Wednesday, December 30, 2009

More counterpoints to the Dartmouth Atlas data

This article from the journal Circulation provides data and analysis that at least suggests that the sweeping conclusions of the Dartmouth group may not tell all of the story. h/t to this entry by the Buckeye Surgeon.

The widely quoted publications of the Dartmouth group that studied the regional variations in Medicare patient death rates have been condensed to a simple recipe to solve at least some of the country's medical problems-let's all be more like the Mayo Clinic and the implication that spending more money necessarily translates into poorer health care.

The Circulation studied looked at the outcomes of Medicare patients in 6 California teaching hospitals.Here is the conclusion of the study's authors:

Conclusions— California teaching hospitals that used more resources caring for patients hospitalized for heart failure had lower mortality rates. Focusing only on expired individuals may overlook mortality variation as well as associations between greater resource use and lower mortality. Reporting values without identifying significant differences may result in incorrect assumption of true differences.

It is only in the context of the hype generated with the Dartmouth studies that one would be surprised that spending more resources on sick patients might actually improve their outcome.It is obviously true at the extreme-if we spend no money at all good outcomes would be unlikely. Within some of the health care "reform" rhetoric we hear the theme that spending more money is necessarily bad and wasteful. Spending more can be wasteful but often it is not. It is an empirical question and very context dependent- not one determined by reference to first principles.

I have written before abut Dr. Richard Cooper's critique and criticism of the Atlas studies.See here for some details of Dr. Cooper's arguments and comments by the economist, Arnold Kling.

Tuesday, December 29, 2009

Will long term endurance exercise prevent your telomeres from shortening?

I hope so and here is some evidence suggesting long term endurance exercise may mitigate the aging process which is part seems to be due to one's "chromosomes shortening". I had written earlier about claims that vitamin D has a similar effect.

This is not the first such article making this type association. This article by La Rocca et al in Circulation demonstrated longer leukocyte telomere length (LTL) in older endurance exercisers and correlated LTL with aerobic capacity and an index of endothelial dilatation.

An interesting study published in the Archive of Internal Medicine which in part involved study of twins showed that the inactive twin had shorter telomeres that the more active sibling. A companion editorial offered the appropriate caveats which might serve to mitigate any undue exuberance forthcoming from overly smug ,older long time runners:

A great deal of research has been done on telomere length in the past few years, and exactly what it is telling us is still being argued. Cross-sectional studies show that telomeres in humans are shorter at older ages and telomere length is shorter in peripheral white blood cells in a variety of chronic diseases. However, although shorter telomere length has been associated with cell senescence, its direct effect on organ function is not well documented, and telomere length in postmitotic cells has not been related to life span in the experimental animal in which it has been extensively studied, Caenorhabditis elegans.

Yeah, I know you shouldn't get carried away by surrogate makers. Further, this study of older Chinese found no such relationship.

So, I continue to run as long as I can even if the effect on telomeres really means little or nothing because after each run I seem reassured that I am not really that old yet (the marked reduction in running speed notwithstanding) as irrational as that belief is.

Monday, December 28, 2009

Is everyone talking about the same health care bill?

Apparently John Goodman on one hand and the American Medical Association and the American College of Physicians on the other are interpreting the thousand of pages of almost impossible to decipher verbiage in vastly different ways.

Here is what Dr. Goodman thinks is the key "accomplishment" of the bill.See here for his entire posting and consider the reasons he lists as to why the nationalizing of health insurance is what it is all about.

Nationalizing health insurance. For the first time ever, the federal government will tell you what kind of insurance you must buy and (effectively) where you will buy it and what price you will pay. You will not be allowed to buy better, cheaper insurance that is more suitable for your and your family’s needs — even if an insurer is willing in principle to sell it to you.

Don’t underestimate the importance of this accomplishment. Nationalization is the abiding, overriding, everlasting, immutable, unending, permanent, unchanging goal of the political left. There is no other there, there. There is no other beef. All else is sound and fury signifying things that are way down the priority list.

Nationalizing the health insurance industry will also politicize it.With the shameless performance of the Senators and the bribes involved in the health care bill passage fresh on our minds, that is a frightening thought.

Thursday, December 24, 2009

It seems very likely than warfarin's days are numbered

The oral, direct thrombin inhibitor, ximilagatran for a while seemed to be poised to be the replacement for warfarin. Early trials indicated its efficacy and safety (at least in terms of bleeding risks) but its further advancement was stymied and ultimately blocked by the observation of what proven to be a unacceptably high level of abnormal liver function test abnormalities.(Direct thrombin inhibitors (DTIs) block thrombin from cleaving fibrinogen to fibrin.)

However, its descendant, dabigatran has successfully made its way through two large randomized clinical trials and seems to be at least as efficacious and at least as safe (in terms of bleeding risks at and no major signals of other adverse effects) and will probably emerge as the long sought after replacement to warfarin.

