to cite a number of experts in the field who favor the notion that RR less than 2 should be- if not dismissed- at least looked at with a very skeptical eye.

While size of the relative risk is not the end of the analysis, it is the case that small RRs are more likely to be generated by undetected systematic error(s) than are large one. A RR of 1.2 should be much more suspect than a RR of 3.2

The observational studies can be considered coarse-grained instruments with bias and confounding being the basis for the coarseness,the hidden variables that can lead to an association that is not real. While calculating a confidence interval takes random variation in the data into account , bias and confounding lie outside its reach.

Sophisticated (and to many medical readers-mysterious) statistical methods such as various types of mathematical modeling may serve to eliminate or minimize some of the systematic errors but in the final analysis the reader or researcher still does not know to what extent biases are not controlled. I have yet to read the discussion section of an observational study in which the authors did not believe that they had "controlled" for sources of bias and confounding even when that study contradicted an earlier one whose authors also believed their methods likely excluded bias.

I believe that the best an ordinary medical reader -one whose wall is not decorated with an advanced degree in epidemiology or statistics-can do is:

1.Be very skeptical of Relative Risks less than 2 and particularly less than 1.5
2.Look in the articles' discussion sections for citation of confirming or contradictory studies.
3.Consider whether the findings fit some concept of reasonable biological plausibility.

Proton pump inhibitors, hip fracture and small relative risks

A JAMA article has generated considerable media attention citing a case control study that linked PPIs (proton pump inhibitors) to an increased risk of hip fracture.

The overall adjusted odds ratio was 1.44 with a confidence interval of 1.3-1.59. There was a dose response relationship demonstrated with duration of therapy.

Observational studies, such as this case-control study, are generally accepted to be so-called "hypothesis generating" studies rather than studies that more suggest a causative relationship (o.k. I'll stipulate causation is a deep, complicated philosophical issue and I use the word here just to indicate that case-control studies are just the beginning of efforts to demonstrate likely causal relationships).

A dramatic example of how observational trials can be misleading can be found in the juxtaposition of two studies in the New England Journal of Medicine dealing with relationship between hormone replacement therapy and coronary artery disease. One study demonstrated a two fold increase in coronary disease risk while the companion article showed a coronary artery risk reduction of 50% in those who used HRT.

There has been a number of conflicting case control studies regarding the relationship between statin use and colon cancer risk which again points our the problems involved when you take the results of one such study too seriously.

Let's quickly apply Bradford Hill's criteria to the PPI-hip fracture issue. The temporal relationship is there. There is a dose response relationship is a reasonable biological plausibility- low stomach acid conditions can interfere with absorption of some forms of calcium.
However, the association (1.44. OR) is not very large and there is not a strong consistency of results in other observational studies. (The JAMA article quote another study with similar results and one that did not demonstrate the association). At the end of the mini-analysis we still don't know if the reported relationship is valid or really know if we should somehow change our practice in regard to PPIs.

How big should the relative risk (RR) or odds ratio (OR) be for us to be concerned with the results? This is the very question asked by Dr. David Sackett in his book " Evidence-Based Medicine. How to practice and Teach EBM", Churchill Livingtone. Second edition,pg 162).For an answer to this the pioneers in EBM turn to argument by authority as opposed to an evidence based reason.

In regard to a case control study he said

We might not want to label an odds ratio from a case-control study as impressive unless it is greater than 4 for minor adverse events and set this value progressively lower [for more serious events].

Further, he says in regard to a cohort study, where there is less potential bias , that a relative risk of greater than 3 might be convincing for a more serious adverse event.I have posted before on the issue of RR in the 1-2 range.

John Ioannidis stirred up the medical community a bit in his article "Why Most Published Research Findings are False" and in regard to small relative risk determinations he is quoted as saying:

The smaller the effect sizes in a scientific field, the less likely the research findings are to be true...more likely true in scientific fields with ...relative risks [ in the 3- 20 range] ...than in scientific fields where the postulated effects are small [in the 1.1-1.5 range]

Could this study, and so many more with RRs less than 2 hit that hit the headline news, not really be worth much concern at all since the reported increased risk is so small ?

Dr. Marcia Angell, NEJM editor, has been quoted as saying that generally they only accept papers if the relative risk is 3 or more, particularly if it is biologically implausible or if it's a brand new finding. In the PPI case, there is some biological plausibility and occurs in the context of at least one study with findings pointing in the same direction.

In some legal venues, a relative risk of 2 or more is required to meet the legal standard of "more likely than not".

The PPI study authors suggest we should recommend that calcium supplements be taken with meals and I would add recommend adequate amounts of vitamin D ( thought to be about 800-1000 units per day now) and to perhaps have a looser trigger finger on the indications for measurement of bone density in those patients who are on long term PPI therapy and/or higher dose. However, I do not think patients whose GERD symptoms have been controlled by PPIs-and sometimes this change has been dramatic-should throw away their pills.

Is being a hospitalist the only way to still be a old time internist?

Dr. Laurence Wellikson seems to believe that the only way -at least a way-to recapture the core of what internist used to do (care for the patient with the complex problem(s))is to become a hospitalist.

Here is a point-counterpoint presentation by Dr. Willikson,CEO of the Society of Hospital Medicine,and Dr. Robert Centor,President of the Society of General Internal Medicine on the topic of "What is an Internist?"

