Is sacubitril a "game changing" breakthrough or approved on basis of a stacked deck trial or something in between?

A  number of medical commenters and pundits have claimed game changer status for sacubitril but also the trial that lead to its approval has been accused of being not a fair test. Two general types of the tricks of the trade that can be employed to make a comparison between treatment better than it really is  are 1) stack the desk and 2) cook the books (AKA  various sometime obscure statistical slights of hand)

In this instance I cannot comment on the second but others have suggested that there was at least a little bit of deck stacking.

Lets look and what was compared with what.

The drug that the FDA approved  is named Entresto and is a combo pill consisting of a first in class drug named sacubitril and valsartan which is a  well proven Angiotensin receptor blocker which has been proven effective in the treatment of heart failure (HF), Sacubitril inhibits neprilysin which in turn is a inhibitor of natriurectic  hormones .The new combination pill is named Entresto.

Entresto was compared with the ACE inhibitor,enalapril.

If someone wanted to determine if the addition of sacubitril  to valsartan was safe and effective and better than valsartan alone why not compare that combination with valsartan ?. Why choose a drug from a different class than valsartan?

 In the ParadigmHF trial, 8442  patients with class 11-IV NYHA heart failure with ejection fractions less than 40%. were treated with either Entresto or with  Enalapril at a dose of 10 mg twice a day.

 So how big was the difference between the two treatment groups? 26.5 % of the control group versus 21.8% of the enalapril treatment group were hospitalized for heart failure. A difference to be sure but enough of a difference to be heralded as a game changer?


But there is as usual more to the story- now there are expressions of concerns about some unusual potential side effects of the breakthrough medication involving some breakthrough complications in  the eye and the brain.see here

Also see here for a JAMA commentary about the concern of a potential increase risk of Alzheimer disease  by inhibiting the action of neprilysin in its putative  role in amyloid degradation. Not to worry though- a projected trial to look into that issue should be ripe for publication circa 2022. See here for a further  discussion of some criticism of the trial including how externally valid is it (how well does it represent real life treatment of HF) and how representative was the dose of the comparative drug.

 Larry Husten  comments on the number of "game changers" in cardiology in 2015 in his posting entitled " 2015 the year we finally cured heart disease".

No replay of the 1914 Chistmas truce in Iraq on this Christmas day

The story of the 1914 ad hoc ,from the bottom up  temporary truce on Christmas day during World War 1 is well known and can be read about in detail here.

This story from the blog site Antiwar.Com tells of deaths in Iraq thought due be due to targeting Christians apparently including some nuns. Of course there is a big difference, France and England  were nominally  Christian countries and both the British and the Germans soldiers had shared very similar Christmas memories from childhood .

Here we just have the unending, unforeseen consequences of just trying  to  "bring Democracy to the Middle East"  of the incredibly bad idea of the war in Iraq.

Will just 2-3 hours of aerobic exercise a week prevent your heart from getting stiff?

With the requisite,appropriate,cautionary,more-work- is needed caveat the authors of a very detailed and elaborate study published in 2014 say that 4-5  one half hour exercise sessions per throughout adulthood will prevent most of the  age related loss of  the  heart's compliance and distensibility .In other words that amount of aerobic exercise will help to prevent the heart chambers from getting too stiff.It would really be nice to think so.

So what is wrong with stiff cardiac muscles ?

Application of the Woody Allen axiom of the pathophysiology of aging tells us that as we get older everything that should be soft gets stiff and everything that should be stiff gets soft.Think lens of eye,arteries and joints to name just a few.

A stiffer left ventricle is not a good thing as far as cardiac function is concerned.

The left ventricle (LV) basically sucks in blood while filling ( diastole) and ejects it during systole.As the heart becomes more stiff, the ventricle fills less easily , less sucking and more push from the atrium.The term diastolic dysfunction refers to this. Diastolic dysfunction (DD)  plays a role in a number of heart diseases and some degree of DD is arguably a "normal" process of aging or as the authors of this article imply "sedentary aging".


Researchers  the Institute for Exercise and Environmental Medicine  in Dallas recruited   healthy subjects over age 64 and screened them for histories of lifetime exercise habits and divided them into four group of about 25 per group.There were sedentary folks with no more than one exercise session per week , those with 2-3 session per week (causal exercisers), those with 4-5 sessions per week, labelled "committed" and the competitive group who trained 6-7 times per week and took part in races. (See here for full text of article) (This group lead by DR. B Levine from Southwestern Medical School has published a number of articles on general topic of cardiac function changes with aging and diastolic dysfunction. )

Extensive physiological tests were done including some involving right sided cardiac catherterization  to measure the  pulmonary capillary wedge (PCW) pressure.  (I am still amazed that they found 100 healthy people who agreed to let some one put a catheter in their pulmonary artery for non-therapeutic reasons).  PCW pressure is believed to be a reasonably accurate measure of the pressure in the left atrium which reflects left ventricular pressure , and elevation of which is a measure of LV failure.By infusing saline IV they were able to obtain curves relating the LV volume at the end of diastole with PCW pressure providing an indicator of LV compliance and distensibility.

The committed exercisers' values for these measures of ventricular compliance were very close to those of the competitive exercisers and definitely better than the sedentary and casual exerciser group as were values for other measures such as maximal oxygen uptake. This data ( shown in their "Central Illustration",p 1263 constitutes the major evidence  for their thesis regarding how much exercise one has to do to maintain some semblance of LV distensibility. The more exercise the less stiffness but what the casual exercisers did was not enough.

 Decrease in LV compliance and distensibility characterize heart failure with preserved  ejection fraction (HFpEF). Other work by these same authors have shown similar pressure volume relationships in patients diagnosed with HFpEF as those seen in the sedentary and casual exerciser groups.They argue that sedentary aging  "sets the stage for this increasingly recognized form of heart failure" It should be noted that heart failure with  preserved EF might more correctly be named HF with preserved EF at rest. The EF does not increase normally with exercise in HFpEF and exercise intolerance is a major feature.

How the stage is set is unclear. Studies of exercise programs in patients with heart failure show improvement in exercise capacity  but do not show improved values for various tests of diastolic function or ,for that matter-ejection fraction. So the improvement seems to occur in the muscles with increased capacity to extract oxygen for muscle function.  Here the oxygen uptake would improve while cardiac output may not -they are able to exercise more because their muscles are better able to extract the oxygen from their limited cardiac output.Remember the Fick equation ( V02=CO X A-V 02 difference).

 There is more to ventricular filling than ventricular compliance- how rapidly the heart muscle can relax following the ejection or systolic phase of the cardiac cycle is important. One aspect of relaxation can be measured by the IVRT ( isovolumic relaxation time) ,This can be measured by the time between aortic valve closure and mitral valve opening. The IVRT and the IRCT ( isovolumic contraction time) both increase as a function of age and are apparently not favorably influenced by life long aerobic exercise.

I have a high school friend who quoted one of his football coaches who was fond of saying "you are only as young as your legs".So some threshold value of regular aerobic exercise may serve to keep the ventricles from getting too stiff while exercise after the onset of HFpEF may still help but this time by  making the legs a little younger.

Marathon running and pacemaker safety

A Dutch group evaluated pacemaker function and safety in nine long distance runners  training for and participating in marathons.The full text article is available.

Here are some of the highlights:

The investigators recruited nine runners who had pacemakers (PM)by sending questionnaires to several Dutch pacemaker centers.

The program consisted of a nine month training program with supervision by running coaches,cardiologists ,pace maker technicians and representative from Medtronic, one of the projects sponsors.(Adidas was the other sponsor)

Pacing and sensing systems were testing during the training and the actual races  ( marathon and half marathon) and no problems were found.The Polar heart rate monitor system was tested as well and in all but one case functioned well without PM interference.A running chip ( Champion) was also tested and found free of interference with or from the PM.

Six had a DDD pacemaker and three a VVIR. (see here to decode the abbreviations)

 Only four of the nine were paced continuously.Three were well trained young athletes  who had PMs because of episodes of asystole and their PM were basically on standby and there was no PM stimulation during training or racing. None had a bi-ventricular PM ( i.e. cardiac re synchronization therapy or CRT)

For those  running with complete heart block the upper pacemaker rate had to be adjusted up to 170- to 180 to maintain 1 to 1 atrial ventricular synchronize during very high heart rates.

For runners who for various reasons develop the need for a PM the report is basically encouraging and good news for runners who need a PM and who want to continue running, even , at least for some- long distances..

But my Cassandra-like side has to wonder if those who were continuously paced and who run a lot ( I believe they all have right ventricular pacing)  might be a risk for the putative deleterious remolding and hypertrophy that a number of long time RV apical  paced patients develop. (See  here for a detailed exposition of Heart failure developing in patients paced from the Right ventricle and the pathophysiology involved.).

There was a two years followup by survey that  showed no evidence of a PM malfunction but I do not believe any cardiac function testing was done.