First dabigatran looked good (in some outcomes better than warfarin and in others, "not inferior") in the RELY trial which studied its use in high risk patients with atrial fibrillation. Next the RE-COVER trial (this is not to be confused with the RECOVER (without the hyphen) trial) compared dabigatran with warfarin in patients with deep vein thrombosis and found similar good results.

So far,dabigatran seems as efficacious and safe as warfarin in atrial fibrillation and in DVT and does not require frequent blood test monitoring nor frequent dose adjustments.

Still there are concerns and questions. Dabigatran is given twice a day so the compliance issue has to be considered. Further,in RELY two doses were tested. At the 150 mg twice a there were fewer strokes so that dose seems more efficacious. At the 110 mg dose there were fewer instance of hemorrhage, so the lower dose seem safer. The 150 mg twice a day dose was used in the RE-COVER dvt trial so that dose may become the one generally used.

Dabigatran is approved in the EU for prophylaxis in total hip and total knee replacements and also in Canada.
2010 will probably see its approval in the U.S, fifty years or more after warfarin was approved.

Friday, December 18, 2009

Will CRP(c-reactive protein) become a cocktail dinner conversation?

The answer to the title question is "probably yes" if the FDA concurs with the recent recommendation of its advisory committee in regard to a "new" indication for rosuvastatin (Crestor).

Dr. Matthew Mintz gives his thoughtful analysis of the panel's decision ( see here) and,in general, he seems to support the decision of the panel. The panel basically approved rosuvastatin for patients with normal LDLs and an elevated hs-CRP (high sensitivity CRP).

As has been pointed out (see here for Sandy Szwarc's detailed comments and critique on the study (Jupiter) that lead to the panel's decision) a very large number of people would be "eligible" for this new indication.I believe her comments contain several important counter-points to the avalanche of glowing comments from well known "thought leaders" that came quickly on the heels of the publication of Jupiter in the NEJM and should be read by someone before planning to check everyone's CRP and treat those eligible folks with CRPs of over 2.Although, I'll bet that the media blitz and specialty society guideline publicity that will blare forth if and when the FDA gives final approval will overwhelm any suggestion by a physician that we might give the matter a little thought before we prescribe Crestor because of an elevated CRP.

A 2009 article by Dr. Erica Spatz concluded " JUPITER’s findings have the potential to impact treatment recommendations for 20% of middle-aged to elderly adults, thus increasing the proportion of this segment of the population with an indication for statin therapy to nearly 80%."

That 80% of middle-aged and elderly should be on a statin is ,to put it mildly, mind boggling.

One comment by a FDA panel member caught my eye-that the increases of new onset diabetes in the Jupiter trial was a "class effect" meaning that all statins tend to do that. For the number of patients for whom I recommended statins I did not see fit to warn them about an increased risk of diabetes. I was not aware of any. In fact, the West of Scotland study (WOSCOPS) found a 30% reduction in the onset of new diabetes in the pravastatin treatment arm. JUPITER had reported the opposite namely that there were 3% new diabetes cases in the treatment arm versus 2.4% in the placebo group. Further, Rajpathak published a meta-analysis of six statin trials that demonstrated a slight increase if the WOSCOPS data were excluded but no difference in onset of diabetes when that data were included. ( I never did understand why they would want to exclude the Scotland study anyway but...) So, if it is a class effect it must be a rather small one and I would worry more about muscle toxicity related side effects in the newly enlarged pool of older eligible patients.

So much has been written,just in the medical blog world,that I won't try and summarize all of the gleeful announcements of a really big breakthrough or the more somber critiques. But if you read only one commentary this one by DrRich would be worthwhile.

You can talk about the fact that Jupiter was terminated prematurely, you can talk about relative risk versus absolute risk reduction and Crestor effect versus class effect but in the end here is the way things seems to work. When you have a large randomized clinical trial that demonstrates a benefit for a given medication and when many well known medical thought leaders endorse it and when it is then approved by the FDA you know that guidelines will be written and quality rule driven medical practitioners will follow and many patients will take the medication and likely insurance companies will pay for some or all of it.So in this case many folks will have their hs-crp checked and they will be prescribed Crestor ( a few will be given lower price statin cousins) and there will be- for a while- talk about crp at parties.

My first prediction for the new year: Look for a surge of CME-oid meetings and articles on the value of CRP for cardiac risk assessment and as basis for statin therapy.Yes, we have heard about CRP for quite a while but soon we will probably have the blessing of the FDA and things will really take off.

Friday, December 11, 2009

What do we really know about Tamiflu and flu?

The latest word ( but likely not the last) on the use of the neuraminidase inhibitors (Tamiflu and Relenza) comes from the Evidence Based Medicine epicenter, The Cochrane review) and can be found here.

The article in the BMJ did not go unnoticed by Dr. Howard Brody who correctly recognized that there was more there than simply a lack of definitive data about the role of Tamiflu. See here for his blog comments regarding that series of events in the broader context of an integrity crisis in medical research which I believe is part of an even broader context of "How the heck do we know what is correct in medical research publications".