Willikson seems right on target when he speaks about "internists [having] devolved into gatekepers and primary care physicians" ...[and] competing with Family Practitioners and Nurse Practitioners to be the traffic cop for resource use and burgeoning specialization."

He then inserts some of the current- in- vogue- jargon of the business consultants and speaks about the importance of preparing a "value proposition" and then makes what I consider to be a "boil the oceans" type suggestion namely to "reset the reimbursement system".

Given the current power relationship between third party payers and physicians it hard to conceive of what doctors could do to change the system. Hospitalists are either employees of the hospitals in which they practice or are contractors. The only tool either group has to bring about change is the strike, an action that physicians have rarely participated in. Changing the current medical care-reimbursement system is going to take more than hospitalists or internists writing a value statement, which I understand to be a statement made by a business explaining what they do and why the targeted customer should by it. (It occurs to me what if other specialists were exhorted to author a value statement.Perhaps neurosurgeons would propose "We take out brain tumors better than anybody."

Hospitalists do seem to spend most of their work day doing what many of us wanted to do when we decided to become internists and I hate to think the only avenue for the Oslerian type internist to travel is that of the hospitalist but that may be the reality though we have not quite arrived at that point yet. I hate to think that because an important part of what I used to do was not only caring for the complicated case in the hospital but also as an outpatient. This was a common occurence with COPD patients with exacerbations requiring hospital and often ICU type care. Internists should be the ones caring for patients with complex medical problems in and out of a hospital setting. There are still internists who care for the complex cases as in and out patients but clearly it is getting harder to do that. Dr. Wellikson seems to think internists should care for complex cases outside the hospital as well but leaves me wondering how he thinks that will happen.

Sowell's "Conflict of Visions" and medicine

Thomas Sowell's book "Conflict of Visions" is one of the most insightful and intellectually satisfying books I have ever read.It deals with the ways in which people differ in their fundamental view of the world.

Sowell observes that "reality is far too complex to be comprehended by any given mind" and therefore humans need maps, or a sense of how the world works to enable them to make sense of it all; he describes these maps as visions or pre-analytic cognitive constructs.

These visions differ about the basic nature of man. Sowell considers that this visions can be categorized into two broad categories are the "constrained view" also called the Tragic view and the "unconstrained view" also called the Utopian view.

In the Tragic view, man is constrained by his moral limitations and his egocentricity. The social challenge is how to work with those limitations rather than engage in energy wasting and ultimately futile efforts to change human nature.In this view, one deals with trade-offs and not solutions. Benefits to society derive from actions largely unintended but emerging from market actions which derive from the pressures of the incentives for individual gain which include the monetary and the psychic. Much of the meat of the constrained view can be picked from Adam Smith's "The Wealth of Nations". In a scheme that values trade offs , prudence assumes a high position. Burke said "Nothing is good but in proportion and with reference."

Steven Pinker in his book, 'The Blank slate' expresses the differences between the visions in this way :

In the tragic vision, humans are inherently limited in knowledge,wisdom and virtue and all social arrangements must acknowledge those limits....in the utopian, psychological limitations are artifacts that come from our social arrangements and we should not allow them to restrict our gaze from what is possible in a better world."

In the Utopian view, social inequalities such poverty,uninsured patients,drug addiction, racial or gender imbalances are seen as resulting from faults in society and therefore warrant that social targets be developed and plans made to rectify the social problems. The tragic Visionist would be concerned with the self interested motive of the people who are tasked with carrying out the programs and also with the unforeseen and unintended consequences that such projects seem to invariably entail.

Uneven distribution of wealth as brought about by a market economy in the unconstrained view is thought of as being unjust and in need of remedy in the name of social justice. The constrained view would argue that the notion of justice does not make sense when applied to an abstraction as society and would speak of justice only in the context of human decisions in a framework of laws.

So what has all of this to do with medicine? I believe the current iteration of Medical Professionalism ( Medical Professionalism in the New Millenium.A Physician Charter.Ann. Int. Med 5 Feb 2002, Vol. 136, pg 243-246) reflects the Utopian View and to a degree I find distressing has become part of the medical education agenda and the writing and speech of academic and organizational physicians. In this new charter, justice is emphasized and the justice proposed in their construct of social justice involves concern about "allocation of medical resources" and physicians considered stewards of society's resources.It talks about "commitment to a just distribution of finite resources" and to be committed to "develop guidelines for cost effective care".

Of course, concern for the individual patient's welfare has not be abolished and the "primacy of the patient welfare " is still said to be fundamental. However, a potentially conflicting principle,the social justice imperative, has been added the physician's obligation list.

I grew up medically with notion of concern for the individual patient being primary-first do no harm and to act always in the interest of the patient. Fiduciary duty was the decision trump card. I wonder at what point the imperative of "just allocation of resources" trumps concern for the welfare of the individual patient. The front line physician battered back and forth in the moment to moment flurry of phone calls, lab tests, patient problems, managed care restraints and hassels will have little time, energy or the tools to somehow factor into his patient decisions concern about "society's resources".

Now American College of Surgeons favor P4P-say it isn't so ,Joe.

Seemingly following in the footsteps of the American College of Physicians (ACP) the executive director of the American College of Surgeons (ACS) has written a letter to the NY Times advocating P4P. Dr. Thomas Russell wrote in part:

"Many physicians have long encouraged efforts to advance evidence-based care such as Medicare's "pay for performance" system. They do so because such steps are in the best interest of patients."

