More on rivaroxaban trials

Recently, I referenced two clinical trials published in the NEJM which compared a new oral anticoagulant,rivaroxaban, with the low molecular weight heparin enoxaparin for thromboprophylaxis in patients undergoing hip arthroplasty and knee replacement surgery.Both studies showed an advantage for rivaroxaban over the comparison drug in terms of fewer thrombotic events and showed no real difference in bleeding.

Dr. RW pointed out that the dose of enoxaparin was lower than the standard recommended dose,that is the dose recommended in the United States. In both studies, the dose of enoxaparin was 40 mg. daily.This is in contrast to the 30 mg. every 12 hours which is the standard dose used. Could the use of the lower dose of the drug to which rivaroxaban was compared be an instance of "stacking the deck"? In the hip surgery study, there were 33 patients out of 1678 with major venous thromboembolism events versus 4 in 1686 patients in the rivaroxaban arm seemingly indicating the superiority of "riva".

Would the higher enoxaparin dose that is typically given resulted in fewer cases making the comparison less favorable to rivaroxaban? Maybe, but in a 1994 dose finding study the outcomes with 40 mg once daily and 30 mg twice daily were not statistically different.There were 27/199 (14%) patients with clots in the 40 mg dose and 22/208 (11%) in the 30 mg twice a day dose, a difference not statistically significant. Admitedly this was not a mega trial so a false negative could have occurred but the 40 mg dose has been used in other trials.The PDR gives the 30 mg. twice daily dose as the recommended dose but also suggests that in hip surgery patients the 40 mg regimen is reasonable alternative.After all of that, it seems to me that the 40 mg. used is not a unreasonable dose and has been used in other trials with enoxaparin .

In regard to the knee surgery study, the authors stated that the enoxaparin dose used was the dose approved in Europe and not the 30 mg twice daily dose approved in the U.S. for that application. Further, they started that a trail is currently in progress with the 30 mg. twice daily dose.

With those considerations in mind my speculation or veiled accusation that the deck was stacked has little evidential support.It may be best to shoot after aiming.

In a thoughtful followup to his first posting Dr RW makes the important fact that you need to look at the facts of how the trial was designed and executed rather than basing any decision regarding the validity of the trial by simply looking at who paid for it. With some of the drug trials scandals (the Ketex studies come to mind)and the possibility that some data has been withheld in some trials I have become so jaded and distrustful that my objectivity titer has diminished and his suggestion to look at trial critically and then look at the funding makes sense.

This time,new oral anticoagulants may well make it to the market

I had my hopes that ximelagatran would be the replacement for warfarin. That did not happen because of liver toxicity problems with the drug. Now several new drugs are traveling through the clinical trial pathways.Most of these are in a new class of anticoagulants known as Factor Xa inhibitors.

The medication leading the pack, in terms of being closest to approval, is rivaroxaban. Clinical trial results are found in the June 26,2008 issue of NEJM for the hip arthroplasty and total knee replacement studies. Both found fewer episodes of thrombosis in the rivaroxaban group and no statistical difference in bleeding when compared with enoxaparin. The liver toxicity that killed ximilagatran so far has not been a problem. Another Factor Xa inhibitor,apixaban, is in trials as is a direct thrombin inhibitor,dabigatran.

If and when the clinical trial(s) comparying "riva" with warfarin in chronic atrial fibrillation demonstrates similar good results we may finally have a new oral anticoagulant than does not require frequent blood test monitoring and may be free of much of the vexing vagaries of trying to get the dose of warfarin right and keeping it there.

More on end of Era of the Oslerian Internist

DB Rants takes on the issue of "what will happen to the Internist" in this entry and more and more internists are offering a pessimistic prediction of their future. It seems the internist has to choose between being a "office internist" and in the view of some being relegated to a position that seems little different from a Family Practice doc except that the FP doc can do more or being a internist who only sees patients in the hospital.

A third option may be the retainer practice in which maybe the internist doc can still do both but even that seems weighted to the out patient practice.

The Happy Hospitalist gives us this mini view of the economic environment that is a main driver for the changed world of the internist.

Help for the environment is on the way but maybe not for asthma patients

Fears of ozone depletion and the purported health effects of that should be soothed somewhat with knowledge that the CFC containing bronchodilator inhalers will be outlawed in December 2008. See here for The FDA message concerning the impending prohibition.

