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.

'Unanticipated" effects of the quality movement-JAMA commentary

Dr. Robert M. Wachter, of UCSF, is well known in medical circles for his writing and activities in the hospitalist phenomenon. In the June 21, 2006 issue of JAMA he writes about the quality and IT "revolutions".

His comments about the unforeseen effects of the quality movement resonant with me and likely many real life physicians who may have found the quality activities impeded their work as doctors.I quote:

" More typically, individuals and institutions begin to focus on improving their performance on the variable measure, in doing so turning away from others. This "playing for the test" is not only expected; in some cases it is the point of the whole exercise."

He comments on the most egregious examples of IT gone bad with the Cedars-Sinai debacle and the tragic increase in pediatric deaths occurring after the introduction of a commercial computer system.(Han,YY et al,Pediatrics,2005:116-1506-1512.)

With those facts on the table I find the following puzzling:

"Importantly,until the science of guidelines development and quality measurement improves, the systems must preserve physician's' ability to apply the art of medicine when patients do not fit the templates, such as in those patients with multisystem illness or rapidly changing disease course."

Of course, physicians must have the final say in clinical management,they cannot be replaced with computers and algorithms. The individual physician must be able to deal with the unique particulars of the case at hand. Wachter's use of the word "until" makes me flinch. He seems to believe that someday computers and IT system and EBM and algorithms will get to the point when physicians will not have to apply the art of medicine and will not be allowed to do so. We cannot escape the contingencies of life and medicine by all encompassing algorithms and computer prompts. I don't really think that Dr. Wachter thinks we can escape them but I worry about that "until".

Are Phase IV trials really "seed" trials-another way to manipulate physician behavior?

Dr. Bruce M. Psaty, a prominent clinical epidemiologist from Seattle, plunges into the topic of Phase IV drug trials in the June 21, 2006 issue of JAMA.

Phase IV trials are post marketing trials that,quotes Psaty, were discussed in a 1994 NEJM article by former FDA head David Kessler as a main technique to promote "me too" drugs.

Kessler said:
...because they are, in fact, thinly veiled attempts to entice doctors to prescribe a new drug being marketed by the company,they are often referred to as "seed trials"...[features include]the use of a design that does not support the stated research goals,the recruitment of investigators not because they are experts or leading researchers but because they are frequent prescribers of competing products [and] sponsorship of the studies by the company's sales and marketing division rather than its research department."

Clearly these seed trials are not high quality studies.Psaty talks about what distinguishes high quality studies. Randomization is not enough.

Psaty says that blood pressure drugs are commonly promoted in these trials.

"industry has supported thousands of small short-term randomized trials..."

Most of these seed trials proudly promote themselves as "randomized" and many are but randomization does not equate to a quality trial nor to one that asks a worthwhile scientific question or is otherwise well designed. As Psaty says other features need be present such as blinding,completeness of followup,ascertainment of outcomes to name a few.Randomization is not a sufficient condition for a trial to be worthwhile and/or meaningful and non-trivial.

At times,big pharma and the contract research organizations have taken some of the concepts and rhetoric of EMB and misused them to promote various products by funding and executing these largely bogus seed trials which may have influenced not only the physicians who participate in them but the other physicians who hear from the "thought leaders" how these randomized trials favor one brand over the other. A veneer of evidence based medicine is glued over what is no more than a promotional activity. If big pharma may have corrupted the EBM process, how should the physicians who take part in them be characterized?

Two nouns come to mind; dupes and co-conspirators and I wish I could think of some less pejorative words as alternatives. Some are simply naive and do not understand what is really going on. Some of the academics, however, probably cannot plead ignorance. They either know better or at least in recent years should know better.

Could the SMART trial have been better designed to bring about the results that GSK did not want?

More than one pulmonary disease specialist has referred to the SMART trial as the [not so] SMART trial. Its design is subject to criticism both in terms of what was offered to the patient volunteers and what was likely to happen in terms of results?

GSK was faced with the task of designing and executing a large clinical trial that had been brought about because of concern that salmeterol might be harmful to some patients with asthma. An earlier trial in Great Britain had shown a numerical increase in salmeterol treated patients that was not statistically significant. One lingering popular explanation for any possible increase in salmeterol treated patient death is that these patients were either under poor control at the beginning of the trial and/or perhaps used the medications improperly or inadequately.

So, what did they do?They recruited patients by advertisements, insuring a high proportion of patients who might not have been receiving good physician care, gave them either salmeterol or placebo and then provided only monthly telephone followup. At this point we have a group of patients, many of whom were not under good control or receiving regular physician hands-on follow up, who were given a medication that was purportedly possibly harmful and not monitored other than by telephone calls. They could not be accused of "cherry-picking" their study subjects in this trial.