His comments seem mainly to be gratuitous asssertions which can be countered by equally gratuitous denials since he offers no arguments in support.Those of us who have serious questions about P4P and believe it to be simply wrong on many levels believe that is not in the interests of patients and that it will not advance evidence-based care.I have been of the opinion that the majority of real life internists in private practice do not share many of the policy decisions of ACP, I would like to hear from the prolific and articulate surgeons bloggers if a similar situation exists in the surgical world. I suspect it does.

More accusations of big pharma behaving very badly

The ethics of business is not the same as the ethics of medicine but if recent accusations against Lilly are true you might conclude that in regard to some businesses the word does not even apply. I have quoted Dr. Patricia Illingworth before:

...some commonly accepted principles of business ethics are fundamentally incompatible with traditional medical ethics...,

These practices include spinning and playing down the negative aspects of your product and intentionally misleading customers and maybe that is why we have laws against deceptive trade practices.

Reuters today published an article saying that the NY Times web site describes Lilly's activities promoting off label use of Zyprexa (olanzapine) and acting to play down Zyprexa's known side effects of significant weight gain and increased risk of diabetes. They are accused of a stealth campaign to promote the drug's use in dementia. Olanzapine has FDA approval for use only in Bipolar disease and schizophrenia.

NY Times writes about internal Lilly documents that suggest Zyprexa be promoted to primary care docs for use in dementia noting that psychiatrists are the physicians who mainly treat schizophrenia and bipolar disorder and primary docs do not feel confident is managing those conditions but they do manage many elderly patients with varying degrees of dementia.

Evidence is presented that indicates sales reps did in fact promote the drug for the off label use with the result of a significant increase in sales and were given monetary incentives for those activities. The promotional program was known as "Viva Zyprexa". A representative for Lilly denies claims of promoting the drug use for non approved indications and is quoted as stating that a Zyprexa-diabetes link has not been proven.

FDA relegates Ketek to second line treatment for community acquired pneumonia

The FDA seems to making some progress in the Ketek matter.Maybe now we will be seeing less of the ubiquitous Ketex advertising owl on the back of medical journals.

I have been concerned with the Ketek issue for some time and have blogged on and on about it on several occasions.I expressed the opinion that there was little if any indication for that drug.It had been approved and marketed for sinusitis,bronchitis and community acquired pneumonia (CAP).Now the FDA panel says use it only as a second line drug for CAP.At least they are heading in the right direction. The risk of liver disease seems real (I believe at least 12 fatal cases so far) and why anyone would use it to treat sinusitis escapes me.

ADDENDUM:(12/19/06) Thanks to an alert reader I was informed I had misspelled the brand name of the drug in question when this message was first published.Since one who controls the present controls the past I am now going to at least partially control the past and republish the corrected posting with the explanatory addendum. James Gaulte

Post-modernism,EBM and George Orwell

Dr. Roy Poses in his Dec.01,2006 posting on Health Care Renewal tackled the topic of the attack of the post-modernists on Evidence Based Medicine (EBM). From time to time, I have written about the mis-use of EBM to cook the RCT books and hype the results and about how some may misunderstand EBM but the post-modernists attack on EBM seems to be basically self contradictory.

As pointed out by Steven Pinker (pg 426 ," The Blank Slate, the modern denial of human nature")

"It is ironic that a philosophy that prides itself on deconstructing the accoutrement's of power should embrace a relativism that makes challenges to power impossible, because it denies that there are objective benchmarks against which the deceptions of the powerful can be evaluated."

Pinker prefaces those remarks by discussing the totalitarian regime found in "Nineteen Eighty Four" and by describing their philosophy as "thoroughly postmodernist".

He quotes from the government agent, O' Brien, as he lectures the protagonist, Winston Smith, who is strapped to a table and tortured and "educated ".

"You believe that reality is something objective,external, existing in its own right. ...But I tell you, Winston, that reality is not external .[it exists] only in the mind of the party, which is collective and immortal"

When there is no objective truth and no means of obtaining the truth,whoever is in charge determines what it true or not. "Who controls the past controls the future:who controls the present controls the past."

A frontal attack on the science of medicine or on science in general is fairly easily beaten back.Nonsense tends to fall on its own weight even if sometimes that fall may take longer than we would like. In regard to medicine and medical education the greater danger seems to be in the infiltration of alternative medicine elements-and its philosophic underpinnings,Post Modernism- into the curriculum of medical schools and even into the clinical services they offer. Dr. RW relentlessly keeps us well informed about the alarming instances of medical schools offering courses and sponsoring clinics for practitioners of the various categories of altie hokum.

Doctors fight back, Insurance company capitulates

The above headline was inspired by a news report in the daily email I get from AMA ( one of the few perks of membership). I had blogged previously about the Blue Shield matter in Seattle.

Apparently, something call the "AMA Litigation Center" joined in a legal action with the Washington State Medical Society and six physicians against the "Select Network Plan" devised by Regence Blueshield. I had not heard of the Litigation Center, but it seems that for the past 10 years it has been involved in legal actions that look after the interests of physicians and has a new initiative to fight back against insurers who play fast and loose with bogus guidelines and performance indicators "delisting" docs and damaging their reputations and practices.

The insurer dropped the plan.