Left Bundle Branch Block (LBBB) is not just a EKG finding, it is a really big deal

The EKG pattern of left bundle branch block (LBBB) has been known for decades and that pattern was considered an indication of heart disease. In Dr. George Burch's text book, written over fifty years ago, A Primer of Heart Disease,  I read that LBBB was a pathognomonic sign of heart disease.

However,at the time, It was not known what was the role of LBBB  in altering cardiac function.Did it cause heart disease- this point is debated still. Did patients with heart disease and enlarged hearts develop LBBB or similar EKG patterns as their disease progressed? Some patients have LBBB secondary to coronary artery disease and an infarct involving the interventricular septum,some have heart failure and some  "just" have a LBBB, the so called lone  or isolated LBBB.

 We know the following about the cardiac functional consequences of LBBB in patient with lone LBBB:

1) Abnormal movement of the interventricular septum early in cardiac contraction ( systole) ie in the pre-ejection phase the septum moves to the left.

 (In most cases the septum moves to the left while lateral left ventricular wall relaxes.The septal movement is observed with cardiac echo and termed as "septal beaking")

2) delayed contraction of the left ventricular wall) reduced ejection fraction (EF)

4) Impaired filling of the left ventricle (diastolic dysfunction)

5) More time wasted with the heart valves  closed ( Technically  measured as prolonged IVCT and IVRT) and measured by the MPI or myocardial performance index (See end note 1)

6) Mitral regurgitation due to asymmetrical contraction of the papillary muscles

7) increased in left ventricular end-diastolic  pressure

8) Increased pulmonary artery pressure during exercise in some patients with normal resting echo

9) impairment of the normal ventricular twisting motion

Basically the right and left ventricle are designed to contract at the same time. In LBBB they do not- the right contracts milliseconds before the left.So there is inter-ventricular loss of synchrony.

The heart's electrical wiring system is designed so that the impulses that cause muscle contraction spread out more or less simultaneously from the two bundle branches. In LBBB the activation pattern is markedly altered so that the  septum is activated from right to left with early septal activation and contraction of septal area during the isovolumic contraction phase of systole and  there is delay of  the impulses arriving  at the lateral and posterior left ventricular wall delaying muscle  contraction.

There is also asynchrony within  the left ventricle  apart from that of the septum and lateral wall being out of sync. Various segments of the Left ventricle  also do not contract as an organized system , some segments contracting and relaxing out of tune with others.This is referred to as intra-ventricular  dysynchrony.

Consider what the development of LBBB does to an otherwise healthy heart and consider how that effect would be more manifest clinically in a diseased heart with failure.

Two studies have shown that the ejection fraction decreases about 10-15%. while another reported only 5.8%. The EF does not tell the whole story as there is also impaired filling of the left ventricle.So not only is the stroke volume diminished by a lower EF but impaired filling leads to less blood to eject.Cardiac output falls and is particularly evident during exercise.

Details regarding cardiac function in patients with LBBB and normal coronary arteries ( most were shown not to have coronary artery disease by angiography) were provided by Ozdemir who studied 45 cases of isolated LBBB ranging in age from 48 to 72.(Effect of isolated left bundle branch block on systolic and diastolic function of left ventricle),  see ref 3 below.

Although the ejection fraction was reduced  "only" 5.8% from controls,there were statistically significantly higher values in the LBBB group  for the left ventricular end-systolic diameter,and the isovolumic relaxation  time and the isovolumic relaxation time and importantly the invasively measured ( done at the time of  coronary angiography)left ventricular end- diastolic pressure ( 14+/-3 versus 10 +/-3) with a normal of 3-12.Earlier work had shown that some patients with "Lone" LBBB -those with no coronary artery disease or obvious heart failure- may have normal or nearly normal  echocardiograms ( but typically have evidence of impaired relaxation on Doppler mitral flow studies) and may  have  clinically significant increased pulmonary artery pressure with exercise.

With increases in the IVRT and IVCT there is less time for the ejection time which leads to an elevated or abnormal MPI ( myocardial performance index).The failing heart  both contracts and relaxes more slowly and the MPI has been proposed as a useful prognostic indicator. There is more time spent with the aortic and mitral values in the closed position leaving less time for the basic work of the heart , which is  ejecting blood, to occur.But in lone LBBB it is not the muscle cells defects that are the problem but loss of the normal incredibly well coordinated contraction and relaxation of the ventricles.

I can add a personal story. When I  recently developed a LBBB my "comfortable "( age appropriate and consistent with what one might expect in an aging runner)  jogging times increased from about 12: 45 minutes per mile to 14 +  minutes per  miles. which represents a 12% decrease. in running speed. Similar stories can be found on the web describing what LBBB does to a person's exercise capacity. It should be noted that all patients with lone LBBB do not have the same cardiac functional impairment nor the same rate of progression of impairment.

But there is more to the functional consequences of LBBB. Some patients  ( many, most ?) with LBBB develop heart failure after a variable lag period. Some of the evidence for this occurrence comes from the clinical experience of patients with heart block who have had pacemakers with the traditional right apical pacing electrode, which in effect is an iatrogenic  LBBB.It is thought that the abnormal contraction patterns due to LBBB may lead to a deleterious cardiac remodeling and ultimate heart failure.  

The introduction and advances in cardiac echocardiography made it possible to gain important insights into what are  the functional consequences of LBBB  and ultimately provided a new treatment for heart failure.

Dr.  IG McDonald in 1973 demonstrated by echocardiography that the interventricular septum moved abnormally. The septal problems were defined more clearly by Curtis in 1983 who showed that various abnormal movements of the septum were associated  with lower cardiac ejection fraction.,some patterns being more detrimental than others. Curtis mentioned that cardiac pacing might mitigate the LBBB induced abnormal ventricular contraction pattern.

 "The early studies described how the abnormal and/or delayed left ventricular activation wave front could lead to a reduction in left ventricular efficiency and performance that is largely independent of myocyte contractile function" Ref 1 see below.

Chaper 7 In Ellenbogen fifth edition of  "Clinical cardiac pacing,defibrillation and resynchronization therapy" quotes a 1974 article by Takshita et al as providing the first direct evidence for an effects of LBBB on LV function (6) in patients with intermittent LBBB.

 But it was not until 1994 that his theorizing was proven true when two clinical  studies demonstrated that pacing targeted to the site of the most delayed left ventricular contraction could improve overall cardiac function. The dyssynchrony could be "fixed" by resynchronization  ( or at least could  provide an effective work around) which became known as CRT or cardiac re-synchronization therapy.( also known as Bi-ventricular pacing, or Bi-V as most CRT is accomplished with Bi-V although more recently there is increasing use of His Bundle Pacing in re-synchronization therapy) .About 1/3 of HF patients treated with CRT do not show improvement, the 2/3 who do are those with  LBBB because in them the dyssynchrony is a major factor in the cardiac impairment and is often improved with Bi-V.

Cardiac pacemakers are nothing new-the first totally implementable pacemaker (PM) was introduced in 1958 and for decades were used to treat patients with heart block .Now a new use for pacing has improved the outlook for many patients with heart failure. It turns out that that the ones benefited are those with LBBB- so would not patients with lone LBBB also benefit from CRT? Is it necessary for a patient with LBBB to develop overt heart failure before pacing is considered or could/should the patient with NYHA class 1 be offered the implant?What about the patients with normal cardiac echo studies and shortness of breath on exercise? On further thought if a patient with LBBB has shortness of breath I would not expect the echo to be perfectly normal.The EF might not be less than the lower limits of normal but there would at least be delayed relaxation evident on echo . and perhaps septal flash .If PM implantation were a completely benign procedure the answer would be easy.

Endnote 1. IVCT is the isovolumic contraction time and the interval between mitral valve closure and aortic valve opening.IVRT is the isovolumic relaxation time and is the interval between aortic valve closure and mitral valve opening 

References:

1)Breihardt,G,and Breithhardt ,O "Left Bundle  Branch Block-an Old-New Entity". J of Cardiovasc Trans. Res. 2012 5: 107-116

2)Grines,CL et al, Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony.  Circulation 1989. 79:845-853

3)Ozdenir,V Effect of the isolated left bundle branch block on systolic and diastolic functions of left ventricle. J Am Soc Echocardiog, 2001 Nov 14, 11 , 1075-9

4) Vaillant, C Resolution of Left Bundle Branch Block-induced cardiomyopathy by cardiac

 resynchornization therapy. J. of Amer College of Cardiology.2013, 61, 1089-1095

5)Yu,cm et al Biventricular pacing in patients with bradycardia and normal ejection fraction. NEJM 2009,363

6) Takshita, A Effect of intermittent  Left bundle branck block on left ventricular performance. AJM 56:251, 1974 (no abstract available on Pubmed)

addendum 12/28/15. Minor editing and addition of a 9th abnormality in LBBB,.

addendum 1/17/16 minor editing.5/22/16 Several spelling errors corrected.

addendum 3/19/17 Three sentences were added to the last paragraph.

addendum 10/12/17 more superfluous fiddling with the wording in several places

Addendum 12/3/17 Mention of His Bundle Pacing added

Addendum 6/2/2020 Takskhita Reference on functional changes in intermittent LBBB added

Was the clinical trial that lead to the approval of Rivaroxaban for A Fib flawed?