The new non-CFC inhalers (some contain HFA) will taste different, need regular priming and cleaning to prevent them from plugging and blocking delivery of medication to the lungs but that is the least asthmatics can do to help the environment. Additionally there are no generics for the non-CFC units so cost will increase. I wonder if we will see black market old fashion type albuterol inhalers.Again it is the least asthma patients can do to prevent sunburn and skin cancer in Australia.

Judging from how hard it may be to instruct someone to properly use an inhaler, I'll bet there will be more than a little trouble in switching over to the new units. There are 4 brand names and apparently the priming and cleaning directions vary by brand.Further, different pharmacy management companies may well favor one unit or another based on deals they make with the manufacturers .

Dr. Mintz in his medical blog does an excellent job of explaining the new inhalers here
Several of his readers replies are also instructive and I think a harbinger of the problems to come.I believe the confusion about them will lead to problems for asthma patients, in some- just inconvenience but for others- poorer control and more visits to the ER before everything is sorted out.

A huge number of skin cancers are alleged to be prevented by the CFC ban ( see here for a old CDC request for comments regarding CFC in asthma inhalers).Here is a link to an entirely different view on the issue which raises issues of the lack of proven safety of the new inhalers and other potential problems they may present and several presumed experts who maintain that any contribution of the CFC from the asthma inhalers is basically too small to have any effect on ozone depletion. The new HFA units have only been used for a relatively short time and recent events involving side effects that became evident long after all the clinical trials leading to approval were completed might give the FDA pause.

At least two questions are raised by the banning action of the FDA.Will the ozone zone recover faster when the CFC ban is completed or will it have any effect and it there any way anyone will even know. I claim no expertise in that area but my basic cynicism leads to think that the stratosphere will not really change much one way or the other long after asthma patients and others with obstructive lung diseases pay more for their medication.

The other interesting aspect is that I think this is the first time that the FDA bans a medication or group of medications not because they are thought or proven to be harmful to those who use but because they are thought to possibly harm folks who do not use it. (OK, the purported skin carcinogenic effect of increased sun rays from the purported decrease in ozone layer thickness would affect everyone- even asthmatics.) Since the task of determining harm to medication users has proven much harder that the FDA or anyone ever thought, it is admirable that the FDA will take on an even more difficult task.

Let us shift the risk factor paradigm-it is about time

The June 6,2008 NEJM published a very important editorial. This is one should be handed out to medical students and house officers. This insightful filled essay was authored by Drs. Harlan Krumholtz and Thomas Lee.Dr. Krumholz is prominent in the area of outcome research and hopefully his views will have a positive impact in reassessing and reining in the current risk factor modification craze which has neglected the fact that how one modifies the factor may change the disease outcome of interest. It might be added that in some instances we have little or no evidence that modifying a risk factor will matter at all as appealing as the pathophysiologic rational may appear.

From the essay we read:

It is increasingly apparent that the specific strategies used to modify them [the risk factors] make a critical difference in patient outcomes.

The now canceled ILLUMINATE trial illustrates dramatically the main point. Raising the HDL with a particular medication (torcetrapib) was associated with a higher mortality rate. How you raise the HDL may well matter.

What do the authors propose?

..we should no longer support the use of target without reference to the strategies used to achieve them....Second, guidelines and performance measures should incorporate more sophisticated and explicit considerations of the risk of the disease and the adverse consequences posed by the intervention.

A clinical trial is ultimately a test of strategy,and we should not be surprised that different strategies may have different effects on patients beyond their effect of risk-factor levels.

You would hope that publishing those thoughts in a high impact journal such as NEJM would have actually have an impact.

Guidelines-good suggestions or edicts or (sometimes) shameless self promotion

Two medical bloggers have recently made very cogent comments regarding medical guidelines,
Dr. Robert Centor and DrRich. Medical students and house officers would do well to read both because they have never lived in a medical world without the guidelines and physicians reading the blogs may get a different perspective on what is being done to them in the name of doing something for them and patients and to further the abstract goal of quality. (the 2 postings are highlighted below)

Both make the very important observation that guidelines that purport to be evidence based may be just as likely as the advice from your uncle Cyrus or your charming used car salesman to reflect their own personal and professional interests and are in word-biased. No, they all are not- at least not to the same degree- if there were things were that simple, you could just ignore all of them.