Dr. Pleasted, president of AMA, is quoted as saying:

"A patient's choice of a physician must not be influenced by a health insurer's mistaken assumption that low cost is the only acceptable measure of quality."

Physicians should not neglect the powerful effect that legal action that sometimes have but what happens now is not clear.What about the patients that received letters from the insurance company informing them that their doctors were not practicing according to some standards? They were said to not be practicing "quality and efficient " medicine. What reparations will be made for lost patients,damaged reputations and lost income? According to AMA websites ,( I believe membership is required to access) the law suit continues in an effort to obtain monetary damages.

JAMA article considers Hospital Performance Measures and mortality rates

In the December 13, 2006 issue of JAMA, Drs. Rachel Werner and Eric Bradlow analyzed data from 3657 acute care hospitals looking at the relationship between certain performance measures and mortality rates. They used 10 measures which are available from CMS and the Joint Commission 's web site. For example, in regard to pneumonia the measures are: 1) timing of initial antibiotic administration, 2) pneumococcal vaccination and 3)whether oxygenation was measured in the first 24 hours.

The authors concluded that:

"hospital performance measures predict small differences in hospital risk-adjusted mortality rates"
and said further:

"Based on these results, the ability of performance measures to detect clinically meaningful differences in quality across hospitals is questionable"

Dr. Susan Horn in her related editorial makes several good points:

1.If these performance measures are not strongly associated with outcomes, why should we bother with them either as basis for P4P of for consumers to use as tools for judging hospitals?
2.Since many( but not all) of these measures were chosen,at least,in part because of the results of RCTs, why are these interventions not associated with better outcomes in practice?

Her answer to the second question is that improving outcomes in actual real world practice is much more complex and multidimensional than using a few, discrete interventions that seemed efficacious and safe in RCTs that typically focus on a single condition in a fairly homogeneous population. In part, it is the question of efficacy versus effectiveness. Measuring quality of care is much more complex and slippery than the ten measures analyzed in their study.

In an earlier article Dr. Werner pointed out some possible unintended consequences of hospital "report card" including treating the chart and excluding sicker patients.

One message should be: we have no business using simple and simplistic measures as a basis for pay for performance or for claiming to be able to distinguish between different hospitals quality of care. Not only may they not deliver on what they promise, they may be harmful.

AMA President nails P4P for what it is at AMA Interim meeting

Dr. William G. Plested III, president of the AMA had this to say regarding pay for performance at the recent Interim meeeting;

I will point out that-reminiscent of the managed care debachle-P4P will allow insurers to dictate the treatment that we give our patients and will publicly label any physician foolish enough to contract with them and not follow their dictates as nonpreferred, substandard or some such label.

This is not just speculation as the physicians in the state of Washington had exactly that happen to them.

Further, he said that he was unaware of any P4P program in place that was in compliance with the AMA suggested guidelines for P4P.

A proposal was made for the AMA to launch a campaign to discredit P4P and correctly label it as economic credentialing. Unfortunately, no resolution was passed. At least, the president of the AMA recognizes P4P for what it is which much more than can be said for the leadership of the American College of Physicians who seem to be working with the third payers payers to move ahead with this very bad idea. ACP seems to believe-or at least their rhetoric suggests-that they can "work with" third payers to ensure that P4P program will improve quality and not just lower costs.

Randomized trials are wonderful but beware of "evidence based paralysis"

The term "evidence based paralysis" came to my attention in a letter to the editor in the Archives of Internal Medicine in the Aug 14/28 2006 Letter to the Editor section. Drs. David Ziemer and Lawrence S. Phillips from Emory used it in their reply to a comment about an article concerning the issue of whether tight control of type 2 diabetic patients is " evidence based ". They also used to term "RCTomyopia" to refer to an " unwillingness to take action without incontrovertible proof from controlled trials".

RCTs and meta-analyses are considered the most reliable tools in the hierarchy of EBM.(For some time I have questioned whether MA belong in that position.) Because of this, some make the mistake of jumping to the position that if there are no RCTs that there is no evidence based reason for action.

Of course, RCTs are good, but there are not good for everything.They cannot answer all the questions physicians need/want to have answered.

They are great for discrete interventions in carefully defined, relatively homogeneous conditions in terms of determining efficacy. They are clearly less good for determining harm and for determining how to diagnosis conditions and for determining prognosis. In regard to harm, RCTs can recognize relatively common adverse effects that occur fairly soon after a medication is started but are less useful in detecting less common and/or delayed side effects.

However, when the questions to be answered arise in and from more complex patient populations in which the patient characteristics and interventions are more complex and heterogeneous it become much more difficult to separate out causality from bias,confounding and even random variation.In fact, some times it is more than difficult in that after the trial has been done and analyzed we still do not know the answer we were searching for. Case in point is the recent back surgery for herniated disc versus conservative management RCT published in JAMA. In this instance, there was so much cross over between the two groups as they were randomized that the "intent to treat" analysis was not considered valid and the "as treated analysis" suffers from the very real risk of selection bias which is why we have randomization in the first place. One is left with the disturbing thought that it may not be possible to solve this clinical issue by doing a randomized trial as long as we deal with patients who are free to do what they think is best for them.

It is important to know the limitations of the RCTs and that the very nature of certain clinical problems may be too complex for RCTs to be of use. Further, RCTs can never be done for all the problems that they are suitable to analyze.There are too many questions, often too little money and interest and with new drugs, procedures and testing methods always evolving-or at least changing-older RCTs lose relevance and the newer treatments may be years away from RCT results.