The Rocket -AF trial was key in obtaining FDA approval for rivaroxaban, ( Xarelto) in part because of the decrease bleeding  in the riva group versus the warfarin group, at least in terms of fatal and intracranial bleeding. It was shown to be non-inferior in regard to stroke prevention.However, questions have been raised about the devices used  to measure to monitor warfarin therapy. It has been alleged that the instruments had a tendency to give falsely low values for the INR. If so , one wonders if the physicians  whoever monitored it would then increase the warfarin dose   to reach the target INR and that might account for the higher bleeding rates in the warfarin group or a relatively lower rate in the rivaroxaban group.

 The warfarin control arms of these trials can be problematic.There is always the issue of what percentage of time were the patients in the target INR range.Further ,heaven forbid, there may be even opportunities  for stacking the deck.

There is still more drama to the story -the FDA panel that reviewed the data did not recommend its approval but the full deciding body at the FDA voted in favor. Some has also expressed concern about the current leading candidate  for the head of the FDA since he was a prominent investigator in the trial.

We may never know  or if we do it may take a while to sort that out, Meanwhile what about all the folks taking Xarelto? Can they be confident that this new or novel anticoagulant affords them greater safety than  warfarin?Should they consider switching to apixaban? Should they even worry , after all there have been other trials that demonstrated efficacy and safety in the setting of venous thromboembolism and for prophylaxis in hip replacement.

More details can be found at Larry Huston;s excellent site  "Cardiobrief". He also raises the issue of possible COI with the candidate for the Head Of the FRA, Robert M Califf who was a principal investigator in the Rocket-Af trial. As usual Dr Roy Poses offers important insights into the issue of COI and the  ever spinning revolving door in health care in regard to the Dr. Califf and the unprecedented endorsement  of him for the FDA post by the editorial folks at the NEJM.See here.

 12/13/15Addendum; The folks who did the Rocket-af say they have now checked into the matter and that there is no need to worry. Sort of a move along nothing to see here type statement.  Unfortunately  they have not yet made public the data they collected and used to reach that reassuring conclusion. Stay tune.See here for details  from the blog Cardiobrief by Larry Hustin which as usual has a wealth of useful information from the world of cardiology.

The Medical Progressives are an influental subset of the Ruling Class

The core belief of the Medical Progressives (MPs) is that medicine and health care are  too important and complex to be left to decisions made by individual patients and their physicians. What is needed , in slightly paraphrased words of one of the MP's upper echelon, Dr Don Berwick: We need wise leaders with ideas.

He and another leader of the MPs, Dr. Troyen Brennan expressed their credo explicitly in their book entitled "New Rules". Here is a key quote.

"Today, this isolated relationship[  speaking of the physician patient relationship] is no longer tenable or possible… Traditional medical ethics, based on the doctor-patient dyad must be reformulated to fit the new mold of the delivery of health care...Regulation must evolve. Regulating for improved medical care involves designing appropriate rules with authority...Health care is being rationalized through critical pathways and guidelines. The primary function of regulation in health care, especially as it affects the quality of medical care, is to constrain decentralized individualized decision making.

Decentralized decision making means individual people making their own individual medical decisions with the counsel of their physicians. There must be a word stronger than hubris to describe the attitude of the medical progressive elite.

The MPs advocate and promote abolition of the traditional fiduciary of the physician to his patient. Phrases like " Rules with authority" and the "constraint of individualized decision making" made it clear what they propose. Some one will be making the rules for everyone rather than the individual physician patient "dyad" and those rules need to be enforced.Advocates of individual liberty should probably thank Dr. Brennan and Berwick for their making  it crystal clear what they want for medical care in this country.

Others in the MP  community have approached that aim with a more opaque and convoluted game plan.

One approach in that regard has been the advocacy of the concept of social justice as a primary precept in the physician's ethics code., particularly as advocated in the new medical professionalism.Advocacy for social justice would appear on the surface to have nothing to do with destruction the medical ethical principle of the fiduciary duty to the patient. But here is how I believe it has worked out.

First the term social justice was promoted as  an obligation of physicians.The Overton window of discourse has been significantly shifted. Social justice was not specifically defined but served  as a general feel good, ambiguous idea that would be be unlikely to generate much opposition.It could mean many things; aid to dependent children,initiative to eliminate racial biases and generally hep the poor- social justice as a egalitarian concept-equal respect for all.   As time went on social justice as a physician obligation took roots and became acceptable part of the rhetoric of health care  and the various problems associated with it although it was never clear exactly how individual docs would fulfill that obligation. It was not long until the MPs made it clear how that should be done.

 Certain factions of the MPs proceeded to phase two of the bate and switch strategy  and quietly and without debate sneaked  in the idea that the social justice obligation of the physicians was actually to be stewards of the nations finite medical resources. Implicit in this concept is the idea that individually owned assets and knowledge and skills composed an entity that was collectively owned to which everyone by virtue of their existence were entitled to their share of this medical commons.

With collective ownership everyone cannot just wade in and consume whatever and everything they want.The commons will be overgrazed .We will need leaders with ideas about how the contents of this collective owned aggregate will be distributed.


Now we can see  the key role of the MPs. Someone has to oversee this collective. Someone has to have the knowledge, and skills to make the decisions as to how this collective  pie will be sliced.Next we are told that the pie is best sliced with the sophisticated tools of cost effectiveness analysis so that everyone can enjoy high value care and we will eliminate low value care.Of course these slicing rules should be translated into guidelines adherence to which will demonstrate the practitioners' fidelity to a social justice quest and a measure of his delivery of quality care .

Thanksgiving thoughts for 2015-be thankful US is still in the top 20 in the freedom index (barely)

According to the latest ( 2015) rating and ranking of economic freedom  from the Libertarian leaning Fraser  Institute in Canada The US is ranking 20 of the 157 countries in their analysis in the year 2000 the US was second only  to Hong  Kong. So what is going on. Was  not the US the country that was the prototype for individual freedom, private property rights, contact law and general rule of law ? Was that not what Jefferson and Madison had in mind?What has happened in the last 15 years?

What does Fraser mean when they speak of economic freedom?

I quote from their website:

" Individuals have economic freedom when property they acquire without the use of force, fraud, or theft is protected from physical invasions by others and they are free to use, exchange, or give their property as long as their actions do not violate the identical rights of others. An index of economic freedom should measure the extent to which rightly acquired property is protected and individuals are engaged in voluntary transactions".



Here is the link to their report entitled "The Human Freedom Index, a global measure of personal,civil and economic freedom"

Here is the listing of countries as reported and commented on the the blog zerohedge:See
 http://www.zerohedge.com/news/2015-08-28/us-falls-behind-canada-finland-and-hong-kong-human-freedom-index



Some of the factors that are the usual suspects in our declining freedom are: increasing use of land use controls including eminent domain ,hypertrophied requirements for licensing  many occupations ( think flower arrangement  and dread lock hair styling),the effect of the various "wars", i.e. war on drugs,war on terror,the Patriotic Act with its warrant less wire taps and secret court proceedings and widespread surveillance of American citizens,etc.

The is little to be optimistic, freedom wise, about on the medical care front.With ACA citizens are forced by law to purchase a product,if physicians choose not to use computers in a very specific way dictated by the government they will be penalized in regard to Medicare and Medicaid payments. And for a list of just some of the liberty limiting things going on now or being proposed see this link from the Weinmann Report.

Does the " gold standard test" for pulmonary emboli have a false postive rate of 5% or 25%?

You can find articles in the medical literature that claim both?

For the most part and for most of the time that CTA  (computed axial tomographic angiography, in this context pulmonary artery CTA) ( AKA pulmonary CT Angiography) has been used the consensus number for the false positive rate is about 5%.

Two more recent articles provide data that strongly suggest that the real false positive rate may be considerably higher than that.

Hutchinson et al published an article in the American Journal of Radiology in August 2015 entitled Overdiagnosis of Pulmonary Embolism by Pulmonary CT Angiography" (august 2015,vol.205, number 2, 271-277)

 In the study all pulmonary CTAs  read-as- positive for pulmonary emboli (PE) done in a referral university hospital over a 12 month period were reviewed . There were 174 cases originally reported as positive for PE. The images were reviewed by a panel of three chest radiologists with over ten yeas of experience. I assume by each.

Those cases in which all three of the radiologists agree that the studies were negative for PE were considered false positive. 45/174 were false positive or 25.9 %,

Cases which were considered false positive tended to be in the segmental or subsegmental vessels .
According to the three judge panel the reasons for false positivity were breath holding artifact and "beam hardening" artifact.