This "phase one " recruitment ended when it appeared the trial would need over 60,000 participants (over twice what the original power computation indicated because of the relatively low mortality rate in both the control and treatment arms) and the recruitment process shifted to study investigators who recruited their own patients.This change brought about a situation at least resembling how the drug might be used in clinical practice.

There was a marked difference in the outcomes based on the method of recruitment. 13 of the 16 asthma related deaths occurred in patients recruited in phase one ( figure 2 in the SMART article in CHEST).There were about 15,00 patients in phase one versus about 11,000 in phase
2. The report's table 7 indicates that there were no statistically significant differences between salmeterol and placebo in any of the primary or secondary outcome measures in the phase 2 patients.

If there had been no phase 1 recruitment, there would likely be no black box warning on salmeterol containing products. It should be noted that this trial was terminated early by GSK. Only half of the subjects had been enrolled and the predefined criteria for terminations had not been met.The reasons given were the disproportionate number of events in African Americans and difficulty in enrollment.

What about the effect of prior or concomitant treatment with an inhaled corticosteroid (ICS) on salmeterol treatment outcomes? This is how salmeterol is currently used according to guidelines. As the study authors said " SMART was not adequate to determine whether or not ICS use affected the incidence of the key outcome events."

To me, the most robust finding of SMART is that asthma treatment is much better when a patient in under a physcian's care than when a prescription is given to a patient and he is told that they will be contacted by phone to see how they are doing.

Will a recent Meta-analysis be the tipping point to remove LABAs from the market?

Long acting bronchodilators (LABAs) have long been accused of increasing the number of asthma related deaths. My 12/23/2005 posting gave a brief summary of events up to that time.

Concern about LABAs was exacerbated by two studies that lead the FDA to issue a black box warning in November 2004.

A 16 week study from Great Britain, the Salmeterol National Surveillance Study (SNS) of 25,180 patients, found 12 deaths in the salmeterol group versus 2 in the placebo group a finding that was obviously numerically greater but not statistically significant.

Of greater concern was the SMART trial. This was a 28 week trial with 26,350 patients which demonstrated a 4.3 fold increase in asthma related deaths,( 13 versus 3) in the salmeterol treated group.

At least one important piece of information was not available from SMART. In the FDA statement we find this statement:

"The data from the SMART trial was not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk."

We really need to know if inhaled steroids mitigate or eliminate the putative increased risk from LABAs.Current recommendations essentially depend on that as the recommendation is to not start a LABA for asthma treatment until the patient is receiving at least moderate doses of steroids.

A recent meta-analysis published in the Annals of Internal Medicine seems to provide that missing information. Dr. Shelley R. Salpeter et al pooled results from 19 trials with 33,826 patients and found that LABAs ( not just salmeterol) increased exacerbations requiring hospitalizations (O.R. 2.6) and asthma related deaths (O.R.3.5). When the authors looked at the trials in which more than 75% of the participants were taking inhaled corticosteroids, the O.R. for hospitalizations was still increased at 2.1 ( 1.3 - 3.4).

While this may not be a slam dunk to answer all we need to know or to settle the issue, it is bound to raise the level of concern to a higher notch. Unfortunately, the authors do not give us more information about that part of their analysis nor do they include it in their article summary.However, in their concluding paragraph they say : " Concomitant inhaled corticosteroids do not adequately protect against adverse effects "

The LABA controversy will not be settled by this meta-analysis. A recent article from Australia quotes a Cochrane systematic review of LABA use in asthma and concludes they are safe and effective. As the editorial in the Annals noted, Evidence Based Medicine exhorts us to use the best evidence. Determining what is best sometimes is no easy matter. The medical literature dealing with the long acting beta agonists is extensive and replete with contradictory data. Since deaths from asthma are relatively uncommon, many physicians who use Advair and other LABA containing medications have not seen serious complications in their patients and typically observe better control in those patients requiring LABAs. It is not surprising that-as noted in the Salpeter article-the Black Box warning has not altered physicians's prescribing habits. Whether those habits should be changed or not seems to still be an open question.