And of course, we should not forget Goodhart's Law, namely when a measure becomes a target it no longer functions as a measure.

Dr. Centor has informed us previously us about the nature of pharyngitis in adults, a subject he has studied and written about for a long time and in this recent entry delves into PSA screening. The bottom line is that there are numerous guidelines and they all don't agree with each other. Various guidelines writing groups begin their task with different world views.

The public health oriented wonks have a different perspective about PSA (or whatever screening procedure is at issue) screening that a practicing urologist might.The former group has to consider the total cost to society( which I believe is basically a bogus concept in that context) while the later wants to detect cancer earlier and yes, he has the economically advantageous opportunity to do more procedures ( from biopsy to surgery) if lots of men have their PSA values measured. If you believe that entities allegedly writing in the context of the greater good, really only have their nebulous goal in mind (this includes the prestigious USPSTF panels), you should read this entry.

DrRich takes us through the fascinating history of the rise and fall and rise of the concept of "metabolic syndrome" and what, if any, specialty medical group should promote and exploit it and coins (I think he coined it) the intriguing and thought provoking term of predatory guidelines.

Physician and lawyer ownership-interesting contrast

Hat tip to the Blog A Stitch in Haste for pointing out this interesting distinction.Physicians, in Mr. Pete Stark's view cannot or should not be trusted to own ,for example,a hospital because of the fear their avarice will overwhelm their fiduciary duty to their patients. ( I have written before about what I believe to be an erosion of that duty by the New Professionalism). Pete Stark has a penchant to introduce legislation to limit what a physician can do in terms of referring patients to various health care facilities. To get flavor of the "Stark Law" go to this analysis of the complexities involved in this statute.More on recent congressional efforts to restrict who can own hospitals can be found here.

By startling contrast-any one but a lawyer is legally not allowed to own a law firm.No one but a lawyer can own a law firm-others cannot be trusted.Of course, owning a law firm is one thing, owning a hospital or imaging center is something else but the disconnect between the general level of public trust for the two professions and the perceived need to control one group to a much greater extent than the other is something to think about.

New Asthma guidelines (again) and another meta-analysis re:LABAs and asthma

The National Heart,Lung and Blood folks have authored still another set of asthma guidelines-all you would ever want to know in 440 pages. (5.22 MB).Several links from the NHLBI site did not work and one version was only 3.88 MB. This one seemed to work, however.Physicians who treat asthma are obligated to plow through it but if you prefer to read the written page as opposed to the computer screen be prepared to replace your print cartridge.

In other asthma news,the issue of the safety of LABA use in asthma has been revisited in a recent issue of the Annals of Internal Medicine.I have written before about the candidate for the worse randomized clinical trial of the century,the memorably flawed SMART trial, and the subsequent impressively flawed meta-analysis (relying heavily on the results of SMART) unfortunately published in the Annals of Internal Medicine by the Salpeter team and the kurfuffle it generated. In an act of apparent contrition, the Annals has published another meta-analysis regarding the use of long acting beta agonists (LABAs) in the treatment of asthma and found LABAs innocent. (Since I have been so critical of certain aspects of meta-analyses,one could ask why I would believe this paticular one. The answer is I believe-or at least I quote- those that conform with my preconceived notions and biases about the subject.) Here is another meta-analysis that provides support for the widely held position and my notion that LABAs are beneficial in COPD.

Used properly LABAs add value to asthma treatment. They are to be added to the treatment program after inhaled corticosteroid (ICS) have been started but along with resuce beta agonist use appear to be inadequate for control. This is the role for LABAs according to the new guidelines. LABAs are not to be used for rescue therapy. Frequent use of a short or long acting beta-agonist in a poorly controlled asthmatic (one who should be on steroids) is a harbinger of ER visits, a required intubation and worse.

It is not your father's medical ethics any more

Can the traditional medical ethical prime directive of placing the individual patient's interest first survive in a financial environment in which physician autonomy is greatly diminished and income for most physicians is controlled by third party payers. More broadly put, Dr. Edmund D. Pellegrino asked in 1995 (JAMA,May 24/31,1995,Vol 273,no 20,) " Is medical ethics a social, historical, or economic artifact?Or are there some universal , enduring principles?