A previous article published in CHEST in 2009 ( Miller wt et al , Frequency and Causes of false-positive CTPA exams in community Hospitals, Chest 2009,,136 4,Meeting Abstract 145) reported a value of 11% for false positive tests.This study , although it involved large numbers of cases, was much less methodologically sound and , perhaps for that reason attracted not much attention. 608 cases originally read as positive for PE were reviewed  by a single radiologist who found that 11% were "either false positive or probably false positive". Most ( 82%) were judged by the reviewing radiologist to be due to technical factors, which included" pulsation artifact,streak artifact,volume averaging, and quantum mottle". 66% of the false positive cases were at the subsegmental level.This article  seemed mainly to be a he said she said type exercise with one radiologist compared with a number of other radiologist's film readings.So how do you know who is right?

It seems well known that technical factors are the major reason for false positive readings and analyzing findings at the subsegmental  level. is particularly difficult.

A widely read and quoted article from the NEJM by Stein in 2006 quote the value of 5% false positive rate and I suspect the 5% value, more or less, is what most physicians accept as correct.

These  data are derived from the famous PIOPED 11 study. The CTAs were read by two radiologists and the  process to determine  positive and negative was rigorous and detailed and can be found in the method section of the article. However it is not the case that the CTA was directly  compared to the then gold standard of pulmonary angiogram,which ,of course, was also not done in the Hutchinson paper. Stein's paper  reported a specificity of 95% .

It is easy to discount the Miller paper but the Hutchinson paper is disconcerting particularly in light of my recent health events.I was diagnosed by CTA as having several PEs.I had the study re-read by a long time friend who is a radiologist  who said he could detect no emboli.To "break the: tie I had my treating physician to review the study with a radiologist of his choice who concluded ( unofficially meaning he did not submit a written report but was a curbstone consultation) that there were several artifacts present that could be mistaken for emboli but that there were  "one or two"  he said likely were clots. My doctor and I agreed to continue the apixaban for the agreed upon 3 months ( this was a provoked embolic situation).More on that "teaching moment " later.

Three months later I had a follow up CTA read by another different radiologist who opined that the emboli( or the artifacts) had resolved


Addendum: 1/19/16 Overdiagnosis and false positive are related but distinctly different concepts. Overdiagnois refers to finding something that is really there but does not really need treatment and false positive refers to thinking you are finding something but it is not really there.Subsegmental emboli in CTPA may exemplify both concepts, particularly i n the case of the reading of a single subsegmental embolus.  See Dr. Samuel Goldhaber's comments from Medscape found here.

Bundled medical payments and the Nirvana fallacy

Browsing the subset of medical literature that deals with policy reveals  a campaign against fee for service in medical care and typically recommends using a bundled payment model in its place as one of several purported ways to improve health care financing and quality.

What are the arguments against the fee for service (FFS) method of medical care payment?

The issue of asymmetrical information is often raised in the argument that physicians know so much more than their patients that they can make recommendations for tests or treatment based more on the economic gain to the docs that the benefit to the patient and the information challenged patients don't know enough to protect themselves from the rapacious docs.

Harold Dementz introduced the term Nirvana fallacy. quoting Dementz:

"The view that now pervades much public policy economics implicitly presents the relevant choice as between an ideal norm and an existing 'imperfect' institutional arrangement. This nirvana approach differs considerably from a comparative institution approach in which the relevant choice is between alternative real institutional arrangements."

At times the less vigorous versions anti FFS argument blend (morph) into a version of the Underware Gnome economics.

Step 1.eliminate fee for service in medical care
Step2.?
Step 3.Achieve less expensive,higher quality care.

 Attempts to avoid  the Gnome paradigm can be avoided by actually proposing an alternative payment system .In that regard a often discussed method is the bundled payment system (BPS).Some have described the BPS scheme as being somewhere between fee for service and a capitation plan. I have had some experience with a plan promoted by Dr. Denton Cooley and his Texas Heart Institute.In this Texas Heart  Institute offered various cardiac services and procedures at a pre agreed upon price to various corporations who self insured.As the employees then had no co pay and the company costs per procedure seemed cheaper- it appeared to be a win win situation. I have not seen the books of Texas Heart but it seems reasonable that that arrangement may have increased their volume even if the charge per encounter was decreased.  However, it is not clear how the purported asymmetrical information problem was abrogated. Would not a cath cardiologist not have the same incentive to recommend a procedure as he would under a straight FFS arrangement?

The anti FFS information asymmetry dates back perhaps to the often quoted article by Nobel prize winning economist Kenneth Arrow. However, to the extend that the asymmetrical argument is salient in regards to medical care, does that not increase the stakes for the patient to have her physician acting as her fiduciary and not as a part time patient advocate and part time steward of society's medical resources which is what the New Medical Ethics seems to advocate..If medical ethics were the protection for patients against the more knowledgeable  physician,does not weakening that ethical imperative  by imposing a co duty to to society to the physician's obligations   leave the information challenged patient even more vulnerable.

Taking a wider view we see that for the most part what passes as fee for service -as least as it  applies to Medicare and Medicaid  is really a system of price controls the negative effects of which are well explained in Eco 101.

Merger of high sounding ideals and narrow self interest yields new medical ethics

Cui Bono. Follow the money or who profits. Ask the question who profits from  what appears to be a sea change in medical ethics in the last decade? What is the sea change? The change is from a basic fiduciary duty of the physician to the patient to the physician now ethically tasked with both doing what is best for the patient and  somehow conserving "society's medical resources". One master less chance of conflict- two masters conflict lurking much of the time and loss of trust.

The new medical ethics is the ethics of the progressive. The progressive ethic is that much of society's affairs ( meaning an individual's affairs) should be managed by an elite.Medical decisions that in the past have been the bailiwick or purvey of the patient in consultation with his physician will in the world of the new medical ethics become decisions that will be made by wise leaders with ideas who pass their wisdom down in the form of guidelines adherence to which is now an ethical imperative. Here we have the merging of the high sounding ideals with the narrow self interests of the third payer payers.Does this not resonant with the notion of the Baptist and the Bootlegger?

Dr. Paul Hsieh discuses certain aspects of the new medical ethics here on PJMedia Blog.

Interestingly this 2012 article by Mark Daniels which reviews certain historical development in medical ethics and discusses various categorical approach to ethics in general ( duty based versus utilitarian etc) makes no mention of a duty of the physician to be a steward of society's medical resources.

The new ethics has been promulgated and promoted by the American Board of Internal Medicine and its foundation and fellow travelers in the American College of Physicians a number of whom have held positions in both organizations. This new duty is manufactured out of whole cloth largely by these two organizations.Their  Choosing Wisely campaign and the Medical Processional for the New Millennium publication have served as vehicles to bamboozle both the medical profession and the public.

Who profits? the third party payers and a number of the progressive medical elite who have positioned themselves to be the movers and shakers in the governmental and quasi governmental
structures that aim to control the practice of medicine and importantly attempt to control the expenditures of the private and public third party payers.

head trauma and football-What we know and what we do not know as another high school season ends

What do we know about head trauma in high school and college football?.

Mild Traumatic Brain Injury ( mTBI) encompasses the clinical entity of concussion. Concussion is defined as a trauma induced alteration of mental status with or without loss of consciousness.

Considerable research has been published regarding concussion and recently more research has been published about the multiple blows to the head that occur in all levels of football in  the absence of a recognized concussion. These "sub-concussive blows" have become the target for various types of brain imaging and cognitive function testing and the results have raised concern about the long term effects on the brains of highs school and college players.

 Some of what we know is :

1.While conventional MRIs and CTs in concussed high school and college football players are normal , Diffusion Tensor Imaging (DTI) and functional MRI have shown abnormal findings some of which may persist for weeks or months. Additionally subtle impairments of verbal memory and other cognitive tests have been reported in concussion cases persisting past the time during which the player has any symptoms.

2.Similar imaging findings and cognitive testing results are being reported in high school and college players after a season of participation in football even thought the players had no reported concussive event.

3.We know that football helmets do not prevent concussions.

4.We know that at least  some  college level contact sport athletes decades later show abnormal white matter by Diffusion tensor imaging and lowered test results on neurocognitive testing

 Some of  what we don't know is :

1.We do not know what pathological changes underlie the imaging findings. Do the scan results indicate transient damage and tissue repair without likely long term sequelae? Is there a recognizable subset of these players with these findings who if  they continue to be exposed to multiple head blows over many years will develop Chronic Traumatic encephalopathy (CTE)? How can those who may be destined to develop CTE be distinguished from the vast majority of players who never will  have those problems

From  the wide range of head hit exposures in those NFL players who have been diagnosed with CTE the obvious implication is that there must be a fairly wide range of thresholds. There are reports of NFL players with as little as five years of play showing  typical pathological findings at autopsy. Further there has been at least one case of a college player diagnosed with CTE.


2.the long term cognitive changing on various tests  and brain imaging abnormalities have been   demonstrated  in  contact sport athletes in college and high school who did not experience a concussion.

 Another high school football season is ending and so far we have reports of11 fatalities. This is about average for the years following the meaningful changes made in the rules and the techniques of blocking and less dangerous ways to tackle. Better helmets probably prevent skull fractures but not concussions.