In treating patients with serious illnesses often we have to act not just sit there. We have to go with the evidence we have not the evidence we would like to have.

Ziemer and Philips had this to say in their letter to editor:

We believe that responsible physicians and patients should make decisions based on the best available evidence-including cell and animal studies, observational studies and controlled trials if available-and the strengths and weaknesses of the findings with each approach should be given due consideration.

I cannot resist when discussing this general topic to throw in the parachute-gravitational challenge comment that I quoted last year.

Preliminary Results of TORCH trial suggest a greater role for combo therapy in COPD

TORCH stands for "Towards a Revolution in COPD Health" and may well earn the yearly prize for the most self aggrandizing name for a trial . Here is a reference explaining some details of the trial and purported reasons for doing it.

Briefly, this was a 6200 patient trial involving 4 arms one of which was B.I.D.administration of an inhaler with salmeterol 50/fluticazone 500- the others were: placebo, LABA alone and ICS alone. COPD patients had to have a FEV1 less than 60 % to be eligible.

Here is a medical newspaper type writeup of the presentation of the results.

There was an all-cause mortality reduction of 17.5 % which was not statistically significant (p = 0.052). As usual, if one statistical parameter is not what you want, you can always do another which was done. In this case,the other one was the Cox proportional analysis by which the hazard ratio was 0.811 and this was statistically significant at p=0.03 and the COPD death reduction was statistically significant. So does the combo improve survival or not? It seems to depend on what statistical test you think better reflects reality.Within the temple of evidence based medicine, priests may differ as to what statistical incantations best produce the truth.

Life is messy and so often are the results of clinical trials. On balance it does look like the 50/500 combo of a ICS and a LABA seemed to be beneficial but we have not heard the end of the argument over "does it really decrease all-cause mortality". No doubt the statistical brain power that GSK can muster will put forth good argument on the pro side. Already we are hearing terms like "landmark" study" and comments like "new hope for COPD patients". The combo of an ICS and a LABA is already widely used in the treatment of COPD. In COPD, it is standard to use a LABA first and then add on an ICS for more severe disease with the opposite sequence being the rule in asthma treatment.

According to the 2006 GOLD criteria, one should recommend a long acting bronchodilator if the FEV1 is between 50% and > 30 %. This would mean that in the TORCH trial patients were given the combo (ICS + LABA) at an earlier stage than suggested by GOLD.In addition many patients with moderate COPD are given a long acting anticholinergic and later an ICS is added So,in a way the trial differs from usual clinical practice.GOLD 's position is that there is no definitive evidence indicating if a LABA is better or worse than an anticholinergic and with the continuing controversy over the safety of LABAs many doctors may well choose to begin with an anticholenergic particularly since there is now one that is long acting (once a day use), i.e. tiotropium (Spiriva).

My sense of it is that many physicians already would add Advair to Spriva as COPD worsens or for more severely impaired COPD patients and that would be my approach.I doubt the TORCH study will be much a "revolution" though some may add the combo earlier than Stage iii after reading TORCH.

Why can't the practice of medicine be more like a widget factory or running an airline?

Perhaps goaded on- in part by the urging of insurers and third party payers to save money- we are from time to time treated to a commentary by a giant or would be giant of industry or business to instruct the generally hapless medical profession about how to run a railroad.

When the extremely competent and accomplished Andy Grove on Intel editorialized on this topic in JAMA , Roy Poses of Health Care Renewal responded with a post worth reading and which more than suggested that Mr. Grove may not know much of the doctor business.

We are often admonished to emulate the principles embodied in the safety practices found in the airline industry and there is truth to be found there. A recent post by Aggravated DocSurg entitled "Fly me to the OR" is a gem -nothing unique there-which makes the point how little being a surgeon has to do with flying an airplane.

There is no substitute for experience

An editorial by Geoffrey Norman, Ph.D entitled "Building on Experience-The Development of Clinical Reasoning" is found in the November 23, 2006 issue of the New England Journal of Medicine.

I have written before on the importance of experience to gather up the particulars necessary to begin to be an expert. Dr. Norman's editorial is a pleasure to read because his views coincide with mine.

He points out that in regard to the nature of expert clinical reasoning there was-for a while- a school of thought that posited that it involved the acquisition of some general problem solving skill. Apparently this approach was wrong. He speaks of "content specificity" which means that success in problem solving was strongly related to have the right kind of content knowledge.

Basically experts have to know their subject matter. Here is a key quote from his editorial:

"The process of pattern recognition, so characteristic of an expert's approach, is a product of extensive experience with patients overlaid on a formal knowledge background."

He continues:

"...trying to teach or evaluate clinical problem solving or clinical reasoning skills is quixotic. Knowledge counts."

It is all about practice and experience and previously I wondered what the consequences are/will be of the time shortened internal medicine training program. Will the novice internists leave their training programs with the expertise needed to qualify as even a rookie expert?

Last year,an Annals of Internal Medicine article highlighted a case of TB that was very badly mishandled in a teaching hospital. The emphasis in the discussion-inappropriately in my view-was on a systems approach fix. What the problem was that the pattern recognition skills of the house officers and apparently the radiologists were seriously lacking.