Growing consensus not to use beta-blockers as initial choice for blood pressure treatment

Fueled largely by the results of the blood pressure arm of ASCOT, various authoritative medical organizations are demoting beta-blockers (BBs) from their former role as first line treatment for elevated blood pressure. NICE (the British National institute for Health and Clinical Excellence) and the British Hypertension Society have recently published guidelines that recommend BBs not be used as first line BP treatment except in cases of angina and HBP or in patients with excessive sympathetic tone or if they cannot tolerate ACEs or ARBs. They also recommend that if a patient is already on beta-blockers and a second BP drug is needed that the additional drug not be a diuretic because of the increased risk of diabetes.(Apparently the argument that since an increased mortality was not seen in ALLHAT patients who developed diabetes it is somehow OK if some medications trigger diabetes did not have much credence with the panel)

For those of us enamored by pathophysiology I refer back to a earlier posting that briefly reviewed data suggesting that beta-blockers are not as good as we once thought because-at least in part- of their failure to lower the central blood pressure while the ACEs and ARBs do.

A nap and a cup of coffee-What a concept.

I have posted before on the excessive sleepiness awareness "educational" programs that are appearing on the free doctor dinner programs and in various publications, there was a interesting juxtaposition of reading material arriving in my mail box.

The Annals of Internal Medicine ( June 6, 2006 issue) featured two articles on the effect of naps and coffee on "real life" situations and an editorial (" Naps and Drugs to Combat Fatigue and Sleepiness") by a well known and prolific sleep researcher, Dr. Christian Guilleminault. ( Annals Internal Medicine-volume 144,number 11 p. 856)

The other was a special issue of Internal Medicine World Report on the topic of excessive Sleepiness (ES). (ES has joined the ranks of conditions designated by an abbreviation and may soon rival ED in the level of promotional material produced.) The Report offered free CME and the authors credited with its material were an academic family doctor teamed with PhD sleep researcher from University of Michigan. The readers are told that the supplement was provided by "CME Outfitters,LLC" and was supported by an educational grant from Cephalon, Inc.,the manufacturer of modafinil (trade name Provigil).

The readers of the supplement are told that in order to accurately diagnose ES a detailed sleep history is necessary. A 14 item list of questions is suggested and the readers are told that it is critical to ask patients about the quality and quantity of sleep. It seems that ES is not only wide spread but it is said to be under recognized so we should seek it out in our patients.The list of "alertness-promoting agents" is reviewed and not surprisingly modafinil seems to be the best choice.

One of the Annals' article dealt with nighttime driving and demonstrated that either a nap or a caffeine containing beverage reduced the number of impaired driving events.A study involving interns showed that naps lead to less sensation of fatigue. Both sets of results conform with common sense and everyday experience (and with references noted in the articles and the editorial) and neither seems particularly monumental and I cannot help but wonder if this was a slow news day at the Annals editorial offices.

I found one of Dr. Guilleminault's editorial comments thought provoking. Apparently some of the interns did not really nap during their nap time.Some worked on the charts and others continued to take call for their own patients. He says :

"Clearly a 'medical culture element' (responsibility for one's own patients) was conflicting with the napping concept." He continues, " Perhaps it is time for medical housestaff to give the same weight to their responsibility to be alert as they do to their responsibility to be available to their patients.".

I will need more time to mull that over. I thought being responsible for your patients was a good thing.

The editorial is supportive of the use of napping and coffee to battle fatigue and sleepiness and is less enthusiastic about modafinil "The shortcomings of modafinil raise questions about the use of pharmacologic agents..."

Those comments are not surprising as a NEJM article and editorial last year seemed to indicate that modafinil was about as good as a big dose of coffee.

To see what P4P is really all about, look at the Seattle Blue Shield experience

The May 26, 2006 posting on Health Care Renewal references a news report on the "quality" and P4P acitvities in Seattle.

As critical as I have been on the P4P issue, the reality seems even worse. In this case, according to the news report,the carrier dropped about 500 physicians from their plans by a secret quality assesment process (using biling records apparently), and sent letters to 8,000 patients telling them their docs were delisted because of quality and efficiency issues.

As an aside I would like to know why this is not libel per se or at least ordinary libel.

But that is not my main point. The following is:

If the physicians who advocate accepting P4P such, as the leadership at ACP, believe that P4P is or will be about thoughtful, well intentioned physicians agreeing on scientifically established quality indicators and compliant physicians being rewarded for showing they comply with them, I cannot help but believe they are either naive or disingenuous.It will be and-as in the Seattle case- already is about saving money and controlling physicians.

It was about a year ago that I blogged about the egregious "performance" program initiated by United Health Group in St. Louis. That program also had no resemblance to the features of a "good " P4P program that the AMA envisioned and was harmful to physicans and patients alike.

Physician groups who advocate P4P argue that if we do not work with the third parties to make the rules, all the rules will be made by them. The Seattle and St. Louis experience-as well as the entire managed care saga-tell us clearly the third party payers will make all the rules anyway.