You see the same parents who carefully made sure their kids did not ride tricycles without  wearing helmets are some of the same ones watching and yelling at Friday night football games and do not see the irony of the common practice of there being an ambulance at the stadium. If their son is the victim of the second hit syndrome, probably an ambulance won't help.


addendum: Change made on 11/20/15 on the Numbers of high school football reacted deaths and typos corrected on 6/13/16

Sarcopenia the largely neglected "penia"

There are now at least four classes of medications that have received FDA approach for the treatment of osteoporosis and, according to various guidelines, for certain instances of " high risk"  cases of osteopenia.Family practitioners,internists and gynecologists have all joined the crusade to detect by using a questionnaire based risk tool and by bone  density scans  those patients thought to be at high risk" for fragility fractures and thousands of prescriptions for the bisphosphonate  category of anti osteoporosis drugs have been written.

In regard to the other age related loss of tissue integrity ,sarcopenia, there are no medications proven to help and no popular screening test.Only resistance exercise along with an adequate protein intake have been shown to mitigate the loss and in some relatively short periods of time in clinical trials have actually increased muscle mass and strength.

In regard to quantification of the loss of muscle size and strength a number of clinical papers have been published.Here are the stylized facts: From abut age 40 to age 70 there is about a 1-1.5% annual loss of strength as least as measured by the leg extension tests. Then  things get worse around  age 70 where losses of 2.5% or more per year have been documented. Men have been shown to show a greater proportional loss than women and in one study Afro Americans showing a greater loss than Caucasians.

There is a  proportionally greater loss in type 11, ( fast twitch)  muscle fibers  than the slow twitch type 1 fibers. Some of the muscle loss is due to a loss of anterior horn cells with aging. with more type 11 muscle cell loss.Some of the type 11 are replaced by type 1 cells.There is also evidence of qualitative  changes in muscles in the elderly among which there is the deposition of fat within fibers and possibly changes in the angular or spatial arrangement of fibers. Walking , cycling and other aerobic type exercises are largely powered by the slow twitch fibers and a  reasonable anti sarcopenia regimen would include aerobic and resistance exercises,the latter to try a preserve some type 11 fivers. .

The age related decline in maximal oxygen uptake can also be blamed in part on loss of muscle function. About half of the loss of max 02 is due to stroke volume of  the heart and about half to decrease in  a-v o2 uptake which is driven by loss of muscle mass with the associated decrease in the capillary density and mitochondrial mass.

Sarcopenia and osteopenia are related in several ways.The prevention of sarcopenia by resistance exercises also can increase bone density.The sarcopenic person is more likely to fall and sustain a fracture.No randomized trials  are likely to be done to compare a program with resistance exercise and weight bearing excise versus any one the anti-osteoporosis medications.

Which goal of the ABIM Foundation is not part of traditional medical ethics?

The ABIM Foundation's mission is  putting the Charter ( insert full name) into practice. The Charter's main themes are patient welfare,patient autonomy and social justice. In their own words the ABIM Foundation to advocate for " a just and cost effective distribution of finite resources." Are just and cost effective independent characteristics i.e  do these modifiers represent different things? Could a distribution be cost effective and unjust? Certainly- at least  by some definitions of what is justice. Rawls has stated that a distribution that is unequal can only be just if it benefits the most disadvantaged. A cost effectiveness decision does not necessarily advantage the least advantaged members of society.

Could a distribution be just and not cost effective. A significant part of our society is designed with a eye toward achieving justice without  cost considerations. It would be much more cost effective to eliminate most all of the rights of the accused in our criminal justice system and simply take all person accused of a crime out and shoot them. The Bill of Rights did not go through a vigorous cost effectiveness analysis before its acceptance. So the ABIDF's advocacy would seem to be for  things that are both just and cost effective yet in Rawls's ethical scheme cost effectiveness is not just because it ignores the separateness of individuals and may sacrifice some individuals welfare for some greater aggregate utility.Or maybe the authors of the ABIM pronouncements just thought the words sounded good together.


Of course, the social justice element of the Charter is what is not part of traditional medical ethics.

The above  quote explains what the social justice element of their mission is about i.e their version of social justice- just and cost effective distribution of medical resources.

D B Wolfson says in regard to their " choosing wisely" program  is about "exactly the care than is needed".

The physicians in the social justice advocacy world of the ABIM Foundation will play key roles in this just and cost effective distribution of finite resources.Actually there will be two levels of activity. Fist there will be the physician planners and analysts who will "determine" what is cost effective and what is not and what is just  and secondly there are the worker bee physicians (or more broadly the health care providers) who will carry out the details of the just and/or cost effective distribution through directives euphemistically called guidelines. In this way the physicians will fulfill their roles as stewards of the finite medical resources. To determine what is just and cost effective is far beyond the pay grade and technical and professional expertise of the practicing physician and must therefore be left to those with special training and expertise.

Implicit in this construct is the collective ownership of the medical resources. Implicit is this construct is the incredibly overgrown hubris of those who claim they are not only able to determine what is best for the individual by for society as well while  providing "exactly" the care that is needed.

The history of the twentieth century should have made it clear how central planning on a social level works out. Even a cursory survey of what transpired in Russia,in communist China,in India in the era of the collectivization of the farms  and the current Korean peninsula should disabuse anyone of the notion that central planning is the way to go..Galbraith recommended Soviet styled five year plans,in India. Yet central planning of medical care is exactly what Drs. Brennan and Berwick recommended in their  "New Rules".

But this time it will be different.Planning for the millions of people in regard to their health care. this time it will be rational and determined to be of  "high value" and the good of all will be achieved though a rational plan providing what some group of platonic guardians have determined exactly what everyone needs, you know the right medicine for the right patient and the right time



 

Geoffey Roses Population Medicine and big Pharma- is this another baptists and bootleggers story?

Goeffrey Rose in his 1985 book "Sick Individuals and Sick Populations" likely never intended to provide the intellectual grist for the mill of the major pharmaceutical industry but I argue he did.

His thesis was that a large number of people at small risk for a given disease may give rise to more cases than the small number of those at high risk. Rose's population strategy was that there would be a large benefit to the population by treating the low risk people .Large benefit to the community may offer little to the each participating person and in some instances harm and bringing more benefit to an individual may have small impact on the population's health. This was labelled the Prevention Paradox. Interesting, this conception assumes that it makes logical sense to speak of the health of an aggregate which I argue is a category error. Is there a health of the community distinct from the health of its individual members?

Rose's imperative was to decrease the total disease burden of a population.What is important in this formulation is that the aggregate is more important that any of the individuals who make up the aggregate.Individual bees mater little , it is the health of the hive that must be promoted.

Next the idea of risk factor comes into play. This notion was brought into prominence and became an accepted item in the jargon of medicine by the  authors of the Framingham study which was  tasked to find the cause of coronary heart disease and concluded there is not one single cause but rather there are a number of factors, designated as risk factors,the possession of which by a person can be considered to increase  his risk of developing coronary heart disease. The field was ripe for the "treatment" of risk factors and "preventative" medicine blossomed ( replacing the archaic " preventive ")

The slippery notion of the nature of risk was given little attention in medical journals ( with the notable exception of this article by  Dr Goodman )- see here- as the risk factor revolution of medicine burst forth, first with coronary heart disease and then for as many diseases whose risk factors the epidemiologists   ( and young general medicine department faculty members with recently minted MPH degrees) could generate with increasingly broad based and coarse grained data dredging .To name a few, osteoporosis,hypertension, diabetes,cancers, all have accumulated their own array of risk factors as have  alcoholic abuse, depression and internet addiction.With greatly increased access to computer statistics programs and processing and p value hacking it seemed that almost everything is a risk factor for something.  and making big deals over small differences ( relative risks less than 2) increased the risk that reading the daily news would makes the average reader think he was at a risk for something.

With Rose's population thesis and the epidemiologists' increasing supply of risk factors the opportunities for the drug companies burst forth.The idea that just about any disease can be described as a public health issue opening the door for "public health solutions" which typically involves governmental involvement if not governable coercion, at least in the form  nudges consisting of grants and public education campaigns.

People were increasing treated for pre-diseases; pre-coronary heart disease, pre- hypertension,pre-diabetes, and even pre-bipolar treatment for moody,irritable ,grumpy kids .Cardiologist Tom Giles sarcastically talked about everyone  possessing the risk factors for  being "pre-dead".

Pre-patients ,after being informed of some risk factor for something,were advised to see their physician health care provider to "determine" their personal risk.This is of course an impossibility because all the provider can do is to parrot what the pre-patient has already read, namely that he is a member of a group   which has allegedly an increased risk, there being no technique learned in medical school  health care provider school that enables the provider to magically provide a personal risk, that concept making no logical sense.

Is FUBAR the basic default position for the world -part 1

"Default" in financial terms means that someone is unable to fulfill an financial obligation and defaults on the loan, i.e. is unable to repay.This is not the default I am talking about.

In the computer world a default is a pre setting and pre build in  arrangement which will become operational unless it is overwritten with some other option. Your computer may come with Internet Explorer as the default browser so when you turn it on there is Explorer. But if you might prefer say Firefox you could program your machine to go to Firefox as the default browser when you turn on the computer.

