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The Evidence Crisis: Causal Inference – Don’t be a chicken (Part 3)

By ANISH KOKA

Part 1

Part 2

Physicians have been making up numbers longer than people have been guessing weights at carnivals.  How much does this statin lower the chances of a heart attack? How long do I have to live if I don’t get the aortic valve surgery?

In clinics across the land confident answers emerge from doctors in white coats.  Most of the answers are guesses based on whatever evidence about the matter exists applied to the patient sitting in the room.  The trouble is that the evidence base used to be the provenance of experts and anecdotes that have in the past concluded leeches were good for pneumonia.

And so came the randomized control trial to separate doctors from homeopaths.  Random assignment seeks to achieve balance between two groups for everything but the treating variable to isolate the effect of the treatment.  But does randomization really guarantee a balance between groups?  At least the known confounders may be measured in the two groups, but what about unknown confounders?

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The EBM Wars: Manufacturing Equipoise (Part 1)

By ANISH KOKA

The phone rings.  It’s not supposed to be ringing.  It’s 2 am.   The voice on the other line is from an apologetic surgery resident.

Resident: There is this patient..

Me: Yes, go ahead. Please.

Resident: He’s tachycardic.

Me: How fast?

Resident: 160 ?

Me: What’s the blood pressure?

Resident: 130/90

Me: Rhythm?

Resident: An SVT I think.. I gave adenosine.  Nothing happened

Me: Audibly groaning.  I’ll be in..

Forty five minutes later I’m at the bedside of a decidedly ill appearing man.

I want to be triumphant that his heart rate is only 145, and a quick glance at the telemetry monitor above his bed uncovers juicy p waves in a cadence that suggests this is no primary electrical arrhythmia.

Something is very wrong somewhere – the heart in this case is an innocent bystander being whipped into a frenzy to compensate for something.

At the moment the whip is a norepinephrine infusion being used to keep his blood pressure up.

I ask the nurse if the amount of norepinephrine infusing has been stable.  She replies that his dose has been slowly escalating.

Eureka! I think – the heart rate response in this case is being driven by the norepinephrine – a powerful adrenaline that acts on beta receptors and alpha receptors within the body that increase heart rate and constrict the blood vessels to raise blood pressure.  Fix the cause of the low blood pressure, come down on the norepinephrine, and perhaps the heart rate would be better.

But it turns out this particular post surgical patient doesn’t have a medical cause of low blood pressure I can find.  I cycle through cardiac ultrasounds, blood gases, steroid and volume challenges, and try inching down on the norepinephrine.

All of it is to no avail.  I’m growing more and more convinced this problem is surgical in nature. Perhaps an infarcted piece of bowel?  All I know is that the man acts like he has no peripheral vascular tone.

An interesting thing happens shortly after.  The norepinephrine drip runs out.

As one nurse runs to get another bag from the pharmacy – a quick cascade of events unfolds.

The brisk upstroke from the arterial line that marks the pressure wave generated with every beat of the heart starts to dampen.  The color seems to visibly drain from the patients face, and he begins to complain that his vision is getting blurry.  His systolic blood pressure is 70 – an almost forty point drop within a minute of the norepinephrine running out.

I call for help.

I try to keep a level tone.  Project control, not panic.

“Open the code cart, I need a half a milligram of epinephrine”

“You’re going to be ok, sir.  Hang with me.”  I squeeze his hand.

He closes his eyes

The code cart – a fully stocked cabinet on wheels with almost everything you need for resuscitation efforts – is wheeled into the room. The epinephrine vial is handed to the nurse, and hurriedly pushed.

Within seconds, I can see the blood pressure and heart rate rise.  The patient’s grip on my hand relaxes.  Or maybe its my grip on his hand.  I forget which.  His vision returns to normal as his blood pressure ‘normalizes’.

Of course nothing has been fixed.  Why his blood pressure remains low continues to be a mystery.  The bag of norepinephrine soon isn’t enough even at its maximal dose.  The same scenario (hypotension -> pallor -> vision loss ) recurs 30 minutes later, and another bolus of epinephrine aborts a rapid spiral towards pulselessness.