In 1988 Hall and Berenson writing in the Annals of Internal Medicine said that "the traditional ideal" was "not compatible with the role that existing insurance contracts and manged care arrangements define for physicians." Their comments were not subtle when they said :

We propose that devotion to the best interests of each individual be replaced with an ethic of devotion to the best interests of the group for which the physician is personally responsible.

Incredibly, the authors claimed that this shift in ethical focus would actually increase patient trust, an attribute that even in the late 80's was in a decline as patients tried to live (sometimes literally) with the HMO's restrictions to medical care. Incredibly, they claimed that by not having the patient's interest as the prime directive there would be increased trust in their physician.

The expected wave of letters to the Annals editors expressed the belief that advocacy for the individual patient was the prime directive and what it was all about and to replace it was to effectively do away with medical ethics as it had been known and practiced for a very long time. This is what would be expected from an audience of internists who had grown up medically inculcated with an ethic which was the polar opposite of what the authors proposed. Practicing internists at that time were reared to believe that the physician was completely and ultimately responsible for their patients.

The average practicing internist if they read the article at all may have thought this was the contrived advocacy of someone who was attempting to make manged care appear ethical. All that was required was to turn medical ethics on its head.When I read that article I thought "you've gotta to be kidding me".

A few years later ,I saw no one was kidding as the ACP, ABIM and the European Federation of Internal Medicine joined forces to formulate what was called the New Professionalism in which physicians were admonished to do more than maximize the health of all the patients in their HMO, which was as far as the Annals author went. Now, they had an ethical obligation to strive for Social Justice.This joint effort was said to be necessary as the "old ethic" needed to be revised to align itself with the new economic environment in which physicians now lived and "medicine's commitment to the patient was being challenged by external forces of change within our society".

While the 1988 article's authors stopped short of suggesting physicians should conserve resources for others in society at large and just concern themselves with their own HMO's population, the new ethics or professionalism as it was now called, headlined social justice raising it to the level of the big three ethical precepts-patient welfare, patient autonomy and social justice.More than one observer has asked does precept three conflict with precept one?

The era from 1963 to about 1990 has been termed the time of "retail medical care". Physicians and patients enjoyed the situation in which a patient's insurance followed the patient so that he could choose any physician and the physicians' fees were not set by the insurer but largely were set by what the physician considered and the payer agreed to be "reasonable,customary,and prevailing".

Things were good for physicians in those days as not only was physician autonomy largely unchallenged,but also Medicare has brought about a large influx of money to be spent largely at the discretion of the doctor and their patients and exciting new diagnostic and therapeutic tools were available. More could be done for your patients and more patients could afford medical care. Referrals could be based on the physician's knowledge of the area consultants and prescriptions were written without concern for some third party's list of permissible choices. But things were to soon change as the era of "wholesale medicine" replaced the old ways with the HMO being the middleman.

A series of articles was published in 1995 in JAMA authored by Dr. David Eddy that discussed the metrics and merits of decision analysis which he hailed to be the mechanism to perform magic. The magic was to increase quality of medical care while reducing cost. But it was all merely playing with words and defining words to suit the argument. Eddy defined quality as the greatest medical good for the greatest number within the eco-medical collective (aka HMO). It did not go unnoticed to the skeptical reader that Dr. Eddy listed his affiliation as "Kaiser Permanente of Southern California")

Pellegrino in 1995 also asked ...can physicians change the ethics of the profession at will ( as proposed by Berenson and Hall) or is there a more fundamental and universal foundation for the ethics of medicine in the special nature of the physician-patient relationship?

Pellegrino's quotes are found in an article entitled "Guarding the Integrity of Medical Ethics-Some Lessons from Soviet Russia" . The subversion of medical ethics in Russia suggested to Pellegrino two lessons. 1) corruption will afflict any health system not designed with care of the patient as the its primary driving force. 2) medical ethics must be independent of political exigency. "... a morally responsive profession is an indispensable safeguard for the sick against the statistical morality of utilitarian politics, even in democracies."

The statistical morality of utilitarian analysis seems to be increasingly unopposed as the group outcome analysis derived data plays an increasingly large role in the decisions regarding the individual patient exhibited in part as guidelines executed by mid level practitioners. In this new day, the physician has more to worry about that just her patient, she must be concerned for everyone but at least she has been removed from the impossible role of being responsible for every aspect of his patient's well being as she is now (merely) a member of a team and part of a system of health care.