Car dealers may have default packing of extras for their various car models . But you can opt for another set of bell and whistles and engines.

FUBAR is said to have originated as a military acronym meaning Fouled up ( more commonly fu**ked up) beyond  all or any repair or reasonable redemption. ( Paraphrased from Wikipedia)
 The military seems to have been the source of so many such situation that it is not surprising the term arouse from that source.

 A series of animated shorts was produced by Warner Brothers in 1944 featuring three brothers, Sergeants  Fubar,Snafu and Tarfu, the latter two standing for situation normal all fouled up and things are really fouled up. The vignettes were prefaced by a promotion to buy war bonds and and the great voice actor Mel Brooks played the brothers.

The writers seemed to recognize a gradation of fouledupness, with SNAFUs perhaps not so bad that they could still be patched up a bit or mitigated , but could progress to the unfixable last phase, the FUBAR.


The more I read about so many things, politics,governmental programs and much to my sorrow the current state of medical practice,the more I think the depressing thought that FUBAR is the default position for about everything Not everything- some things still work pretty well, but so many don't.

And yet the incredible progress  of the world since the 1700s give clear evidence that all is is not fubar, There are there patterns of activity that predispose to fubar situations  and some that do much less so. The thing that stands out is that central planning is the most fertile ground ever for fubaring .
 Societies with strong property rights,rule of law, contract law and  individual freedom while far from perfect and certainty not foolproof seem less like to end up as irreparably broken. although 90 years of progressivism just might do it.

Effect of aging on pulmonary function, structure and exercise capacity

Most of the blame for the progressive age related decrease in exercise capacity is correctly directed at the  cardiovascular system. Traditionally focus has been on the maximal oxygen uptake ( O2 Max) decrease with exercise with both components of that value , the cardiac output and the a-v 02 difference both contributing.The stylized physiological narrative is that O2Max decreases about 5-10% per decade on average although there are some outliers whose per decade loss is much less. It has been suggested that about half of that loss is due to decrease in the heart's stroke volume and about half of the blame goes the a decreased A-V o2 difference-i.e. the ability of muscles to take up O2 efficiently.The benefit of exercise in heart failure is likely due mainly to the effects of exercise on the muscles and their mitochondria and capillary density and less on making the heart beat better.


O'Donnell   and co-authors in their paper "Physiological Impairment in Mild COPD" tell us that mild COPD  and the effects of aging are qualitatively similar While arterial blood gas values change little  and acid base balance is maintained there are well described age related functional and structural changes.

Airway resistance increases as large and small airway narrow and there are also some age related enlargement of the air spaces.Residual  volume increases while inspiratory capacity decreases while total lung volume changes little.Airway resistance increases as air flow increases and compliance fall a phenomenon called frequency dependent compliance, once a source of interest to pulmonary physiologists but not so much with pulmonary doctors.

When older endurance athletes are compared with young subjects several workers  have demonstrated that the older subject have a higher ventilation for a given work load.The minute ventilation (VE and VE/VCo2) are increased said to be due to greater dead space ventilation  which is considered  one form of  ventilation perfusion inequality. The mechanism for this V/Q imbalance is not clear.

So getting older, lung wise is a bit like mild COPD  similar to getting older heart wise is similar to a little of diastolic dysfunction.-more on that later.




O'Donnell, DE et al. " Physiological Impairment in Mild COPD), Respirology , 2015 doi 10 1111/resp.12619 Published on line 2 Sept 2015

Does The American College of Physicians see everything through the lens of the progressive mind set?

Arnold Kling' useful framework of describing how libertarians,conservatives and progressives see the world is thoughtful and has more than a little predictive value.The progressive's lens is shaped  to see things in terms of the oppressed and the oppressor while the libertarian tends to see things in terms of freedom and coercion and the conservative sees the world often in terms of the civilization and barbarism.He calls this notion the Three Axis Model and is available on Amazon  in an inexpensive Kindle format.

Applying this to the issue of concierge  or retainer model of medical practice ( also known as Direct Paitent Care Plan or DPCP) the recent response of the ACP ( see here) fits well with the progressive view which I claim is their default analysis for many issues.

(Mr Bob Dohrty , who is the senior VP of government affairs and public policy of the ACP, inexplicably has denied my claim that their policies are progressive. See here.)

In regard to concierge practice or DPCP, ACP said in part " it must be recognized that DPCPS potentially exacerbate racial,ethnic and socioeconomic disparities in  health care and impose too high cost on some lower income patients".


The progressive view sees things in terms of the oppressor-oppressed model and often uses a defining metric of  inequality along some  or other parameter. IMHO It seems that ACP thinks  most everything about medical care is all about social justice.

New and better ways to distinguish "athlete's heart" from abnormal heart enlargement

It has been long recognized that athletes may have larger hearts and changes on the EKG that are difficult to distinguish from abnormal findings such as those seen in an abnormally enlarged thickened  left ventricle with hypertrophic muscles as is seen in long standing hypertension and in hypertrophic cardiomyopathy(HCM).

In fact . athletes have enlarged heart muscle as well and cardiologists have attempted to provided some wall thickness values above  which it indicated abnormality. . A distinction  based on various  EKG criteria have never been that reliable.

In addition, all athletic activity does not seem to bring out the same type of physiological adaptive changes. A distinction is typically made between endurance athletes and strength athletes, recognizing that some athletes do both endurance and strength training.

Generally endurance athletes increase cardiac output under conditions of  reduced peripheral resistance while strength trained athletes increase cardiac output against increased peripheral resistance. It would  be expected that these difference would be reflected in the heart's adaption

The stylized facts are that  the endurance athletes have increased wall thickness  as do the strength folks but endurance athletes have larger chambers . e.g left atrial size and left ventricular diastolic diameters. The usual definition of the upper limit of normal for the left atrium is often said to be 35ml while one  study of endurance athletes has shown value of 37.7 ml.The left  ventricular wall is sometimes greater than 13 mm ( in one study of elite endurance athletes 13% were greater than 13 but none above 15 mm.  About 1/3 of elite endurance athletes have LV cavity end diastolic greater than 60 ml. whereas  upper  normal is typically consisted 55 ml .Typically endurance  athletes are said to have eccentric hypertrophy while endurance athletes have concentric but that concept has  been challenged.

At least one study reported that endurance athletes had indicators of  better diastolic function that do strength trained athletes. (Vinereanu,D, Clin Sci 2002).However, overall the data are conflicting as to whether endurance exercise improves diastolic filling apart from  heart rate changes and
 as to whether any diastolic function improvement persists in senior athletes to significantly mitigate the seemingly universal age related increases   myocardial stiffness. ( Perhaps another example of the Woody Allen physiological maxim ,paraphrased when you get old everything  that should be soft gets hard and everything that should be hard gets soft.)

In any event the athletes hearts seems to work quite well particularity when compared with the enlarged hearts that can result from hypertension both in terms of pumping  the blood during systole but also  in rapidly refilling the ventricular chamber in diastole preparatory for the next ejection

Athletes hearts  pump more effectively  blood during systole This is   usually expressed as as EF, value ( ejection fraction) which is  generally greater in endurance athletes than in  normals but the range overlaps. .But also the athlete's  ventricles  fill faster in the relation phase of the left ventricle , i.e. diastole so their enhanced cardiac output results from more filling  and more ejection giving them higher stroke volumes.

Using various indicators of diastolic function ( such as the early phase of filling versus the later phase of filling (an e/a ratio being one such measure) it has been  clearly demonstrated that left ventricular filing is normal or supra normal in the endurance  athletes with increased wall thickness while the opposite occur to varying degrees in hypertensive heart disease and other causes of LVH such as aortic stenosis and hypertrophic cardiomyopathy .

Newer echo techniques have provided even more evidence of a distinction   between the enhanced  cardiac function of the endurance trained athletes and those with hypertensive heart disease and to aid in the differential diagnosis of hypertrophic cardiomyopathy.

In the last ten years a technique referred to as deformation imaging ( which can be subdivided into 1)TDI and 2)speckle-tracing 2D strain imaging)  has provide a new way to elucidate cardiac physiology. The techniques can distinguish between active and passive myocardial segment motion.

In echo speak "strain" mean deformation, unlike the  everyone day English language meaning  and these techniques measure strain and strain rate.Strain is considered the fractional change in length of a myocardial segment and can be expressed as a percentage.Ultra sound images contain natural acoustic markers, called speckles, which can be tracked as muscle segments move during contraction and relaxation and actively contracting muscles segment can be distinguished from areas moving poorly. 

Speckle tracing studies have shown that the ventricular hypertrophy as in  hypertension is associated with decrease strain ,that is less deformation, which is functionally disadvantageous while the hypertrophy of endurance athletes does not differ appreciably from normal controls and is not associated with  functional impairment.In other words this is  an advantageous remodeling.

A similar distinction between pathological left ventricular hypertrophy and  physiologic athletic hypertrophy  has been made using MRIs of the heart. ( Peterson SE, 2005 , J Cardiovas Mag Reason 2005:7,(3) 551. Speckle tracing is much less expensive .