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Fighting Hubris in Medicine

By ANISH KOKA

The weekend started with a tweet about an elderly man with atrial fibrillation.  Atrial fibrillation is an arrhythmia of the heart that predisposes those who suffer with it to strokes.  The strokes are a  result of clots being thrown from the heart into the brain.  The typical treatment for this condition in those deemed high enough risk is to thin the blood to help prevent these clots from forming, and thus reducing the risk of stroke.

The problem with thinning the blood is that the risk of bleeding increases, and it does so especially as one advances in age.  It doesn’t help matters that the risk of having a stroke also increases with age.

In a 101 year old deciding on the best course of action is thus a challenging one.  It is easiest when patients are adamant about a certain path.  Far be it from me to tell a centenarian what to do.   In this case, the man who had been alive for two world wars chose to come off the anticoagulant he had been dutifully prescribed.

I queried the audience

Most leaned towards stopping Pradaxa, and some responded that there wasn’t a wrong answer.

I asked the question because this was a decision that had been made four years earlier.  The consequences of that decision were playing out now.

No one lives forever.  In a parallel world, the anticoagulant continues and this is a discussion about the brain hemorrhage that resulted.  These aren’t the only two possibilities. He could also have avoided both types of stroke, attended a few more great grand kids birthdays and passed away in his sleep from a cardiac arrhythmia.

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A Tale of 2 FDAs

By ANISH KOKA

Frances Oldham Kelsey by all accounts was not mean to have a consequential life.  She was born in Canada in 1914, at a time women were meant to be seen and not heard.  Nonetheless, an affinity for science eventually lead to a masters in pharmacology from the prestigious McGill University.  Her first real break came after she was accepted for PhD level work in the pharmacology lab of a professor at the University of Chicago.  An esteemed professor was starting a pharmacology lab and needed assistants, and the man from Canada seemed to have a perfect resume to fit.  That’s right, I said man.  Frances was thought to be a man’s name, and the acceptance letter accepted Mr. Frances Oldham.  Given the times, her Canadian mentor advised the young Frances she not write to inform the Chicago professor of the mistake but to simply sign the acceptance letter as Miss Oldham.  The rest, as they say, is history.  Ms. Frances Oldham arrived in Chicago in 1936, and just two years later was asked to work on figuring out what caused one of the worst poisonings in American history by the nascent US Food and Drug Administration (FDA).

The FDA at the time was a small organization within the federal government that had come into being a few decades earlier after the passage of one of many progressive laws passed to protect consumers from rapacious pharmaceutical companies of the day.  At the time there was no standard for claims that could be made to an unsuspecting public and no requirement that drug companies specify what ingredients were being consumed by the public.  The companies of the day would take alcohol, water and coloring mixed together – give the formulation a name, get a US patent, and make millions by heavily marketing testimonials of cures to all that ails directly to the consumer.  At one point, it was estimated that there was more alcohol being sold via ‘patent medicines’ than at liquor stores.

Sadly, it was not medical professionals that put a stop to this, but muckraking journalists like Samuel Hopkins Adams who exposed the seamy underside in a series of articles for Collier’s Weekly entitled The Great American Fraud.   Popular outrage followed publication of this series in 1905 and in response, the first draft of the FDA came into being by order of Congress in 1906.

The initial purpose of the FDA was a small, but important one – ensure the correct labeling of drugs being sold to the public.  The 1906 act – fought tooth and nail by industry – mandated that ingredients such as alcohol, cocaine, heroin, morphine and cannabis be accurately labeled with contents and dosage.  To understand the scope of the problem at the turn of the century, understand that Coca-Cola (Coke) was sold initially as a ‘patent medicine’ that was marketed as a cure for headaches, impotence, morphine addiction as well as a number of other ills.  The main ingredients?  Cocaine and Caffeine.  Current drinkers of Coke will be happy to know that cocaine was eliminated from the formula in 1903.