Still more on the SMART trial and the Salpeter Annals article

I have written several times before on the SMART trial and the meta-analysis (MA) written by the Salpeter family team in the Annals of Internal Medicine and suggest that the former might serve as a teaching tool on how not to do a clinical trial and believe the latter could be instructive to those who wish to publish a flawed and opinion laden meta-analysis.

Letters to the editor of the Annals and now a more formal rejoinder has been published-all very critical of the MA and defending the use of a long acting beta agonists (LABA) in conjuction with a inhaled corticosteroid (ICS) in asthma. This article and a 2005 Cochrane review
both provide good data and analysis that lead to the conclusion that LABAs when used in conjunction with ICS in asthma leads to better control, fewer exacerbations and not only does not pose the risk claimed by Salpter but represents the standard of care for patients with more severe asthma.

Mark Twain or Bismark or someone supposedly said that there are two things you should never watch being made- a law and sausage and it has been suggested that MAs should be added to the list.Yet accepting the results of a MA without knowing how it was really made is an act of faith which supposedly we decry in the "age" of evidence based medicine.When your MA turns on the results of one large trial and that trial is seriously flawed the MA is worthless and potentially harmful which is what happened with the SMART trial and the Salpeter Meta-analysis.

Hopefully,the recent Annals article will clear the air. The above cited reference regarding sausages also makes the important point that MA s should include- along with experts in the methodology used- subject matter experts. Some MAs that I see seem to be written by authors who are excited about their meta-analytic skills and seem to believe they can analyze the forests so well that they need not bother to ask a tree expert for input.

Even the PPD may be replaced?

Nothing seems secure from progress or change or innovation.The Mantoux skin test has been around for over 60 years and is now being challenged by two commercially available tests that measure the blood levels of interferon-gamma release from sensitized T cells after stimulation by antigens fairly specific ( apparently there is some sharing of antigen with M. Kansasii) to Mycobacterium tuberculosis.

The QuantiFERON-TB gold Assay has been approved and in 2005 CDC recommended its use in all situations where PPD has been used. The results can be obtained quicker and the assay kits are said to have greater specificity and equivalent sensitivity.The blood must be received in the laboratory within 12 hours, which can be a drawback.The test is to be used just as the PPD is used.A good review of particulars is found here. CDC is recommending its use as a replacement not as an addition to the PPD. The in vitro assays should eliminate the problem of the booster phenomenon which in the past has lead to pseudo-mini-epidemics of TB in hospital personnel, described here, and the vagaries of interpretation of the PPD in a person who has received BCG.

The other assay is called T-Spot.TB.Here is a interesting comparison of how results from the two tests may differ.

Surgical versus nonoperative treatment of herniated lumbar disk-a randomized trial

The SPORT trial results are published in the November 22,2006 issue of JAMA. The Spine Patient Outcomes Research Trial was a 501 patient randomized trial involving 13 centers over a 4 1/2 year period. All patients had imaging confirmed lumbar intervertebral disk herniation with persistent symptoms and signs lasting for at least six week.Surgery was a diskectomy with at most a small portion of the superior facet being removed and a disc fragment removed and the nerve root decompressed.

It is generally agreed that the appropriate way to analyze results in a randomized trial is by a " intent-to-treat" analysis. However, in this case because there was such a large percentage of patients who crossed over to the other treatment arm and a significant amount of missing data that the intention-to-treat analysis was not informative about which approach was better and in the words of the authors "conclusions about the supriority or equivalence of the treatments are not warranted based on the intent-to-treat analysis alone". However, it did show small and non statistically significant advantages to the surgical approach for most measures with a statistical improvement in sciatica.Here is an excellent discussion of intent to treat analysis and the traps involving in attempts to consider the problems of lack of adherence and loss of data in a clinical trial from Dr. Gerald Dallal,a Yale epidemiologist .

When one analyzes the as-treated groups there was a definite advantage to surgery.But the validity of this conclusion is clouded by the concern about confounders as the two groups were no longer randomized. So it seems that we cannot know if surgery is better or not regardless of which analytic technique is used. If you do look at the groups as treated there are much larger effects in favor of surgery which did not disappear after correction for recognized covariates.

It seems that at the end of the day this fairly large, multi center multi year trial did not provide the answers to the questions for which the trial was designed. So what is next?

One of the two editorialists in the same issue of JAMA, Dr. David R. Flum, believes the only way to answer the still unanswered questions raised in SPORT is to have a randomized, placebo controlled trial. Placebo control in this sense means sham operations. The authors of SPORT ruled out sham operations because they believed subjecting a control group to general anesthesia with its attendant risks was not ethical. Flum disagrees. He says that sham procedures would be ethically justified on the "question of community exposure to an invasive, high risk procedure with associated risk ". I think he is saying that since large numbers of folks are"exposed" to the risk of diskectomy a sham controlled RCT would be justified to learn the answer to the question, " Is the procedure justified?" This, I think, is a type of public health style justification implying that diskectomy is some sort of risk that people are exposed to against their will as opposed to a decision made by the individual patient to undergo the procedure.

I realize that sham surgery RCTS have been beneficial in the past at times showing the lack of value of certain operative procedures, internal mammary ligation for angina for one, but the dramatic improvement ones sees when someone with severe pain, and objective weakness, improves immediately after surgery is hard to attribute to a placebo effect particularly when the surgeon sees a nerve root being compressed and relieves that compression.