For the most part newer testing techniques have done away with concerns about exercise causing the heart to enlarge in a deleterious physiological way with the interesting possible exceptions of  harmful changes or remodeling of the right ventricle and of the left atrium with a putative increased risk of atrial fibrillation. Several authors have argued and provided some evidence that prolonged endurance type exercise can bring about a condition similar to an inherited disease called arrhythmogenic  right ventricular hypertrophy (ARRV), a topic I wrote about before see here.

addendum: added 10/1/15 5:46 PM.  Here is more on the differences between strength athletes and endurance athletes. Rowers were compared with Long distance runners and the authors fond  that the runners had larger left ventricular volumes,lower and in the normal range for ventricular mass and a tendency to less thickened left ventricular walls.  (Wasfy,M Endurance exercise-induced cardiac remodeling: Not all Sports are created equal,Journal of the American society of echocardiography, 2015,Sept 9


addendum 2/9/16. Minor wording changes made in last paragraph.
  addendum 6/6/21 Several typos corrected.

George Soros's Open Society Institute and American Board of Internal Medicine Foundation programs,strange bedfellows or birds of a feather?

Medical Professionalism for the new Millennium; A Physician's Charter was published in 2002 both  in the Annals of Internal Medicine and in the Lancet reflecting an international authorship. In 2003, George Soros's Open Society Institute founded a think tank, advocacy organization called Institute on Medicine as a Profession. (IMAP) with a 7.5 million dollar grant.

Later two grants ($350,000 in 2003 and $ 60,000 in 2008) was  given to IMAP by the ABIMF.ABIMF is chiefly funded by the ABIM and has a common leadership roster.In turn ABIM makes its money by testing internists and managing their Maintenance of Certification (MOC) program,a program that has generated a firestorm of protests from practicing internists and a serious effort to establish a rival means of maintenance of certification.

What is the ACP-ABIM(F) version of medical professionalism. Among other features, this "charter" calls for physicians to be "stewards of society's medical resources" and to work for social justice. It speaks of an obligation not only to the patient but to society as least in the sense of conservation of these allegedly common resources and to work for a just distribution of these resources.

The Charter was not cut from whole cloth, neither was it a tailored answer to the alleged problems that were claimed to be causing physicians angst  in the new millennium.Rather it was another manifestation or application of the new Bioethics about which Pope Benedict XVI had this to say in his 2010 address to the Pontifical Academy for Life:

"Under traditional medical ethics the guiding principle is 'do no harm". But contemporary bioethics abandons this in an effort to find the utilitarian goal of the greatest good for the greatest number Under these principles preserving the life of the human patient is not considered paramount."

Wait. what  does the charter have to say about greatest good for the greatest number? Explicitly it said nothing but advocating social justice.

Social Justice is a loose , vague and indeterminate term, which although it has a useful rhetorical value   might puzzle physicians as to how they might actually work for the nebulous social justice in their everyday practices. The ABIMF in its publications and on its website made it explicit -follow the guidelines. In that way they claim  resources would be wisely distributed and fairly  thus furthering social justice. Here we get the greatest good for the greatest number in the collective. The collective may just be the HMO or ACO or possibly all members of society.So while the Charter seems on the surface to be medical ethical Principlism , a la Beaumont and Childress, underneath there is a strong utilitarian initiative .

ABIMF's mission appears to be to further this brand of medical professionalism and to
champion the "Choosing Wisely" initiative.

 The Soros funded IMAP describes its mission in the following way:
Their vision of medical professionalism  embodies 4 values;

1) altruism that is a unwavering commitment to the patient.
2)Physician Self regulation
3)Maintenance of technical competence-a commitment to life long learning
4)Civic engagement "Physicians should enlarge their scope of concerns from the welfare of the individual patient to a concern for the welfare of all patients" ( my underlining)

This parallels the outline of the Charter which continues to speak of duty to the patient but an additional obligation was grafted on to that traditional prime directive namely to conserve resources and work for an efficient and fair distribution of resources.Numbers 1,2, and 3 add nothing to traditional medical ethics but number 4 is another matter.

So IMAP more or less recapitulates the Charter blending the traditional mom and apple pie medical ethics with a new obligation to work somehow for all patients.It should be no mystery why ABIMF might share some of its resources with another advocacy group with similar if not identical goals. My question is why does Soros wish to promote the new professionalism i.e. the Charter ?

So here it is- the physician's goal should not just be the welfare of her patient but rather the welfare of everyone.And the best way she could accomplish that goal is to follow guidelines which will provide the best bang for the buck (efficient "parsimonious care") .And one way to save money is  to limit care to the elderly which is being sold as improving the quality of life in folks in their twilight days and months.

One of the leaders in the effort to limit care to the elderly , Dr.Joanne Lynn,perhaps said more that she intended when she said:"Not only the right thing to do, it makes good business sense".

Good business sense, is that what Choosing Wisely is all about?And whose business are we talking about.


 Addendum: 4/1/16 Minor changes in wording made.

Still more data linking endurance exercise and atrial fibrillation

A number of  studies have shown a relationship between long time endurance exercise and increased  risk of atrial arrhythmias. and there is a growing consensus that this is a causal relationship. As a long time marathoner I don't welcome the news but I cannot no longer ignore it and have to worry about it. 

One of Bradford Hill's classic  criteria for assessing if a relationship between variables is causal is the dose response principle also referred to as biological gradient. This simply means that a larger dose or exposure should lead to a greater incidence of the effects.Myrstar and co authors  have published a study demonstrating a dose response relationship between years of endurance type activity and risk of atrial fibrillation and atrial flutter. In this article Myrstad and co-authors reported an odds ratio of development of atrial fibrillation of 1.16 per ten years of endurance exercise. (confidence interval 1.06--1.29).

 In another study from Norway the same lead author reported in regard to  a cohort study  of 2626 long time cross-country skiers and 2326 people from the general population. He found a prevalence of 12.3%  of self reported atrial fibrillation (AF) in the skiers versus 5% in the non-skiers. Of those, 64% continued to engage in regular endurance exercise after the onset of AF.Interestingly some 1/3 of AF patients did not use oral anticoagulants even though they had a CHA2DS-VASc scored of greater than or equal to 2,a score that current conventional medical wisdom believes anti coagulation is needed to decrease stroke risk.

 To get some approximation of context consider the ATRIA study (Go,A, et al, JAMA 2001:285:2370) which reported a prevalence of 0.1% in those younger than 60 years,3.8 % age 60 and older, and 9 % age 90 and older More extensive data can be found here in the discussion of a pooled analysis of five randomized clinical trials in which the relative risk of a fib increased 1.4 by decade ( C.I. 1.1 to 1.8). Some older runners would like to take those factoids to suggest that getting old is even more risky than running.

 An enlarged left atrium  has thought to be the  likely link between atrial fibrillation and hypertension.Some long term endurance athletes have been demonstrated to have larger left atria and while it can be considered a "physiological" adaption to increased exercise and periods of increased cardiac output the increased surface per se  may predispose to atrial rhythm mischief.Is the enlarged athletes' left atrium less pathological than that of the long term hypertensive patient?


Most of this is a "dog bites man" or duhh story but I continue to be impressed with how easily one can effortlessly find medical articles even in Journals that are not that widely read. The second article mentioned above was first published  in the official journal of the German Cardiac Society, one that I do not typically read. The ease with which you can follow current journal articles on a number of topics of your choosing on the free app QxMD is amazing particularly for someone who grew up wrestling the unwieldy Index Medicus tomes and wandering the medical library book stacks to find the volume of interest missing.You can easily learn more in an hour with that app and your tablet than you could in all day at the medical library.


addendum:10/1/15 some editorial flourishes made.

addendum: 12/2/2016 Another article presented some  data on dose response relationship.Anderson and co workers from Sweden compered the risk of atrial fib and brady rhythm problems in a large cohort of cross-country skiers. Those who took part in five or more events were compared with those who only completed on one  90km race and found a hazard ratio of 1.3 (1.08--1.58) for those who raced more. Though a increased risk of atrial fibrillation gets most of the attention , this study  showed a greater risk of bradyarrhythmias with a HR.of 1.85 , though not statistically  significant with a CI of 0.97--3.54.The quantification of the "dose" is crude as well but data are suggestive.
(Anderson, K et al., Risk of arrhythmias in 52 775 long-distance cross country Skiers: a cohort study.
European Heart Journal 2013 34: 3264 )

Born to run (slowly) and to loaf-The Leiberman hypothesis?

Harvard Professor David E. Leiberman  has taken Theodosius Dobzhansky's maxim to heart; "Nothing in biology makes sense except in the light of evolution."

Leiberman,also known as the barefoot professor for his interest and advocacy of barefoot running ,expounded his thesis along with co author Dennis Bramble in a 2004 article in Nature entitled " Endurance running and the evolution of the genus homo."

Quoting from the above article ;" The fossil evidence of these features [features that facilitate endurance running] suggests that endurance running is a derived capability of the genus Homo, originating about 2 million years and may have been instrumental in the evolution of he human body form."