The FDA as we know it now is a result of the passage of the Federal, Food, Drug and Cosmetic Act (FFDCA) of 1938 that came as a reaction to national tragedy in 1937 that once again drove home the point that the public needed protection from private corporations.   The matter was a simple one that involved an ingredient that actually worked – sulfanilamide.  Sulfanilamide was an antibiotic that killed bacteria by preventing the synthesis of Folic Acid.  Humans are relatively primitive and don’t make Folic acid – so it isn’t toxic to humans.  That is, unless you’re the chief chemist of  S. E. Massengill Company, and you create a preparation of sulfinilamide that is dissolved in di-ethylene glycol (DEG).  DEG is toxic to humans – the first case reports of toxicity had been reported six years earlier.  Unfortunately the chemist, Harold Watkins, who worked for the company was unaware as this was not widely known at the time.  Watkins simply added some raspberry flavor to the sulfa dissolved in DEG, and the company founded by a Tennessee medical student who saw more opportunity in selling drugs to doctors than practicing medicine started distributing the drug widely.  No animal studies or any type of premarket testing was required at the time, and so the drug went straight from the lab to the consumer.  More than a hundred people died.

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The Ethics of Keeping Alfie Alive

By SAURABH JHA

Of my time arguing with doctors, 30 % is spent convincing British doctors that their American counterparts aren’t idiots, 30 % convincing American doctors that British doctors aren’t idiots, and 40 % convincing both that I’m not an idiot.

A British doctor once earnestly asked whether American physicians carry credit card reading machines inside their white coats. Myths about the NHS can be equally comical. British doctors don’t prostate every morning in deference to the NHS, like the citizens of Oceania sang to Big Brother in Orwell’s dystopia. Nor, in their daily rounds, do they calculate opportunity costs for keeping patients alive on ventilators.

Conversations such as this are vanishingly rare.

Administrator: “It’s costing an arm and leg keeping this sick baby alive – to balance the annual budget we need to stop dialyzing a granny.”

ICU doctor: “We’ll have to send poor Ethel to her grave. That’s a shame. She was beginning to grow on me.”

Health Ethicist: “Wait, let me check with National Institute of Clinical Excellence, the rationing experts, who should be relieved of intensive care first. Perhaps it should be Winston, not Ethel – because Winston is an alcoholic. We need to make rationing scientific and fair.”

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The Case For Real World Evidence (RWE)

Randomized control trials – RCTs – rose to prominence in the twentieth century as physicians and regulators sought to evaluate rigorously the performance of new medical therapies; by century’s end, RCTs had become, as medical historian Laura Bothwell has noted, “the gold standard of medical knowledge,” occupying the top position of the “methodologic heirarch[y].”

The value of RCTs lies in the random, generally blinded, allocation of patients to treatment or control group, an approach that when properly executed minimizes confounders (based on the presumption that any significant confounder would be randomly allocated as well), and enables researchers to discern the efficacy of the intervention (does it work better – or worse – than controls) and begin to evaluate the safety and side-effects.

The power and value of RCTs can be seen with particular clarity in the case of proposed interventions that made so much intuitive sense (at the time) that it seemed questionable, perhaps even immoral, to conduct a study. Examples include use of a particular antiarrhythmic after heart attacks (seemed sensible, but actually caused harm); and use of bone marrow transplants for metastatic breast cancer (study viewed by many as unethical yet revealed no benefit to a procedure associated with significant morbidity).

In these and many other examples, a well-conducted RCT changed clinical practice by delivering a more robust assessment of an emerging technology than instinct and intuition could provide.

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Alfie Evans and the Medical Ethics of Suffering

Sadly, the case of Alfie Evans came to a close this week, as he passed away in his hospital room surrounded by his parents. The debate over the medical ethics involved goes on.

Ultimately, there are extensive moral, philosophical, and medical issues involved with the policies over these cases. They are complicated, messy, and often times heart wrenching. But let’s put some misconceptions aside to begin with, some propagated by the most extreme and emotional participants in this debate.

Those of us that took issue with the handling of this case for the most part do not believe the doctors involved were evil, murdering individuals. There was no malicious intent from the NHS or physicians involved. I am sure the physicians meant well, from their point of view.