This and other trials have shown that after 2 years there may be little difference in the outcomes in the surgery and non surgical groups but when you have unrelenting neuropathic pain-for which typically usual analgesics work poorly-the option of quick relief is something I would opt for. In the long run the two approaches seem very similar in terms of outcome but remember what John Maynard Keynes said about the long run.

Do ABIM and ACP differ regarding P4P?

The American College of Physicians (ACP) has supported P4P. An organization,the American Board of Internal Medicine,frequently sees eye to eye with ACP. Apparently this is not the case in regard to P4P according to a recent letter to the editor published in the November 2006 issue of "ACP Observer". Dr. Christine Cassel is president and CEO of ABIM and says the following in her letter:

"ABIM does not 'support' pay for performance."

"... pay for performance is a strategy that has yet to prove itself as a mechanism to improve quality of care"

The apparent link from ABIM to P4P may lie in the fact that physicians who are taking part in the ABIM's " Maintenance of Certification" program can receive credit from many health plans and that credit could be linked to a P4P arrangement. So it seems like ABIM is sort of working with insurance plans on activities tied to "incentive" programs but do not support P4P and consider it a unproven way to improve quality. I can see why Dr. Cassel saw fit to write a letter to explain the situation because some would consider their arrangement with health plans "support".

Do thiazide diuretics cause "benign" diabetes?

That thiazides precipitate "benign"diabetes is, in part, the argument made in the recent issue of the Archives of Internal Medicine in an editorial accompanying still another analysis of data from the ALLHAT trial.This study was a post-hoc analysis with a followup time of five years in which three groups were compared-those on a diuretic, those on a calcium channel blocker ( CCB) and those on an ace inhibitor (ACEi).

Those taking a CCB or a ACEi were statistically less likely to develop diabetes than those receiving a thiazide. Strong advocates of ALLHAT's preference for thiazides have put forth what I consider to be a strange argument that I think goes something like this; Yes, thiazides cause more diabetes but it doesn't seem to alter the outcomes. This they say because the various post hoc analyses fail to show a mortality excess. But the time frame of these studies is short-five years in the current Archives article with an average time of followup of 3 years- and are post hoc, sub group analyses which in the catechism of evidence based medicine are not very high on the evidentiary pecking order. The absence of proof of an effect is not the same as proof that the effect does not occur.

Although the editorialist repeatedly admonishes the readers with references to adhere to the principles of evidence based medicine I think it takes quite a leap of faith- not reliance on evidence, which so far is inadequate- to accept the notion that drug induced diabetes is harmless and somehow the patient with diabetes precipitated by thiazides is immune to the ravages of micro and macro vascular disease. While it is possible that the elevated blood sugar in the thiazide treated patients does not represent the disease that we designate as type 2 diabetes the burden of proof lies with the moving party i.e. the one saying this type of "diabetes" carries no cardiovascular or renal risk. The short period of follow up is a major weakness in the study particularly in regard to end stage renal disease but even CV effects may occur only after prolonged periods of elevated blood sugar as was the case in the Diabetes Control and Complications Trial.Further, nearly half of the study group did not have fasting glucose levels measured.

The patient with the metabolic syndrome which we think is driven by high insulin levels secondary to resistance to insulin in various tissues may also be the person with decreasing numbers of pancreatic beta cells and is already close to having elevated fasting blood glucose levels and have his glucose pushed up a bit by thiazides. It is hard to believe his risk of CV disease over the long run is not going to not be elevated. The deleterious processes of type 2 diabetes are at work for years before the fasting blood glucose becomes elevated.I have felt uneasy about prescribing to the diabetes-waiting-to- happen- patient a drug that is well recognized to increase the risk of diabetes.

In spite of the valid criticisms of ALLHAT's original design and its lack of correspondence to real life treatment of HBP we continue to see more re-analyses of the data that was flawed to begin with.

And the number one reason to oppose P4P- It is unethical

Dr. Edmund Blum, an internist from Brooklyn makes the argument that pay for performance (P4P) involves a "irresolvable conflict " with the ethical standards of the medical profession.

His persuasive arguments can be found in the November 6,2006 issue of American Medical News (subscription required) in their "Professional Issue" section.

He says that P4P rests on 3 flawed premises or fallacies the most important of which is that P4P is consistent with medical ethics. He argues that it is not. (The other 2 fallacies are:P4P rests on a valid statistical foundation and P4P will improve the safety and quality of patient care)

I quote;

"[medical] standards derive from a core of fiduciary responsibility, in which one person, the patient, depends on the superior knowledge and skills of another, the physician, and places complete confidence in that person in regard to a particular transaction-in this case, medical care."

"The fiduciary is held to a higher standard of legal and moral conduct and trust than a stranger or a business person...[This] obligates the physician to do his or her best for the patient regardless of reward.The duty goes beyond the 'due care' standard or tort law to a higher level of loyalty and commitment that is not contingent or rewards or penalties."

The idea of P4P involves an assumption that "the fiduciary relationship is insufficient motivation for the physicians to do their best."

To accept P4P is to accept the notion that physicians have not already been obligated to do their best for the patient and to place patient welfare above financial rewards and that they have to be giving a tip or a bribe to do their job. Dr. Faith Fitzgerald was on target when she said

" We must not servilely accept gratuities for doing our duty."