Leiberman's theory suggests that Homo evolved the ability to run long distances and hunt and forage in the heat before the human brain grew and humans got smart enough to  rule the roost .

The creature than evolved  could be described as a fur less,short toed,sweaty bipedal endurance athlete who was typically at the edge of negative calorie balance and who tended to loaf and rest whenever he could to conserve energy as food was scarce and difficult to obtain.These were the hunter gatherers whose survival depended on their ability to track and hunt animals over long distances in the climates of the African savannas as well as to dig around and find what they could to eat. That stylized story is that is how our ancestors lived as recently as some 600 generations ago, according to some estimates.

As the pressing need to work very hard physically became less and less necessary for more and more people the evolved human's drive to rest and conserve energy persisted and when not countered by lots of exercise obesity and the modern maladies such as  arterial diseases and type 2 diabetes went from rare to increasingly common.

It is an appealing story,one that resonates with those among us who like to do endurance type exercise. This includes Leiberman .  Much of it seems to make sense and is rich in physiologic insights, but is it all  just an "as if story"?

Hans Vaihinger is known as the philosopher of "as if". His view was that one should not ask if a theory or belief was true in some deep probably unknowable objective sense but rather is it useful to act as if the theory were true. ( I think Milton Freidman spoke of economic models or theory in that way, that is are they useful.) From reading descriptions of Vaihinger's work, I think it seems to him maybe most stories are "as if stories". George Box is quoted as saying that all models are wrong but some are useful.

Leiberman writes and speaks well in an entertaining way and regales us with mechanisms  such why tighter ( rather than more lax) Achilles tendon enables running and why longer toes are a detriment to running  and how sweating works much better as a heat dissipation mechanism than panting.

Bob Wachter's defense of ABIM's shenanigans and Mel Brooks

Dr. Bob Wachter,former chair of the ABIM, has spoken out in defense of ABIM and , of course, of himself.

Several medical bloggers have offered their critique of his comments including Michel Accad,  ,Walter Bond. and Dr RW..In my opinion all make  some good points with which I agree.

But I think Med Brooks' comments  may be the most appropriate.

Can Dr. Cassel and her collaborators at the National Quality Forum repeal Goodhart's Law?

In the December 4, 2014 issue of the NEJM, Dr. Chistine K.Cassel et al expound on performance measures.She freely admits there have been some problems but also apparently some successes.It is just a matter of learning from the mistakes and  leveraging the successes. We just have to work harder and be smarter. "Getting More Performance from Performance Measurements" Cassel, CK et al , NEJM 371,23 2014). When people talk about "leveraging" you can be sure the tripe level is dangerous high.

She offers her explanation of  why the notorious "four hour pneumonia rule" did not work out well. That particular clinical situation was "not the right place to intervene". .."There was too much clinical variability for the measure to help physicians on exactly the right course of action." True enough but that was not the reason.

The underlying insight is found in Goodhart's Law which states that when a measure becomes a target it loses its value as a measure.A more basic insight is that people respond to incentives. When folks are graded, or rewarded or punished based on some measure they will find ways to achieve that target and if better care results fine but there is not reason to think apriori  that it will. Teachers will teach to the tests and students will study for the test regardless of how well or how badly the test reflects the students' mastery of the subject.


Goodhart wrote about his "law " in 1975 and in 1976 Donald Campbell wrote in regard to education and testing :

"achievement tests may well be valuable indicators of general school achievement under conditions of normal teaching aimed at general competence. But when test scores become the goal of the teaching process, they both lose their value as indicators of educational status and distort the educational process in undesirable ways.

It is tempting to substitute medical care for  the teaching process and we get "But when quality measures become the goal of the medical care process , they both loose their value as indicators of medical care and distort the process in undesirable ways."

I submit that devising better measures will not change the situation.

Dr. Cassel et al would disagree with my view and she closes her commentary with  the usual boiler plate words about "stakeholders"  and better quality down the road. "All stakeholder groups are now invested in getting more  performance out of measurements ,which should ultimately drive the care improvements that patients need and deserve."

 The economist,Arnold Kling, give his take on performance measures or P4P  here.

I have commented on this general subject before and here  the issue of a conflict between P4P and traditional medical ethics is talked about.

The folks at the National Quality Forum can no more negate Goodhart's law than they can make it now longer the case that people respond to incentives.The stakeholders of which Cassel speaks , of course, included the NQF itself as it is in the business of writing quality standards .

There are some amazing octogenarians out there

Some  know-it-all-officious-busybodies   medical progressive elite presume to know when various medical procedures should be limited on the basis of age. Some even presume to know how long someone will live as in recommendations regarding limiting of medical procedures for those deemed to have less than ten years life expectancy or using 75 as a cut off date for certain type of screening tests.My pathology professor in medical school was fond of saying when you tell someone how long he has to live they may piss on your grave.Spock's "live long and prosper" butts up against Dr.Zeke's proposed forgoing of preventive measures for those 75 and older, well at least for him, or so he claims now.

Two recent journal articles shed some physiological light on  some  folks in their 80s,folks about whom some of the progressive elite would desire to limit medical care.

Trine Karlsen et al described a remarkable 80 year old Norwegian.The authors believe that the subject of their study may have a world record for maximal oxygen uptake (VO2max). for his age 50,ml/kilo/min.Accordingly to the authors this value is compatible of a normal, active, non endurance trained 35 year old Norwegian man.(How to be 80 year old and have a V02max of a 35 year old, Case Reports in Medicine, Vol 2015, article id 909561). The "how " seems to be to have great genes and to be very physically active.


 To put V02 max  in some perspective; It is a measure of the highest rate at which oxygen can be utilized by the body during intense exercise.It is a function of how much blood the heart can deliver to the muscle ( cardiac output) and how  much oxygen the muscles can take up measured by the a-v oxygen difference.


It is generally believed to peak somewhere between age 25 and 35 and decreases afterwards. Various estimates of the rate of decline have been made. A stylized version is that the decrement is of the order of 5-10 % per decade until about age 70 and then V02 max declines more rapidly.For those who continue to do endurance exercise training the decrease is in the 5% per decade range.Some data indicate that endurance athletes' VO2 max actually decreases more per decade in absolute terms ( ml/minute/kilogram) but since they begin the decline with a higher absolute value their percentage decline is about half of that of the non trained healthy person. In that regard as in most things there are some conflicting data and considerable individual variation. Karlsen's subject has his 02 max measured at age45 so that the calculated decrease in his 02 max  from age 45 to age 80 was a remarkable 2.3 ml/min/kilo per decade while previous reports suggested the average decrease is 5.4 ml/min/kilo per decade. At age 25 he was measured at 75 ml,min/kilo.

World class endurance athletes typically have values in the 70s and 80's. The value of 90 is often quoted as the highest record, this in a 24 year old cross country skier while other publications quote the recording of 95 . The value of 17.5 ml/kilo/min ( 5 mets)  has has been labelled the aerobic frailty level, the value below which a person is by one  imprecise definition, frail, and would find the activities of every day life consuming such a high percentage of their O2 max that fatigue would greatly limit function.A value of 7 ml oxygen /kilo is said to be the lowest level compatible with life.Endurance exercise training programs typically increase 02 max by 10-15% ( with the occasional outlier of more than 30%) but those folks in the 70 plus range can thank their parents ( at least one of them) for their exercise capacity.The sled dogs who race have 02 max values in the range of 240!


Scott Trappe and co authors in an earlier article in the Journal of Applied Physiology ( see here) published detailed physiological data including results of muscle biopsies and muscle enzyme studies on 15 active healthy octogenarians (one actually was 91).Nine were long time endurance athletes and 6 were age matched healthy untrained men without serious medical conditions and who were fit enough to do the exercise testing. Not only had the athletic group been competitive cross country skiers in their youth, they had continued with vigorous programs and all had trained  on average 8 hours a week for the last fifty years. ( Fifty years is not a typo).The endurance athletes had 02 max values between 34 and 42 while the healthy non endurance folks had on average a 21.

And then there is Ed Whitlock.See here for details of his setting the marathon time record for a 82 year old human . He finished at 3:41:58 which is nine minutes 49 second per mile.Whitlock is also noted for being the only man to run a sub three hour marathon at age 70 or older.Estimating his V02 max using table 2.3 from Tim Noakes's Lore of Running ( which is derived from data of Davies and Thompson) gives a value of about 48 ml/kilo/min, which is close to Karlsen's subject's measured value..

 
addendum: 8/28/2015
Ed Whitlock is not the only 80something who ran a sub four hour marathon. Ed Benham ran a 3:48 marathon at age 82 and Harold Wilson did 3:58 in Boston at age 80. In the half marathon category Anne Garrett ran 2:13 at age 80 .

 Addendum: 1/19/16 Thee were four men 80 and over ( who made the six hour cutoff, in the 2016 Houston Marathon, the fastest of which ran a 4 hour 23 minute race. According to the guesstimate form the above quoted table from Noakes,he would have a 02 max of  39-40 , not too far from Karlsen's subject and way out of the curve for 80 years olds.