A second point: this was not a case about preservation of resources for the greater good. In this case, the parents had found alternative sources to fund the care they wished for their son.  So those arguing that we need to make such decision to prioritize money for those that can be aided the most is largely off target, and not relevant to the case at hand. I also don’t believe that the single payer system of the NHS in England inherently caused their mistakes; I think any system that is blind to its own deficiencies could lead to such mistakes.

That said, what were the issues that were in dispute here?

First and foremost, what was the ultimate intent of the care providers in this specific case?  Both sides basically admitted, early on, that Alfie’s prognosis was dire.  The reality is this child was likely going to die, and even the experts preferred by the parents readily admitted this in court documents.

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Trump and Rx Drug Prices: Let the Games Begin

President Trump is scheduled to deliver a major speech on drug prices today.  This post is intended to start a dialogue on what he says and proposes.     

It’s unclear whether Trump will provide specifics or whether those will be rolled out in coming weeks.   As is always the case with Trump, there’s concern he’ll go off script despite apparent careful preparation of the speech.     

The speech is reportedly going to coincide with an RFI from HHS on ways to restrain drug prices, building on ideas proposed in the administration’s fiscal 2019 budget request.   That sounds like a delay tactic, but we’ll see.    

Notably, Alex Azar and Scott Gottlieb, health secretary and FDA Commissioner, respectively, have recently hinted at substantial policy proposals.  Azar, for example, has proposed shifting some of the drugs now paid for under Medicare Part B (such as chemotherapy drugs administered in doctors’ offices) to Part D, where private plans would have clout to push for lower prices. 

Azar and CMS administrator Seema Verma have also suggested requiring PBMs to share the savings from drug rebates with consumers. Continue reading…

Empowering Patients through Decentralized Information Governance

Seema Verma is right, US health care will be transformed if we empower patients and physicians through access to information. Don Rucker is right to focus attention on APIs to enable the transformation. A year and a half into the new administration and the massively bipartisan 21st Century Cures Act, the Department of Health and Human Services (HHS) is having to navigate between the shoals of highly unpopular Meaningful Use regulations and the apparent need for regulation to undo the damage of market consolidation that they caused. From my perspective, it looks like HHS is doing a good job.

Prediction is a dangerous game but it’s necessary for investments that depend on health information technology. Nowadays, pretty much everything in healthcare depends on information technology, particularly if we need effective quality measures to enable transition to value-based healthcare.

Based on Verma’s most recent remarks, it’s safe to predict that HHS will use the power of the $900 Billion purse as a way of avoiding regulation as it tries to break down the oligopoly of the consolidated “integrated delivery networks” and their even more consolidated EHR vendors. What’s more interesting is to anticipate how Rucker’s recent remarks about Persistent Access will be translated into decision support information for patients and physicians that will actually drive the practice innovation Verma is talking about.

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MedStar Franklin Center:  The Case Against Global Capitation

Baltimore County, Maryland is one hour north of Washington DC, where politicians appear impotent to contain runaway healthcare expenditures.  In January 2014, the Centers for Medicare and Medicaid Services (CMS) in partnership with the state of Maryland, piloted an “All Payer Model,” where every insurer, including Medicare and Medicaid, paid a fixed annual amount irrespective of inpatient or outpatient hospital utilization.  Maryland agreed to transition hospitals from fee-for-service arrangements to this global capitation model over five years. 

Capitation, in general, reimburses a fixed amount per patient, unrelated to service volume.  This sets an artificial fiscal ceiling and disincentivizes hospitals, physicians, and other healthcare personnel to provide healthcare. The philosophy is if hospitals or physicians reduce their output and save money, the unused funds can be kept by the organization. The basic premise of capitation pays hospitals, physicians, and others to AVOID providing care, an unfortunate consequence. 

Maryland is experimenting with global capitation, which allots a fixed sum to an institution from each payer, making revenue predictable, while at the same time, encouraging stewardship by the hospital to allocate funds wisely.  When expenses are lower than the prearranged sum, that hospital retains the leftover funds as additional profit.  To ensure care is not withheld to increase revenue, quality measures are assessed and shared publicly.  A 2015 report in the New England Journal of Medicine showed expenditure reductions of 0.64% and inpatient admissions decreased by 5%.   However, with unproven payment arrangements, unintended consequences always occur. 

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