An ingrained as Tamiflu is in the current medical thinking about management of flu (and anything that looks like flu) I doubt the BMJ article will have any significant impact on the sales of the drug. I bet that sometime in the near future we will see a meta-analysis to counter the analysis from Cochrane.

Thursday, December 10, 2009

Will the senate Health care reconstruction bill cover acupuncture and bee pollen? Maybe

The answer seems to be "maybe" because while there is no specific mention of bee pollen ( no, I have not read the entire bill to be sure there is in fact no mention of bees) there is the issue of interpretation of the "non-discrimination provision which is discussed here. (h/t to John Goodman).The hyperlink cited also has a link to the bill itself)

The provision at issue states that insurers shall not discriminate against any health care provider that is licensed by the state. Many states do license "providers" who are,to be politically correct,alternative medicine practitioners. So does it follow that insurers will have to pay for whatever brand of woo dished out by certain alternative woo providers as long as they are licensed by the state?

The alternative medicine lobby along with the lobbyists for supplements would seem to be happy with the senate bill and both Senator Harry Reid and Senator Harkin also with Senator Hatch seem supportive of both interests according to the LA Times article referenced above.

How many more gems of silliness and special interest provisions will turn up in the compromise bill once the Senate passes something?

Thursday, December 03, 2009

Maybe we should worry more about Lemierre Syndrome than rheumatic fever given a sore throat in adolescents

An important and perhaps a paradigm shifting article is found in the Dec 1,2009 issue of the Annals of Internal Medicine by Dr.Robert Centor. See here for the abstract.For the full article subscription required or wait 6 months.

For the past many decades medical students have been taught to be wary of the possibility of the later development of rheumatic fever in a sore throat patient and that possibility is one reason for treatment of beta strep sore throats,suppurative complication being the other.

The various treatment algorithms are based on the concern about beta strep infection but Centor warns us that a different bacteria may pose a greater risk in one age group, one that seemingly is not considered in the usual treatment guidelines.

Dr Centor puts forth a good argument that in the age group 15-24 years an equally important concern (perhaps a greater concern) is that the pharyngitis is due to Fusobacterium necrophurum and if so there is a real risk of the subsequent development of something called Lemierre syndrome . This is a potentially life threatening condition in which there is bacteremia and a suppurative thrombophebitits of the internal jugular vein. While rheumatic fever and patients with rheumatic heart disease were common when I trained in the late sixties and early seventies, can anyone remember the last case of rheumatic fever that they saw?

A clinical pearl is that typically worsening clinical symptoms with neck swelling in a 15-24 year old may signal the condition. Treatment for a beta-strep negative patient in whom you suspect F. necrophorum is with penicillin or a cephalosporin and not the ever popular macrolides. With bacteremia the recommended treatment is penicillin plus metronidazole or clindamycin alone.

Robert Centor has studied and written extensively on the topic of pharyngitis for a number of years he should be listened to and hopefully his article in this widely read journal will have some impact. Any bacteria with "necro" in its name should be taken seriously. Go here to his blog to read some of his comments on this issue.

Diminishing returns on heart attack treatment innovation leads to new targets

JAMA offers this excellent commentary on the topic of diminishing returns in reducing mortality in the treatment of myocardial infarction by further therapeutic innovations.We have come a long way but to go much further in terms of mortality reduction becomes progressively more difficult and this can be expressed both in terms of cost of the clinical trial and the number needed to enroll in clinical trials.

How far have we come? Consider ISIS 2 and the subsequent innovations in the treatment of acute myocardial infarction.

ISIS2 was published in 1988 and demonstrated that the combination of aspirin and streptokinase decreased the 35 day mortality from acute myocardial infarction from 13.2 % ( in the control group) to 8 % in the treatment arm.This is a five percent absolute reduction and about a 20% decrease in relative risk.

Over the next decade or two we saw the introduction of TPA ,and angioplasty and then coronary artery stents and drugs to inhibit the platelets and the mortality rate dropped to around 4%.In some more recent trials the mortality rate of acute MI is actually closer to 2%.

The authors assert that is a mathematical truism that , given the diminished control rate,future innovations can never match the benefits already realized (at least in terms of case fatality).
( by "control rate" the authors mean the rate of death in an control group as it would be constituted today with the current standard of care)

Why not? Is it simply the mathematics involved?

They explain that the mortality reduction by successive trials with a constant relative risk reduction can be characterized by a declining exponential function for mortality and an increasing exponential function for the sample size necessary to show the effect. (Their mathematical argument seems reasonable to me but I'll admit I am easy to fool with that type of thing)

The argument continues that if larger and larger sample sizes will be required then the use of surrogate measures and combined end points increasingly come into play.Also those planning clinical trials will turn to the use of control groups with higher rates of mortality as can be found in less developed countries and utilize non-inferiority trials.It does seem we have be seeing more and more of these type trials particularly trials with combined end points .