Forty years ago,I began the transformation from a lay person to a physician. Part of what was branded in to my limbic cortex in that years long process was the responsibility physicians have for their patients, a responsibility to do what is right for the patient,a responsibility to place their welfare above personal financial concerns. The acceptance of P4P is so antithecal to that tradition that I cannot believe some professional organizations of physicians are supporting it. It seems to me that support and advocacy for P4P is equivalent to saying the ethics and culture of physicians are not adequate and to provide good clinical care it is necessary for third parties to proscribe behavior and reward and sanction accordingly. To sanction such thinking, in the words of Dr. Blum, is to "push us farther down the slippery slope to deprofessionalization".

Physician group sues insurance company for defamation

According to an article in the November 1, 2006 of Internal medicine News (www.internalmedicine.com) six Washington state physicians and the Washington State Medical Association have filed a suit against Regence Blue Shield. This insurance company notified some 500 physicians that they did not meet the "standards" and were dropped from the network. But they went further- they then contacted 8,000 of those physicians' current patients and informed them that the docs did not meet quality standards basically claiming they did not practice quality medicine.

Attacks on professional integrity or on a professional person's integrity in some jurisdictions may be considered "per se" defamation. I had written before about the Washington state situation and wondered then if there might be a case of legal action and it looks like there may be and I applaud the Washington docs for taking action doing what they can to protect their rights and level the playing field .Other state medical associations have had some success in battling the big insurers, witness the Texas Medical Association action against several large HMOs under RICO.

The lawsuit claims deceptive trade practices,breach of contract and defamation.

Dr. Gail Wilensky (Ph.D) was also quoted in the article as she continues to play the strings of the support-P4P effort and supported the position of the insurance company saying in part "All data has errors but that doesn't mean the suggested conclusions are faulty "

Dr. Wilensky is often described in news articles as a senior fellow at Project HOPE and a member of the Institute of Medicine panel [onP4P]. Often not mentioned is the fact she is on the board of Unitedhealth Group,holds about $800,000 worth of UNH stock or that she cashed in 1.3 million dollars in UNH options in 2005. (information from Yahoo finance as of 11/11/06).

Annals Internal Medicine article"Former CEO Aetna recommends P4P

Dr. John W. Rowe, who is not without impressive academic credentials, recently retired as CEO of Aetna recently authored a five page article in the American college of physician's' journal advocating pay for performance. ACP's position on this is fairly well known and readers will not be surprised to see an article advocating its implementation. However, it does seem a bit audacious to have the former CEO of a major health insurer to pontificate on the "moral basis for physicians...to support efforts to control costs,improve quality of care and participate in pay-for-insurance initiatives."

Some internists members of the ACP might be puzzled as to how an insurance company executive
becomes qualified to lecture them on morality particularly when that insurance company- as well as others- was taken to court by numerous medical societies charging it with various illegal practices designed to seriously curtail payments to physicians and limit patients access to care.

There is, of course, no love lost between practicing physicians and insurance companies in general ,but at least in my experience, Aetna 's reputation in dealing with doctors is near the bottom. The editors of the Annals seem out of touch with real life practicing internists when they choose a former CEO of one of the least liked insurance companies to promote pay for performance.

NEJM "Perspective"Nov.2,2006:Misleading soundbite for P4P- "Shift from autonomy to accountability"

Dr. Elliot S. Fisher is the author for the NEJM piece "Paying for Performance-Risks and Recommendations" (NEJM 355:18 1845). Dr. Fisher has published many articles documenting the "remarkable variation in performance" by the players in ambulatory and hospital based care so we should not be surprised that he favors doing something about it-namely pay for performance (P4P).

Amazingly, after listing some of the major concerns about P4P he dispenses with them by simply saying that the concerns were discussed in a report by the Institute of Medicine (IOM) but that the IOM committee,of which he is a member" then "strongly recommended moving forward with pay for performance." This is a curous argument, indeed, that lists serious problems with the proposal, offers little reason to accept it (he does say payers are "demanding accountability") and then strongly recommends it. The arguments against P4P that he briefly covers are:

1.Concerns about the underlying goal. He says physicians fear that cost control will be the only focus.

2.Are the [quality] measures adequate? He says in part [medical care] "often requires a careful balancing of risk, benefits and patients' preferences, not rigid adherence to clinical guidelines."

3.Is implementation feasible? He acknowleges that for small office practices "costs will be high"

4.Could there be unintended consequences? Such as avoiding sick or challenging patients. (You think there might be a problem if physicians start avoiding sick patients)

Fisher then points out the funding problem. He proposes that the increased funds to "reward" (aka bride" docs for doing their job would be derived from cuts in the CMS programs so that " some providers would see little or no increase in fees."

Fisher then tells the readers that the IOM committee recognized that the evidence underlying P4P is weak and that unintended effects are possible and therefore the federal government was advised to have an effective monitoring and evaluation system in place to recognize potential harms and correct them. This would be a first- a government system that includes some sort of super-system to monitor itself and make mid-course corrections as it goes.

He closes with the claim that the "shift from autonomy to accountability" seems inevitable. This misleading and fradulent semantic ploy is reminiscent of the bogus term "managed care". Of course, physicians are already accountable-to their patients as well as to medical boards of examiners just as care was managed by physicians long before third party payers used the managed care mantra to cut costs.

Thoracic imaging for lung cancer screening-here we go again

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.

"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.

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.